Serology repertoire for the diagnosis and prognosis of inflammatory bowel disease

Abstract

This disclosure provides for method for the diagnosis, prognosis and treatment of inflammatory bowel disease (IBD) and clinical subtypes of IBD in a subject by detecting the presence or level of one or more immune responses to self and microbial antigens in a sample from a subject.

Description

SEROLOGY REPERTOIRE FOR THE DIAGNOSIS AND PROGNOSIS OF INFLAMMATORY BOWEL DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 672,634, filed July 17, 2024, the entire contents of which are each incorporated herein by reference.FIELD OF INVENTION

[0002] This disclosure generally relates to methods for diagnosis, classification, prognosis and treatment of inflammatory bowel disease (IBD).BACKGROUND

[0003] Inflammatory bowel disease (IBD) is a chronic inflammation of tissues in the digestive track marked by cycles of active disease and remission. Types of IBD include ulcerative colitis (UC), Crohn’s disease (CD), and undifferentiated IBD. IBD, together with irritable bowel syndrome (IBS), will affect one-half of all Americans during their lifetime, at a cost of greater than $2.6 billion dollars for IBD and greater than $8 billion dollars for IBS. A primary determinant of these high medical costs is the difficulty of diagnosing digestive diseases and how these diseases will progress. The cost of IBD and IBS is compounded by lost productivity, with people suffering from these disorders missing at least 8 more days of work annually than the national average.

[0004] Inflammatory bowel disease has many symptoms in common with irritable bowel syndrome, including abdominal pain, chronic diarrhea, weight loss, and cramping, making definitive diagnosis extremely difficult. Of the 5 million people suspected of suffering from IBD in the United States, only 1 million are diagnosed as having IBD. The difficulty in differentially diagnosing IBD and determining its outcome hampers early and effective treatment of these diseases.

[0005] Thus, there is a need for improved methods for diagnosing an individual with IBD, and determining the clinical subtypes subtype, such as CD and UC. The present invention satisfies these needs and provides related advantages as well.SUMMARY

[0006] In one aspect, provided herein is a method of diagnosing inflammatory bowel disease (IBD) in a subject, the method comprising: in a sample obtained from the subject, detecting the presence or level of one or more immune response to microbial antigens, wherein the one or more immune response to microbial antigens include two or more of at least one anti-yeast immune response at least one anti-flagellar immune response, and at least one anti-bacterial immune response, and detecting the presence or level of one or more immune response to self antigens; determining (i) a first score based on the presence or level of the one or more immune response to microbial antigens, and (ii) a second score based on the presence or level of the one or more immune response to self antigens; diagnosing the subject with IBD based on the first and second scores.

[0007] In some embodiments, the one or more immune response to microbial antigens includes at least one anti-yeast immune response and at least one anti -flagellar immune response. In some embodiments, the one or more immune response to microbial antigens includes at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response.

[0008] In some embodiments, the presence or level of at least one anti-yeast immune response includes an anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response, an anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response, or a combination thereof.

[0009] In some embodiments, the presence or level of at least one anti-flagellar immune response includes an anti -FLAX immune response, an anti-CBIR-1 immune response, an anti-FLA2 immune response, or any combination thereof.

[0010] In some embodiments, the presence or level of at least one anti-flagellar immune response includes the anti-CBIR-1 immune response.

[0011] In some embodiments, the presence or level of at least one anti-bacterial immune response includes an anti-E. coli OMPC immune response.

[0012] In some embodiments, the presence or level of one or more immune response to microbial antigens above a cutoff. In some embodiments, the cutoff for the anti- Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 11.9 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 10.8 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9.2 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 20.4 units / mL. In some embodiments, the cutoff for the anti-OMPC immune response is about 6.0 units / mL. In some embodiments, the cutoff for the anti-FLAX immune response is about 36.0 units / mL. In some embodiments, the cutoff for the anti-FLAX immune response is about 36.6 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about 35.4 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about 53.8 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about 32.4 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about 38.9 units / mL.

[0013] In some embodiments, the one or more immune response to self antigens includes at least one of an anti-proteinase 3 (anti-PR3) immune response, a perinuclear anti-neutrophil cytoplasmic antibody (pANCA) immune response, an anti-integrin immune response or any combination thereof. In some embodiments, the one or more immune response to self antigens includes the anti-PR3 immune response, and the anti-integrin immune response. In some embodiments, the one or more immune response to self antigens includes the pANCA immune response, and the anti-integrin immune response.

[0014] In some embodiments, the presence or level of the one or more immune response to self antigens is above a cutoff. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 2.5 units / mL. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 20.0 units. In some embodiments, the cutoff for the pANCA immune response is about 2 on an intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the pANCA immune response is about 1 on an intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the anti-integrin immune response is about 5 units / mL. In some embodiments, the cutoff for the anti-integrin immune response is about 3.1 units / mL.

[0015] In some embodiments, the first score is calculated on a scale of 0 to 5 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

[0016] In some embodiments, the second score is calculated on a scale of 0 to -3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

[0017] In some embodiments, the subject is not diagnosed with IBD if the first score and the second score have a value of 0. In other embodiments, the subject is diagnosed with IBD if the first score and / or the second score are different than 0.

[0018] In some embodiments, the method further includes diagnosing the subject with a clinical subtype of IBD. In some embodiments, the subject is diagnosed with Crohn’s disease (CD) if the first score is different than 0, and the second score has a value greater than 0. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3.

[0019] In some embodiments, the subject is diagnosed with ulcerative Colitis (UC) if the second score is different than 0, and the first score has a value of lesser than 0. In some embodiments, the second score is at least -2. In some embodiments, the second score is -3. In some embodiments, the subject is diagnosed with undifferentiated IBD if the first score and the second score are different than 0.

[0020] In some embodiments, the method further includes determining a composite score based on the first and the second scores. In some embodiments, determining the composite score includes the addition of the first and the second scores. In some embodiments, the subject is diagnosed with seronegative IBD or undifferentiated seropositive IBD if the composite score is 0.

[0021] In some embodiments, the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens. In some embodiments, the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

[0022] In some embodiments, the method further includes determining an interception score based on the first and the second scores. In some embodiments, determining the interception score includes the addition of the first and the second scores. In some embodiments, the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0. In some embodiments, the subject is diagnosed as having medium likelihood of IBD if the interception score has a value of 0 to 2. In some embodiments, the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12.

[0023] In some embodiments, the method further includes diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD. In some embodiments, the method includes adding the negative value of the first score and the second score to determine a stratification score. In some embodiments, the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1. In some embodiments, thesubject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4.

[0024] In a second aspect, provided herein is a method of classifying a clinical subtype of inflammatory bowel disease (IBD) in a subject having IBD, the method comprising: in a sample from the subject, detecting the presence or level of one or more immune response to microbial antigens, wherein the one or more immune response to microbial antigens include two or more of at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response, and detecting the presence or level of one or more immune response to self antigens; calculating (i) a first score based on the presence or level of the one or more immune response to microbial antigens, and (ii) a second score based on the presence or level of the one or more immune response to self antigens; classifying a clinical subtype of IBD in the subject based on the first and second scores.

[0025] In some embodiments, the one or more immune response to microbial antigens includes at least one anti-yeast immune response and at least one anti -flagellar immune response. In some embodiments, the one or more immune response to microbial antigens includes at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response.

[0026] In some embodiments, the clinical subtype of IBD is Ulcerative Colitis (UC), Crohn’s disease (CD), or undifferentiated IBD.

[0027] In some embodiments, the presence or level of at least one anti-yeast immune response includes an anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response, an anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response, or a combination thereof.

[0028] In some embodiments, the presence or level of at least one anti-flagellar immune response includes an anti -FLAX immune response, an anti-CBIR-1 immune response, an anti-FLA2 immune response, or any combination thereof. In some embodiments, thepresence or level of at least one anti -flagellar immune response includes the anti-CBIR-1 immune response.

[0029] In some embodiments, the presence or level of at least one anti-bacterial immune response includes an anti-E. coli OMPC immune response.

[0030] In some embodiments, the presence or level of the one or more immune response to microbial antigens is above a cutoff.

[0031] In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 11.9 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA- IgA) immune response is about 10.8 units / mL. In some embodiments, the cutoff for the anti- Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9.2 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 20.4 units / mL. In some embodiments, the cutoff for the anti-OMPC immune response is about 6.0 units / mL. In some embodiments, the cutoff for the anti-FLAX immune response is about 36.0 units / mL. In some embodiments, the cutoff for the anti-FLAX immune response is about 36.6 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about 35.4 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about53.8 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about 32.4 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about38.9 units / mL.

[0032] In some embodiments, the presence of one or more immune response toself antigens includes at least one of an anti-proteinase 3 (anti-PR3) immune response, an perinuclear anti-neutrophil cytoplasmic immune response (pANCA), and an anti-integrin immune response, or any combination thereof. In some embodiments, the presence of one or more immune response to self antigens includes the anti-PR3 immune response, and the anti- integrin immune response. In some embodiments, the presence or level of one or more immune response to self antigens includes the pANCA immune response, and the anti- integrin immune response.

[0033] In some embodiments, the presence or level of the one or more immune response to self antigens is above a cutoff. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 2.5 units / mL. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 20.0 units. In some embodiments, the cutoff for the pANCA immune response is about 2 on an intensity scale ranging from 0 to 4.In some embodiments, the cutoff for the pANCA immune response is about 1 on an intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the anti-integrin immune response is about 5 units / mL. In some embodiments, the cutoff for the anti-integrin immune response is about 3.1 units / mL.

[0034] In some embodiments, the first score is calculated on a scale of 0 to 5 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

[0035] In some embodiments, the second score is calculated on a scale of 0 to -3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

[0036] In some embodiments, the IBD is classified as Crohn’s disease (CD) if the first score is different than 0, and the second score has a value of 0. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3.

[0037] In some embodiments, the IBD is classified as Ulcerative Colitis (UC) if the second score is different than 0, and the first score has a value of 0. In some embodiments, the second score is at least -2. In some embodiments, the second score is -3.

[0038] In some embodiments, the IBD is classified as undifferentiated IBD if the first score and the second score are different than 0.

[0039] In some embodiments, the method further includes determining a composite score based on the first and the second scores. In some embodiments, determining the composite score includes the addition of the first and the second scores. In some embodiments, the subject is diagnosed with seronegative IBD or undifferentiated seropositive IBD if the composite score is 0.

[0040] In some embodiments, the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

[0041] In some embodiments, the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

[0042] In some embodiments, the method further includes determining an interception score based on the first and the second scores. In some embodiments, determining the interception score includes the addition of the first and the second scores. In some embodiments, the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0. In some embodiments, the subject is diagnosed as having mediumlikelihood of IBD if the interception score has a value of 0 to 2. In some embodiments, the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12.

[0043] In some embodiments, the method further includes diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD. In some embodiments, the method includes adding the negative value of the first score and the second score to determine a stratification score. In some embodiments, the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1. In some embodiments, the subject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4.

[0044] In a third aspect, provided herein is a method of treating a subject having inflammatory bowel disease (IBD), the method comprising: in a sample from the subject, detecting the presence or level of one or more immune response to microbial antigens, wherein the one or more immune response to microbial antigens include two or more of at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response, and detecting the presence or level of one or more immune response to self antigens; calculating (i) a first score based on the presence or level of the one or more immune response to microbial antigens, and (ii) a second score based on the presence or level of the one or more; and administering an IBD-therapeutic agent to the subject based on the first and second scores.

[0045] In some embodiments, the one or more immune response to microbial antigens includes at least one anti-yeast immune response and at least one anti -flagellar immune response. In some embodiments, the one or more immune response to microbial antigens includes at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response.

[0046] In some embodiments, the IBD is Ulcerative Colitis (UC), Crohn’s disease (CD), or undifferentiated IBD.

[0047] In some embodiments, the presence or level of at least one anti-yeast immune response includes an anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response, an anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response, or a combination thereof.

[0048] In some embodiments, the presence or level of at least one anti-flagellar immune response includes an anti -FLAX immune response, an anti-CBIR-1 immune response, an anti-FLA2 immune response, or any combination thereof. In some embodiments, the presence or level of at least one anti -flagellar immune response includes the anti-CBIR-1 immune response.

[0049] In some embodiments, the presence or level of at least one anti-bacterial immune response includes an anti-E. coli OMPC immune response.

[0050] In some embodiments,

[0051] the presence or level of one or more immune response to microbial antigens above a cutoff. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 11.9 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA- IgA) immune response is about 10.8 units / mL. In some embodiments, the cutoff for the anti- Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9.2 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 20.4 units / mL. In some embodiments, the cutoff for the anti-OMPC immune response is about 6.0 units / mL. In some embodiments, the cutoff for the anti-FLAX immune response is about 36.0 units / mL. In some embodiments, the cutoff for the anti-FLAX immune response is about 36.6 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about 35.4 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about53.8 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about 32.4 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about38.9 units / mL.

[0052] In some embodiments, the one or more immune response to self antigens includes at least one of an anti-proteinase 3 (anti-PR3) immune response, an perinuclear antineutrophil cytoplasmic immune response (pANCA), an anti-integrin immune response, or any combination thereof. In some embodiments, the one or more immune response to selfantigens includes the anti-PR3 immune response, and the anti-integrin immune response. In some embodiments, the one or more immune response to self antigens includes the pANCA immune response, and the anti-integrin immune response.

[0053] In some embodiments, the presence or level of the one or more immune response to self antigens is above a cutoff. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 2.5 units / mL. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 20.0 units. In some embodiments, the cutoff for the pANCA immune response is about 2 on an intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the pANCA immune response is about 1 on an intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the anti-integrin immune response is about 5 units / mL. In some embodiments, the cutoff for the anti-integrin immune response is about 3.1 units / mL.

[0054] In some embodiments, the first score is calculated on a scale of 0 to 5 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

[0055] In some embodiments, the second score is calculated on a scale of 0 to -3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

[0056] In some embodiments, the subject is administered a Crohn’s disease (CD)- therapeutic agent if the first score is different than 0, and the second score has a value of 0.

[0057] In some embodiments, the first score is at least 2.

[0058] In some embodiments, the first score is at least 3.

[0059] In some embodiments, the subject is administered an Ulcerative Colitis (UC)- therapeutic agent if the second score is different than 0, and the first score has a value of 0. In some embodiments, the second score is at least -2. In some embodiments, the second score is -3.

[0060] In some embodiments, the subject is administered an undifferentiated IBD- therapeutic agent if the first score and the second score are different than 0.

[0061] In some embodiments, the method further includes stopping treatment of the subject with the IBD-therapeutic agent if the first score and second score have a value of 0.

[0062] In some embodiments, the method further includes determining a composite score based on the first and the second scores. In some embodiments, determining the composite score includes the addition of the first and the second scores. In some embodiments, administering of the IBD therapeutic agent is based on the composite score.

[0063] In some embodiments, the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

[0064] In some embodiments, the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

[0065] In some embodiments, the method further includes determining an interception score based on the first and the second scores. In some embodiments, determining the interception score includes the addition of the first and the second scores. In some embodiments, the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0. In some embodiments, the subject is diagnosed as having medium likelihood of IBD if the interception score has a value of 0 to 2. In some embodiments, the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12. In some embodiments, the subject is administered an IBD-therapeutic agent.

[0066] In some embodiments, the method further includes diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD. In some embodiments, the method includes adding the negative value of the first score and the second score to determine a stratification score. In some embodiments, the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1. In some embodiments, the subject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4. In some embodiments, the subject is administered a Crohn’s disease (CD)-therapeutic agent. In some embodiments, the subject is administered an Ulcerative Colitis (UC)-therapeutic agent. In some embodiments, the subject is administered an undifferentiated IBD-therapeutic agent

[0067] In some embodiments, the method further includes stopping treatment of the subject with the therapeutic agent if the interception score has a value of 0 or lower.

[0068] In some embodiments, the IBD-therapeutic agent targets at least one pathway selected from an Tumor Necrosis Factor (TNF) pathway, an interleukin- 12 (IL-12) pathway, an interleukin-23 (IL-23) pathway, a sphingosine- 1 -phosphate pathway, or a j anus kinase (JAK) pathway. In some embodiments, the IBD therapeutic agent includes infliximab (IFX), adalimumab (ADA), ustekinumab (UST), mirikizumab, guselkumab, ozanimod, etrasimod, upadacitinib, ivarmacitinib, or a biosimilar thereof.

[0069] In a fourth aspect, provided herein is a method for selecting a subject having inflammatory bowel disease (IBD) for treatment with an IBD-therapeutic agent, the method comprising: in a sample from the subject, detecting the presence or level of one or more immune response to microbial antigens, wherein the one or more immune response to microbial antigens include two or more of at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response, and detecting the presence or level of one or more immune response to self antigens; calculating (i) a first score based on the presence or level of the one or more immune response to microbial antigens, and (ii) a second score based on the presence or level of the one or more; and selecting the subject for treatment with the IBD therapeutic agent based on the first and second scores.

[0070] In some embodiments, the one or more immune response to microbial antigens includes at least one anti-yeast immune response and at least one anti -flagellar immune response. In some embodiments, the one or more immune response to microbial antigens includes at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response.

[0071] In some embodiments, the IBD is Ulcerative Colitis (UC), Crohn’s disease (CD), or undifferentiated IBD.

[0072] In some embodiments, the presence or level of at least one anti-yeast immune response includes an anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response, an anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response, or a combination thereof.

[0073] In some embodiments, the presence or level of at least one anti-flagellar immune response includes an anti -FLAX immune response, an anti-CBIR-1 immune response, an anti-FLA2 immune response, or any combination thereof. In some embodiments, thepresence of at least one anti-flagellar immune response includes the anti-CBIR-1 immune response.

[0074] In some embodiments, the presence or level of at least one anti-bacterial immune response includes an anti-E. coli OMPC immune response.

[0075] In some embodiments, the presence or level of one or more immune response to microbial antigens above a cutoff. In some embodiments, the cutoff for the anti- Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 11.9 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 10.8 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9.2 units / mL. In some embodiments, the cutoff for the anti- Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 20.4 units / mL. In some embodiments, the cutoff for the anti -OMPC immune response is about 6.0 units / mL. In some embodiments, the cutoff for the anti-FLAX immune response is about 36.0 units / mL. In some embodiments, the cutoff for the anti-FLAX immune response is about 36.6 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about 35.4 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about 53.8 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about 32.4 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about 38.9 units / mL.

[0076] In some embodiments, the presence of one or more immune response to self antigens includes at least one of an anti-proteinase 3 (anti-PR3) immune response, an perinuclear anti-neutrophil cytoplasmic immune response (pANCA), an anti-integrin immune response, or any combination thereof. In some embodiments, the presence or level of one or more immune response to self antigens includes the anti-PR3 immune response, and the anti- integrin immune response. In some embodiments, the one or more immune response to self antigens includes the pANCA immune response, and the anti-integrin immune response.

[0077] In some embodiments, the presence or level of the one or more immune response to self antigens is above a cutoff. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 2.5 units / mL. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 20.0 units. In some embodiments, the cutoff for the pANCA immune response is about 2 on an intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the pANCA immune response is about 1 on an intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the anti-integrin immuneresponse is about 5 units / mL. In some embodiments, the cutoff for the anti-integrin immune response is about 3.1 units / mL. In some embodiments, the first score is calculated on a scale of 0 to 5 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

[0078] In some embodiments, the second score is calculated on a scale of 0 to -3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

[0079] In some embodiments, the subject is selected for treatment with the IBD therapeutic agent if the first score and second score are different than 0.

[0080] In some embodiments, the subject is selected for treatment with a Crohn’s disease (CD) therapeutic agent if the first score is different than 0, and the second score has a value of 0. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3.

[0081] In some embodiments, the subject is selected for treatment with an Ulcerative Colitis (UC) therapeutic agent if the second score is different than 0, and the first score has a value of 0. In some embodiments, the second score is at least -2. In some embodiments, the second score is -3.

[0082] In some embodiments, the subject is selected for treatment with the IBD therapeutic agent if the first score and the second score are different than 0.

[0083] In some embodiments, the subject is not selected for treatment with the IBD therapeutic agent if the first score and second score have a value of 0.

[0084] In some embodiments, the method further includes administering the IBD therapeutic agent to the subject.

[0085] In some embodiments, the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

[0086] In some embodiments, the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

[0087] In some embodiments, the method further includes determining an interception score based on the first and the second scores. In some embodiments, determining the interception score includes the addition of the first and the second scores. In some embodiments, the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0. In some embodiments, the subject is diagnosed as having mediumlikelihood of IBD if the interception score has a value of 0 to 2. In some embodiments, the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12. In some embodiments, the subject is selected for treatment with an IBD -therapeutic agent.

[0088] In some embodiments, the method further includes diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD. In some embodiments, the method includes adding the negative value of the first score and the second score to determine a stratification score. In some embodiments, the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1. In some embodiments, the subject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4. In some embodiments, the subject is selected for treatment with a Crohn’s disease (CD)-therapeutic agent. In some embodiments, the subject is selected for treatment with an Ulcerative Colitis (UC)-therapeutic agent. In some embodiments, the subject is selected for treatment with an undifferentiated IBD-therapeutic agent

[0089] In some embodiments, the method further includes administering the IBD therapeutic agent to the subject.

[0090] In some embodiments, the method further includes determining a composite score based on the first and the second scores. In some embodiments, determining the composite score includes the addition of the first and the second scores. In some embodiments, the subject is selected for treatment with the IBD therapeutic agent based on the composite score.

[0091] In some embodiments, the IBD-therapeutic agent targets at least one pathway selected from an Tumor Necrosis Factor (TNF) pathway, an interleukin-6 (IL-6) pathway, an interleukin- 12 (IL-12) pathway, an interleukin-23 (IL-23) pathway, a sphingosine- 1- phosphate pathway, or a j anus kinase (JAK) pathway. In some embodiments, the IBDtherapeutic agent includes infliximab (IFX), adalimumab (ADA), ustekinumab (UST), mirikizumab, guselkumab, ozanimod, etrasimod, upadacitinib, ivarmacitinib, or a biosimilar thereof.

[0092] In a fifth aspect, provided herein is a method for monitoring the effectiveness of an inflammatory bowel disease (IBD)-therapeutic agent in a subject with IBD, the method comprising: in a sample from the subject, detecting the presence or level of one or more immune response to microbial antigens, wherein the one or more immune response to microbial antigens include two or more of at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response, and detecting the presence or level of one or more immune response to self antigens; calculating (i) a first score based on the presence or level of the one or more immune response to microbial antigens, and (ii) a second score based on the presence or level of the one or more; and adjusting the amount of IBD therapeutic agent being administered to the subject, based on the first and second scores.

[0093] In some embodiments, the one or more immune response to microbial antigens includes at least one anti-yeast immune response and at least one anti -flagellar immune response. In some embodiments, the one or more immune response to microbial antigens includes at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response.

[0094] In some embodiments, the IBD is Ulcerative Colitis (UC), Crohn’s disease (CD), or undifferentiated IBD.

[0095] In some embodiments, the presence of at least one anti-yeast immune response includes an anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response, an anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response, or a combination thereof.

[0096] In some embodiments, the presence or level of at least one anti-flagellar immune response includes an anti -FLAX immune response, an anti-CBIR-1 immune response, an anti-FLA2 immune response, or any combination thereof. In some embodiments, the presence or level of at least one anti -flagellar immune response includes the anti-CBIR-1 immune response.

[0097] In some embodiments, the presence or level of at least one anti-bacterial immune response includes an anti-E. coli OMPC immune response.

[0098] In some embodiments, the presence or level of one or more immune response to microbial antigens above a cutoff. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 11.9 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 10.8 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9.2 units / mL. In some embodiments, the cutoff for the anti- Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 20.4 units / mL. In some embodiments, the cutoff for the anti-OMPC immune response is about 6.0 units / mL. In some embodiments, the cutoff for the anti-FLAX immune response is about 36.0 units / mL. In some embodiments, the cutoff for the anti-FLAX immune response is about 36.6 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about 35.4 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about 53.8 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about 32.4 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about 38.9 units / mL.

[0099] In some embodiments, the one or more immune response to self antigens includes at least one of an anti-proteinase 3 (anti-PR3) immune response, an perinuclear antineutrophil cytoplasmic immune response (pANCA), an anti-integrin immune response, or any combination thereof. In some embodiments, the one or more immune response to self antigens includes the anti-PR3 immune response, and the anti-integrin immune response. In some embodiments, the one or more immune response to self antigens includes the pANCA immune response, and the anti-integrin immune response.

[0100] In some embodiments, the presence or level of the one or more immune response to self antigens is above a cutoff. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 2.5 units / mL. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 20.0 units. In some embodiments, the cutoff for the pANCA immune response is about 2 on an intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the pANCA immune response is about 1 on an intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the anti-integrin immune response is about 5 units / mL. In some embodiments, the cutoff for the anti-integrin immune response is about 3.1 units / mL.

[0101] In some embodiments, the first score is calculated on a scale of 0 to 5 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

[0102] In some embodiments, the second score is calculated on a scale of 0 to -3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

[0103] In some embodiments, the amount of the IBD-therapeutic agent being administered to the subject is increased if the first score and second score are different than 0.

[0104] In some embodiments, the amount of the IBD-therapeutic agent being administered to the subject is decreased if the first score and second score have a value of 0.

[0105] In some embodiments, the method further includes determining a composite score based on the first and the second scores. In some embodiments, determining the composite score includes the addition of the first and the second scores. In some embodiments, the amount of the IBD-therapeutic agent being administered to the subject is increased if the composite score has a value different than 0.

[0106] In some embodiments, the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

[0107] In some embodiments, the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

[0108] In some embodiments, the method further includes determining an interception score based on the first and the second scores. In some embodiments, determining the interception score includes the addition of the first and the second scores. In some embodiments, the amount of the IBD-therapeutic agent being administered to the subject is maintained or increased if the interception score has a value of 0 to 2. In some embodiments, the amount of the IBD-therapeutic agent being administered to the subject is increased if the interception score has a value of 2 to 12. In some embodiments, the amount of the IBD- therapeutic agent being administered to the subject is decreased if the interception score has a value of 0 or lower.

[0109] In some embodiments, the IBD-therapeutic agent targets at least one pathway selected from a Tumor Necrosis Factor (TNF) pathway, an interleukin- 12 (IL-12) pathway, an interleukin-23 (IL-23) pathway, a sphingosine- 1 -phosphate pathway, or a j anus kinase (JAK) pathway. In some embodiments, the IBD therapeutic agent includes infliximab (IFX), adalimumab (ADA), ustekinumab (UST), mirikizumab, guselkumab, ozanimod, etrasimod, upadacitinib, ivarmacitinib, or a biosimilar thereof.

[0110] In some embodiments of any of the methods provided herein, the presence or level of the one or more immune response to microbial antigens and / or the one or more immune response to self antigens is detected with a hybridization assay, an amplification-based assay, an immunoassay, or an immunohistochemical assay.

[0111] In some embodiments of any of the methods provided herein, the sample is selected from the group consisting of serum, plasma, whole blood, and stool.

[0112] In some embodiments of any of the methods provided herein, the subject is a human subject.

[0113] In some embodiments of any of the methods provided herein, the statistical model used to calculate the first score and / or the second score includes logistic regression.BRIEF DESCRIPTION OF DRAWINGS

[0114] FIG. 1 shows the immune response to microbial and self antigens in inflammatory bowel disease (IBD; left panel), Ulcerative Colitis (UC; middle panel), and Crohn’s disease (CD; right panel).

[0115] FIG. 2 shows an exemplary output of a logistic regression model of the probability of IBD and the immune response to microbial and self antigens.

[0116] FIG. 3 shows an exemplary graph of the probability of IBD by number of immune responses to microbial and self antigens.

[0117] FIG. 4 shows an exemplary plot of the IBD serology and disease interception across patients.

[0118] FIG. 5 shows an exemplary graph of the positive predictive value (PPV) for detection of IBD versus irritable bowel syndrome (IBS).

[0119] FIGS. 6A-6B show exemplary graphs of the probability of CD (FIG. 6A) or UC (FIG. 6B) by number of immune responses to microbial and self antigens.

[0120] FIG. 7 shows an exemplary receiver operator characteristic (ROC) curve of the probability of CD versus UC by number of immune responses to microbial and self antigens.

[0121] FIG. 8 shows an exemplary graph of the frequency of seronegative and undifferentiated IBD in a cohort of patients.

[0122] FIG.9 shows an exemplary graph of the probability of CD or UC across a spectrum of immune responses to microbial and self antigens.

[0123] FIGS. 10A-10B show exemplary graphs of the probability of CD (FIG. 10A) or UC (FIG. 10B) across a spectrum of immune responses to microbial and self antigens.

[0124] FIG. 11 shows an exemplary distribution of collected specimens across the repertoire of immune response to self and microbial antigens in a cohort of patients.

[0125] FIG. 12 shows an exemplary model for classification of IBD and clinical subtypes based in immune responses to self and microbial antigens.

[0126] FIG. 13 shows an exemplary distribution of the immune response to microbial and self antigens in a cohort of patients.

[0127] FIG. 14 shows an exemplary model for target selection and complementary diagnosis of IBD based on immune response to self and microbial antigens.

[0128] FIG. 15 shows an exemplary heatmap of immune responses to self antigens. As used in the figure: CD, Crohn’s Disease; UC, ulcerative colitis; and GI, gastrointestinal.

[0129] FIG. 16 shows an exemplary heatmap of prevalence of immune responses to microbial antigens. As used in the figure: CD, Crohn’s Disease; UC, ulcerative colitis; and GI, gastrointestinal.

[0130] FIG. 17 shows an exemplary prevalence of three or more immune responses to microbial antigens across IBD subtypes. As used in the figure: CD, Crohn’s Disease; UC, ulcerative colitis; and GI, gastrointestinal.

[0131] FIG. 18 shows an exemplary ROC curve of the probability of IBD versus non- IBD by detection of immune responses to self and microbial antigens in training and validation data sets.

[0132] FIG. 19 shows an exemplary ROC curve of the probability of IBD versus non- IBD by detection of immune responses to self and microbial antigens in a validation data set.

[0133] FIG. 20 shows an exemplary ROC curve of the probability of CD versus UC by detection of immune responses to self and microbial antigens in a training and validation data sets.

[0134] FIG. 21 shows an exemplary ROC curve of the probability of CD versus UC by detection of immune responses to self and microbial antigens in a validation data set.

[0135] FIG. 22 shows a schematic of a two-tiered analysis model for diagnosis and classification of IBD based on the detection of immune responses to self and microbial antigens.

[0136] FIG. 23 shows an exemplary ROC curve of the probability of CD versus UC 7in IBD-positive subjects by detection of immune responses to self and microbial antigens in training and validation data sets.

[0137] FIG. 24 shows an exemplary analysis of CD complications and number of immune responses to microbial antigens.DETAILED DESCRIPTION

[0138] Aspects of the present disclosure relate to methods for diagnosing inflammatory bowel disease (IBD) in a subject, methods for classifying a clinical subtype of IBD in a subject having IBD, methods for treating IBD in a subject, methods for selecting a subject having IBD for treatment with an IBD-therapeutic agent, and methods of monitoring the effectiveness of an IBD-therapeutic agent in a subject with IBD. In particular, the methods provided herein include detecting the presence or level of one or more immune responses to microbial antigens, and detecting one or more immune responses to self antigens.

[0139] There is considerable interest in identifying novel pathways, and hence potential targets, in the treatment of immune mediated inflammatory diseases such as IBD. In IBD, the outcome with anti-cytokine therapies has undoubtedly led to significant advance in the treatment of the disease, yet the overall proportion of patients achieving sustained disease control is low, and over two third of patients do not achieve the expected clinical benefit from these therapeutic interventions. Poor outcomes in IBD are often related to improper dosing. However, in some patients with IBD, either Crohn’s disease (CD) or Ulcerative colitis (UC), worse outcomes have been observed in relation to the presence of immune response which classifies them as seropositive IBD.

[0140] The methods provided herein address this problem. The methods described herein rely on the detection of the presence of immune responses to microbial and self antigens in four different groups: (i) subjects that manifests as seropositive CD has an immune response to microbial antigens (ii) subjects that manifests as seropositive UC, and have immune response to self-antigens; (iii) subjects that have overlapping immune response to microbial and self which classifies them as undifferentiated IBD; and (iv) subjects that are seronegative in the absence of known immune response to microbial and self.

[0141] The methods described herein rely on the detection of a combination of immune responses to microbial and self-antigens found to be advantageous for detecting the presence of IBD in a subject and classify the clinical subtype of IBD, for selection of subjects for treatment with an IBD-therapeutic agent, and for monitoring the effectiveness of the IBD- therapeutic agent in the subject. In addition, the methods provided herein can lead to the identification of additional inflammatory pathways and pharmaceutical targets that can be generalized across the spectrum of IBD disease.

[0142] Although the disclosure describes various exemplary alternatives and implementations as provided herein, it should be understood that the various features,aspects, and functionality described in one or more of the individual alternatives are not limited in their applicability to the particular alternative with which they are described. Instead, they can be applied alone or in various combinations to one or more of the other alternatives of the disclosure, whether the alternatives are described or whether the features are presented as a part of the described alternative. The breadth and scope of the present disclosure should not be limited by any exemplary alternatives described or shown herein.I. Definitions

[0143] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some embodiments, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0144] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Any reference to “or” herein is intended to encompass “and / or” unless otherwise stated.

[0145] The use of the alternative (e.g., “or”) should be understood to mean either one, both, or any combination thereof of the alternatives.

[0146] As used herein, the term “and / or” should be understood to mean either one, or both of, or any combination of the alternatives.

[0147] Reference throughout this specification to “some embodiments,” “further embodiments,” or “a particular embodiment,” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase “in some embodiments,” or “in further embodiments,” or “in a particular embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0148] As used herein, the term “about” or “approximately” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% compared to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight orlength. In some instances, the term “about” or “approximately” refers a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1% of a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0149] As used herein, the terms “administration,” “administering” and variants thereof refer to the introduction of a therapeutic agent (e.g., an IBD therapeutic agent) into a subject. Administration of the composition or therapeutic agent (e.g., an IBD therapeutic agent) into a subject is by any suitable route, including orally, pulmonarily, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), rectally, intralymphatically, or topically. A suitable route of administration allows the composition or the agent to perform its intended function. Administration also includes self-administration and the administration by another. The administration can also be performed systemic, or it can be local.

[0150] The term “sample” may include one or more samples. Non-limiting examples of a “sample” include any material from which nucleic acids and / or proteins can be obtained. As non-limiting examples, this includes whole blood, peripheral blood, plasma, serum, saliva, mucus, urine, semen, lymph, fecal extract, cheek swab, cells or other bodily fluid or tissue, including but not limited to tissue obtained through surgical biopsy or surgical resection. In some instances, the sample includes tissue from the large and / or small intestine. In some instances, the large intestine sample includes the cecum, colon (the ascending colon, the transverse colon, the descending colon, and the sigmoid colon), rectum and / or the anal canal. In some instances the small intestine sample includes the duodenum jejunum, and / or the ileum. Alternatively, a sample can be obtained through primary patient derived cell lines, or archived patient samples in the form of preserved samples, or fresh frozen samples.

[0151] The terms “detecting,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include detecting if an element is present or not. These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence or level of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0152] As used herein, the terms “individual,” “patient” and “subject” interchangeably refer to any animal, including, but not limited to, humans, non-human primates, rodents, and domestic and game animals, which is to be the recipient of a particular treatment. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., Rhesus.Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon. In some instances, a subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment. In some instances, the subject is a human. In some instances, the subject previously diagnosed with or identified as suffering from or having a condition may or may not have undergone treatment for a condition. In yet other instances, a subject can also be one who has not been previously diagnosed as having a condition (i.e., a subject who exhibits one or more risk factors for a condition). A “subject in need” of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at risk of developing that condition.

[0153] The term “inflammatory bowel disease” or “IBD” as used herein refers to gastrointestinal disorders of the gastrointestinal tract. The term IBD also includes clinical subtypes of IBD. Non-limiting examples of clinical subtypes of IBD include, but are not limited to, Crohn's disease (CD), ulcerative colitis (UC), indeterminate colitis (IC), microscopic colitis, diversion colitis, Behcet’s disease, undifferentiated IBD, and other inconclusive forms of IBD. In some instances, IBD includes fibrosis, fibrostenosis, stricturing and / or penetrating disease, obstructive disease, or a disease that is refractory (e.g., mrUC, refractory CD), perianal CD, or other complicated forms of IBD.

[0154] The term “immune response,” as used herein refers to a type of an antigenic response in a subject that may be detected in the serum of the subject. In some instances, the immune response is an antigenic response towards a microbial antigen (e.g., a fungal antigen or a bacterial antigen). In other instances, the immune response is an antigenic response towards a self antigen. In some instances, the immune response is an adaptive immune response. In some instance, the immune response includes production of antibodies against the microbial antigen (e.g., an anti-microbial antigen antibody) or against the self antigen (e.g., an autoantibody). The Immune response can also involve production of cytotoxic cells or memory cells specific to the microbial or self antigens).

[0155] As used herein, the term “seropositive,” when used in reference to IBD, refers to a subject that is positive for one or more specified serological markers.

[0156] As used herein, the term “seronegative,” when used in reference to IBD, refers to a subject that is negative for specified serological markers.

[0157] The terms “treat,” “treating,” and “treatment” as used herein refers to alleviating or abrogating a disorder, disease, or condition; or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating a cause of the disorder, disease, or condition itself. Desirable effects of treatment can include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishing any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state and remission or improved prognosis.II. Methods

[0158] Certain aspects of the disclosure relate to methods for diagnosing inflammatory bowel disease (IBD) in a subject. In some embodiments, the method for diagnosing IBD in a subject includes (i) detecting the presence or level of one or more immune responses to microbial antigens, and (ii) detecting the presence or level of one or more immune responses to self antigens in a sample obtained from the subject; determining (i) a first score based on the presence or level of the one or more immune responses to microbial antigens, and (ii) a second score based on the presence or level of the one or more immune responses to self antigens; and diagnosing the subject with IBD based on the first and second scores.

[0159] In some embodiments, the first score is calculated on scale using a statistical model. In some embodiments, the first score is calculated on a scale of 0 to 5 using a statistical model. In some embodiments, a first score of 0 is indicative of the absence of the one or more immune responses to microbial antigens. In some embodiments, a first score different than 0 is indicative of the presence or detectable level of the one or more immune responses to microbial antigens.

[0160] In some embodiments, the second score is calculated on scale using a statistical model. In some embodiments, the second score is calculated on a scale of 0 to -3 using a statistical model. In some embodiments, a second score of 0 is indicative of the absence of the one or more immune responses to self antigens. In some embodiments, a second score different than 0 is indicative of the presence or detectable level of the one or more immune responses to self antigens.

[0161] In some embodiments, the subject is not diagnosed with IBD if the first score and the second score have a value of 0.

[0162] In other embodiments, the subject is diagnosed with IBD if the first score and / or the second score are different than 0. In some embodiments, the first score is at least 1, atleast 2, at least 3, at least 4, or at least 5. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3. In some embodiments, the first score is at least -1, at least -2, or at least -3. In some embodiments, the second score is at least -2. In some embodiments, the second score is at least -3.

[0163] In some embodiments, the method for diagnosing IBD in a subject further includes diagnosing the subject with a clinical subtype of IBD. In some embodiments, the clinical subtype of IBD is Crohn’s Disease (CD), Ulcerative Colitis (UC), or undifferentiated IBD. In some embodiments, the subject is diagnosed with Crohn’s disease (CD) if the first score is different than 0, and the second score has a value of 0. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, or at least 5. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3. In some embodiments, the subject is diagnosed with ulcerative Colitis (UC) if the second score is different than 0, and the first score has a value of 0. In some embodiments, the first score is at least -1, at least -2, or at least -3. In some embodiments, the second score is at least -2. In some embodiments, the second score is at least -3. In some embodiments, the subject is diagnosed with undifferentiated IBD if the first score and the second score are different than 0.

[0164] In some embodiments, the method for diagnosing IBD in a subject further includes determining a composite score based on the first and the second scores. In some embodiments, determining the composite score includes the addition of the first and the second scores. In some embodiments, the subject is diagnosed with seronegative IBD or undifferentiated seropositive IBD if the composite score is 0. In some embodiments, the subject is diagnosed with UC or CD if the composite score is different than 0.

[0165] In some embodiments, the method for diagnosing IBD in a subject further includes administering an IBD -therapeutic to the subject after the diagnosing.

[0166] In other embodiments, the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens. In some embodiments, the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6. In some embodiments, the subject is diagnosed with ulcerative Colitis (UC) if the second score is different than 0, and the first score has a value of 0. In some embodiments, the first score is at least 1, at least 2, or at least 3.

[0167] In some embodiments, the method further includes a step determining an interception score based on the first and the second scores. In some embodiments, determining the interception score includes the addition of the first and the second scores.

[0168] In some embodiments, the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0.

[0169] In some embodiments, the subject is diagnosed as having medium likelihood of IBD if the interception score has a value of 0 to 2. The interception score has a value of 0, 1 or 2. In some embodiments, the interception score has a value of 0. In some embodiments, the interception score has a value of 1. In some embodiments, the interception score has a value of 2.

[0170] In some embodiments, the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12. The interception score has a value of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, the interception score has a value of 2. In some embodiments, the interception score has a value of 3. In some embodiments, the interception score has a value of 4. In some embodiments, the interception score has a value of 5. In some embodiments, the interception score has a value of 6. In some embodiments, the interception score has a value of 7. In some embodiments, the interception score has a value of 8. In some embodiments, the interception score has a value of 9. In some embodiments, the interception score has a value of 10. In some embodiments, the interception score has a value of 11. In some embodiments, the interception score has a value of 12.

[0171] In some embodiments, the method further includes diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD. In some embodiments, the method includes adding the negative value of the first score and the second score to determine a stratification score.

[0172] In some embodiments, the subject is diagnosed with likelihood of inconclusive IBD. In some embodiments, the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1.

[0173] In some embodiments, the subject is diagnosed with likelihood of Crohn’s Disease (CD). In some embodiments, the subject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In someembodiments, the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1.

[0174] In some embodiments, the subject is diagnosed with likelihood of Ulcerative Colitis. In some embodiments, the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4.

[0175] Certain aspects of the disclosure relate to methods for classifying a clinical subtype of IBD in a subject having IBD. In some embodiments, the method for classifying a clinical subtype of IBD in a subject having IBD includes (i) detecting the presence or level of one or more immune responses to microbial antigens, and (ii) detecting the presence or level of one or more immune responses to self antigens in a sample obtained from the subject; determining (i) a first score based on the presence or level of the one or more immune responses to microbial antigens, and (ii) a second score based on the presence or level of the one or more immune responses to self antigens; and classifying a clinical subtype of IBD in the subject based on the first and second scores. In some embodiments, the clinical subtype of IBD is Crohn’s Disease (CD), Ulcerative Colitis (UC), or undifferentiated IBD.

[0176] In some embodiments, the first score is calculated on scale using a statistical model. In some embodiments, the first score is calculated on a scale of 0 to 5 using a statistical model. In some embodiments, a first score of 0 is indicative of the absence of the one or more immune responses to microbial antigens. In some embodiments, a first score different than 0 is indicative of the presence or detectable level of the one or more immune responses to microbial antigens.

[0177] In some embodiments, the second score is calculated on scale using a statistical model. In some embodiments, the second score is calculated on a scale of 0 to -3 using a statistical model. In some embodiments, a second score of 0 is indicative of the absence of the one or more immune responses to self antigens. In some embodiments, a second score different than 0 is indicative of the presence or detectable level of the one or more immune responses to self antigens.

[0178] In some embodiments, the IBD is classified as Crohn’s disease (CD) if the first score is different than 0, and the second score has a value of 0. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, or at least 5. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3. In some embodiments, the IBD is classified as Ulcerative Colitis (UC) if the second score is differentthan 0, and the first score has a value of 0. In some embodiments, the first score is at least -1, at least -2, or at least -3. In some embodiments, the second score is at least -2. In some embodiments, the second score is at least -3. In some embodiments, the IBD is classified as undifferentiated IBD if the first score and the second score are different than 0.

[0179] In some embodiments, the method for classifying a clinical subtype of IBD in a subject further includes determining a composite score based on the first and the second scores. In some embodiments, determining the composite score includes the addition of the first and the second scores. In some embodiments, the IBD is classified as seronegative IBD or undifferentiated seropositive IBD if the composite score is 0. In some embodiments, the IBD is classified as UC or CD if the composite score is different than 0.

[0180] In some embodiments, the method for classifying a clinical subtype of IBD in a subject having IBD further includes administering an IBD-therapeutic to the subject after the diagnosing.

[0181] In other embodiments, the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens. In some embodiments, the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6. In some embodiments, the subject is diagnosed with ulcerative Colitis (UC) if the second score is different than 0, and the first score has a value of 0. In some embodiments, the first score is at least 1, at least 2, or at least 3.

[0182] In some embodiments, the method further includes determining an interception score based on the first and the second scores. In some embodiments, determining the interception score includes the addition of the first and the second scores.

[0183] In some embodiments, the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0.

[0184] In some embodiments, the subject is diagnosed as having medium likelihood of IBD if the interception score has a value of 0 to 2. In some embodiments, the interception score has a value of 0, 1 or 2. In some embodiments, the interception score has a value of 0. In some embodiments, the interception score has a value of 1. In some embodiments, the interception score has a value of 2.

[0185] In some embodiments, the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12. In some embodiments, interception score has avalue of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, the interception score has a value of 2. In some embodiments, the interception score has a value of 3. In some embodiments, the interception score has a value of 4. In some embodiments, the interception score has a value of 5. In some embodiments, the interception score has a value of 6. In some embodiments, the interception score has a value of 7. In some embodiments, the interception score has a value of 8. In some embodiments, the interception score has a value of 9. In some embodiments, the interception score has a value of 10. In some embodiments, the interception score has a value of 11. In some embodiments, the interception score has a value of 12.

[0186] In some embodiments, the method further includes diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD. In some embodiments, the method includes adding the negative value of the first score and the second score to determine a stratification score.

[0187] In some embodiments, the subject is diagnosed with likelihood of inconclusive IBD. In some embodiments, the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1.

[0188] In some embodiments, the subject is diagnosed with likelihood of Crohn’s Disease (CD). In some embodiments, the subject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1.

[0189] In some embodiments, the subject is diagnosed with likelihood of Ulcerative Colitis. In some embodiments, the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4.

[0190] Certain aspects of the disclosure relate to methods for treating a subject having IBD. In some embodiments, the method for treating a subject having IBD includes (i) detecting the presence or level of one or more immune responses to microbial antigens, and (ii) detecting the presence or level of one or more immune responses to self antigens in a sample obtained from the subject; determining (i) a first score based on the presence or levelof the one or more immune responses to microbial antigens, and (ii) a second score based on the presence or level of the one or more immune responses to self antigens; and administering an IBD-therapeutic agent to the subject based on the first and second scores. In some embodiments, the IBD is Crohn’s Disease (CD), Ulcerative Colitis (UC), or undifferentiated IBD.

[0191] In some embodiments, the first score is calculated on scale using a statistical model. In some embodiments, the first score is calculated on a scale of 0 to 5 using a statistical model. In some embodiments, a first score of 0 is indicative of the absence of the one or more immune responses to microbial antigens. In some embodiments, a first score different than 0 is indicative of the presence or detectable level of the one or more immune responses to microbial antigens.

[0192] In some embodiments, the second score is calculated on scale using a statistical model. In some embodiments, the second score is calculated on a scale of 0 to -3 using a statistical model. In some embodiments, a second score of 0 is indicative of the absence of the one or more immune responses to self antigens. In some embodiments, a second score different than 0 is indicative of the presence or detectable level of the one or more immune responses to self antigens.

[0193] In some embodiments, the subject is administered the IBD-therapeutic agent if the first score and / or the second score have a value different than 0. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, or at least 5. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3. In some embodiments, the first score is at least -1, at least -2, or at least -3. In some embodiments, the second score is at least -2. In some embodiments, the second score is at least -3.

[0194] In some embodiments, the subject is administered a Crohn’s disease (CD)- therapeutic agent if the first score is different than 0, and the second score has a value of 0. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, or at least 5. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3. In some embodiments, the subject is administered an Ulcerative Colitis (UC)- therapeutic agent if the first score has a value of 0, and the second score has a value different than 0. In some embodiments, the first score is at least -1, at least -2, or at least -3. In some embodiments, the second score is at least -2. In some embodiments, the second score is at least -3. In some embodiments, the subject is administered an undifferentiated IBD- therapeutic agent if the first score and the second score are different than 0.

[0195] In some embodiments, stopping treatment of the subject with the IBD-therapeutic agent if the first score and second score have a value of 0.

[0196] In some embodiments, the method for treating a subject having IBD further includes determining a composite score based on the first and the second scores. In some embodiments, determining the composite score includes the addition of the first and the second scores. In some embodiments, the administering of the IBD-therapeutic agent is based on the composite score. In some embodiments, the IBD-therapeutic agent is administered if the composite score is different than 0.

[0197] In some embodiments, the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens. In some embodiments, the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6. In some embodiments, the subject is diagnosed with ulcerative Colitis (UC) if the second score is different than 0, and the first score has a value of 0. In some embodiments, the first score is at least 1, at least 2, or at least 3.

[0198] In some embodiments, the method further includes determining an interception score based on the first and the second scores. In some embodiments, determining the interception score includes the addition of the first and the second scores.

[0199] In some embodiments, the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0.

[0200] In some embodiments, the subject is diagnosed as having medium likelihood of IBD if the interception score has a value of 0 to 2. In some embodiments, the interception score has a value of 0, 1 or 2. In some embodiments, the interception score has a value of 0. In some embodiments, the interception score has a value of 1. In some embodiments, the interception score has a value of 2.

[0201] In some embodiments, the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12. In some embodiments, the subject is administered an IBD-therapeutic agent. In some embodiments, the interception score has a value of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, the interception score has a value of 2. In some embodiments, the interception score has a value of 3. In some embodiments, the interception score has a value of 4. In some embodiments, the interception score has a value of 5. In some embodiments, the interception score has a value of 6. In someembodiments, the interception score has a value of 7. In some embodiments, the interception score has a value of 8. In some embodiments, the interception score has a value of 9. In some embodiments, the interception score has a value of 10. In some embodiments, the interception score has a value of 11. In some embodiments, the interception score has a value of 12.

[0202] In some embodiments, the method further includes diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD. In some embodiments, the method includes adding the negative value of the first score and the second score to determine a stratification score.

[0203] In some embodiments, the subject is diagnosed with likelihood of inconclusive IBD. In some embodiments, the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1. In some embodiments, the subject is administered an undifferentiated IBD-therapeutic agent

[0204] In some embodiments, the subject is diagnosed with likelihood of Crohn’s Disease (CD). In some embodiments, the subject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is administered a Crohn’s disease (CD)-therapeutic agent.

[0205] In some embodiments, the subject is diagnosed with likelihood of Ulcerative Colitis. In some embodiments, the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4. In some embodiments, the subject is administered an Ulcerative Colitis (UC)-therapeutic agent.

[0206] In some embodiments, the method further includes stopping treatment of the subject with the therapeutic agent if the interception score has a value of 0 or lower.

[0207] Certain aspects of the disclosure relate to methods for selecting a subject having IBD for treatment with an IBD-therapeutic agent. In some embodiments, the method for selecting a subject having IBD for treatment with an IBD-therapeutic agent includes (i) detecting the presence or level of one or more immune responses to microbial antigens, and(ii) detecting the presence or level of one or more immune responses to self antigens in a sample obtained from the subject; determining (i) a first score based on the presence or level of the one or more immune responses to microbial antigens, and (ii) a second score based on the presence or level of the one or more immune responses to self antigens; and selecting the subject for treatment with the IBD therapeutic agent based on the first and second scores. In some embodiments, the IBD is Crohn’s Disease (CD), Ulcerative Colitis (UC), or undifferentiated IBD.

[0208] In some embodiments, the first score is calculated on scale using a statistical model. In some embodiments, the first score is calculated on a scale of 0 to 5 using a statistical model. In some embodiments, a first score of 0 is indicative of the absence of the one or more immune responses to microbial antigens. In some embodiments, a first score different than 0 is indicative of the presence or detectable level of the one or more immune responses to microbial antigens.

[0209] In some embodiments, the second score is calculated on scale using a statistical model. In some embodiments, the second score is calculated on a scale of 0 to -3 using a statistical model. In some embodiments, a second score of 0 is indicative of the absence of the one or more immune responses to self antigens. In some embodiments, a second score different than 0 is indicative of the presence or detectable level of the one or more immune responses to self antigens.

[0210] In some embodiments, the subject is selected for treatment with the IBD therapeutic agent if the first score and second score are different than 0. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, or at least 5. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3. In some embodiments, the first score is at least -1, at least -2, or at least -3. In some embodiments, the second score is at least -2. In some embodiments, the second score is at least -3.

[0211] In some embodiments, the subject is selected for treatment with a Crohn’s disease (CD)-therapeutic agent if the first score is different than 0, and the second score has a value of 0. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, or at least 5. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3. In some embodiments, the subject is selected for treatment with an Ulcerative Colitis (UC)-therapeutic agent if the first score has a value of 0, and the second score has a value different than 0. In some embodiments, the first score is at least -1, at least - 2, or at least -3. In some embodiments, the second score is at least -2. In some embodiments,the second score is at least -3. In some embodiments, the subject is selected for treatment with an undifferentiated IBD-therapeutic agent if the first score and the second score are different than 0.

[0212] In some embodiments, the subject is not selected for treatment with the IBD- therapeutic agent if the first score and second score have a value of 0.

[0213] In some embodiments, the method for selecting a subject having IBD for treatment with an IBD-therapeutic agent further includes determining a composite score based on the first and the second scores. In some embodiments, determining the composite score includes the addition of the first and the second scores. In some embodiments, the subject is selected for treatment with the IBD-therapeutic agent is based on the composite score. In some embodiments, the subject is selected for treatment with the IBD-therapeutic agent if the composite score is different than 0.

[0214] In some embodiments, the method for selecting a subject having IBD for treatment with an IBD-therapeutic agent further includes administering the IBD therapeutic agent to the subject.

[0215] In some embodiments, the method for selecting a subject having IBD for treatment with an IBD-therapeutic agent is a method for selecting a subject having IBD for inclusion in a clinical trial. In some embodiments, the method for selecting a subject having IBD for inclusion in a clinical trial includes (i) detecting the presence or level of one or more immune responses to microbial antigens, and (ii) detecting the presence or level of one or more immune responses to self antigens in a sample obtained from the subject; determining (i) a first score based on the presence or level of the one or more immune responses to microbial antigens, and (ii) a second score based on the presence or level of the one or more immune responses to self antigens; and selecting the subject for inclusion in a clinical trial based on the first and second scores. In some embodiments, the IBD is Crohn’s Disease (CD), Ulcerative Colitis (UC), or undifferentiated IBD.

[0216] In some embodiments, the first score is calculated on scale using a statistical model. In some embodiments, the first score is calculated on a scale of 0 to 5 using a statistical model. In some embodiments, a first score of 0 is indicative of the absence of the one or more immune responses to microbial antigens. In some embodiments, a first score different than 0 is indicative of the presence or detectable level of the one or more immune responses to microbial antigens.

[0217] In some embodiments, the second score is calculated on scale using a statistical model. In some embodiments, the second score is calculated on a scale of 0 to -3 using astatistical model. In some embodiments, a second score of 0 is indicative of the absence of the one or more immune responses to self antigens. In some embodiments, a second score different than 0 is indicative of the presence or detectable level of the one or more immune responses to self antigens.

[0218] In some embodiments, the subject is selected for inclusion in the clinical trial if the first score and second score are different than 0. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, or at least 5. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3. In some embodiments, the first score is at least -1, at least -2, or at least -3. In some embodiments, the second score is at least -2. In some embodiments, the second score is at least -3.

[0219] In some embodiments, the subject is not selected for inclusion in the clinical trial if the first score and second score have a value of 0.

[0220] In some embodiments, the method for selecting a subject having IBD for inclusion in a clinical trial further includes determining a composite score based on the first and the second scores. In some embodiments, determining the composite score includes the addition of the first and the second scores. In some embodiments, the subject is selected inclusion in the clinical trial based on the composite score. In some embodiments, the subject is selected inclusion in the clinical trial if the composite score is different than 0.

[0221] In some embodiments, the method for selecting a subject having IBD for treatment with an IBD-therapeutic agent further includes administering the IBD therapeutic agent to the subject.

[0222] In some embodiments, the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens. In some embodiments, the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6. In some embodiments, the subject is diagnosed with ulcerative Colitis (UC) if the second score is different than 0, and the first score has a value of 0. In some embodiments, the first score is at least 1, at least 2, or at least 3.

[0223] In some embodiments, the method further includes determining an interception score based on the first and the second scores. In some embodiments, determining the interception score includes the addition of the first and the second scores.

[0224] In some embodiments, the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0.

[0225] In some embodiments, the subject is diagnosed as having medium likelihood of IBD if the interception score has a value of 0 to 2. In some embodiments, the interception score has a value of 0, 1 or 2. In some embodiments, the interception score has a value of 0. In some embodiments, the interception score has a value of 1. In some embodiments, the interception score has a value of 2. In some embodiments, the subject is selected for treatment with an IBD-therapeutic agent.

[0226] In some embodiments, the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12. In some embodiments, the interception score has a value of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, the interception score has a value of 2. In some embodiments, the interception score has a value of 3. In some embodiments, the interception score has a value of 4. In some embodiments, the interception score has a value of 5. In some embodiments, the interception score has a value of 6. In some embodiments, the interception score has a value of 7. In some embodiments, the interception score has a value of 8. In some embodiments, the interception score has a value of 9. In some embodiments, the interception score has a value of 10. In some embodiments, the interception score has a value of 11. In some embodiments, the interception score has a value of 12. In some embodiments, the subject is selected for treatment with an IBD-therapeutic agent.

[0227] In some embodiments, the method further includes diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD. In some embodiments, the method includes adding the negative value of the first score and the second score to determine a stratification score.

[0228] In some embodiments, the subject is diagnosed with likelihood of inconclusive IBD. In some embodiments, the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1. In some embodiments, the subject is selected for treatment with an undifferentiated IBD-therapeutic agent

[0229] In some embodiments, the subject is diagnosed with likelihood of Crohn’s Disease (CD). In some embodiments, the subject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1. In some embodiments, the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In someembodiments, the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1. In some embodiments, the subject is selected for treatment with a Crohn’s disease (CD)-therapeutic agent.

[0230] In some embodiments, the subject is diagnosed with likelihood of Ulcerative Colitis. In some embodiments, the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4. In some embodiments, the subject is selected for treatment with an Ulcerative Colitis (UC)-therapeutic agent. In some embodiments, the method further includes administering the IBD therapeutic agent to the subject.

[0231] Certain aspects of the disclosure relate to methods for monitoring the effectiveness of an IBD-therapeutic agent in a subject with IBD. In some embodiments, the method for monitoring the effectiveness of an IBD-therapeutic agent in a subject with IBD includes (i) detecting the presence or level of one or more immune responses to microbial antigens, and (ii) detecting the presence or level of one or more immune responses to self antigens in a sample obtained from the subject; determining (i) a first score based on the presence or level of the one or more microbial serological markers, and (ii) a second score based on the presence or level of the one or more immune responses to self antigens; and adjusting the amount of IBD therapeutic agent being administered to the subject based on the first and second scores. In some embodiments, the IBD is Crohn’s Disease (CD), Ulcerative Colitis (UC), or undifferentiated IBD.

[0232] In some embodiments, the first score is calculated on scale using a statistical model. In some embodiments, the first score is calculated on a scale of 0 to 5 using a statistical model. In some embodiments, a first score of 0 is indicative of the absence of the one or more immune responses to microbial antigens. In some embodiments, a first score different than 0 is indicative of the presence or detectable level of the one or more immune responses to microbial antigens.

[0233] In some embodiments, the second score is calculated on scale using a statistical model. In some embodiments, the second score is calculated on a scale of 0 to -3 using a statistical model. In some embodiments, a second score of 0 is indicative of the absence of the one or more immune responses to self antigens. In some embodiments, a second score different than 0 is indicative of the presence or detectable level of the one or more immune responses to self antigens.

[0234] In some embodiments, the amount of the IBD-therapeutic agent being administered to the subject is increased if the first score and second score are different than 0. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, or at least 5. In some embodiments, the first score is at least 2. In some embodiments, the first score is at least 3. In some embodiments, the first score is at least -1, at least -2, or at least -3. In some embodiments, the second score is at least -2. In some embodiments, the second score is at least -3.

[0235] In other embodiments, the amount of the IBD-therapeutic agent being administered to the subject is decreased if the first score and second score have a value of 0.

[0236] In some embodiments, the method for monitoring the effectiveness of an IBD- therapeutic agent in a subject with IBD further includes determining a composite score based on the first and the second scores. In some embodiments, determining the composite score includes the addition of the first and the second scores. In some embodiments, the amount of the IBD-therapeutic agent being administered is adjusted based on the composite score. In some embodiments, the amount of the IBD-therapeutic agent being administered to the subject is increased if the composite score has a value different than 0.

[0237] In some embodiments, the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens. In some embodiments, the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens. In some embodiments, the first score is at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6. In some embodiments, the subject is diagnosed with ulcerative Colitis (UC) if the second score is different than 0, and the first score has a value of 0. In some embodiments, the first score is at least 1, at least 2, or at least 3.

[0238] In some embodiments, the method further includes determining an interception score based on the first and the second scores. In some embodiments, determining the interception score includes the addition of the first and the second scores.

[0239] In some embodiments, the amount of the IBD-therapeutic agent being administered to the subject is maintained or increased if the interception score has a value of 0 to 2. In some embodiments, the interception score has a value of 0, 1 or 2. In some embodiments, the interception score has a value of 0. In some embodiments, the interception score has a value of 1. In some embodiments, the interception score has a value of 2.

[0240] In some embodiments, the amount of the IBD-therapeutic agent being administered to the subject is increased if the interception score has a value of 2 to 12. In some embodiments, the interception score has a value of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, the interception score has a value of 2. In some embodiments, the interception score has a value of 3. In some embodiments, the interception score has a value of 4. In some embodiments, the interception score has a value of 5. In some embodiments, the interception score has a value of 6. In some embodiments, the interception score has a value of 7. In some embodiments, the interception score has a value of 8. In some embodiments, the interception score has a value of 9. In some embodiments, the interception score has a value of 10. In some embodiments, the interception score has a value of 11. In some embodiments, the interception score has a value of 12.

[0241] In some embodiments, the amount of the IBD-therapeutic agent being administered to the subject is decreased if the interception score has a value of 0 or lower.Serological Markers

[0242] In some embodiments, the methods provided herein include detecting the presence or level of one or more immune responses to microbial antigens. Non-limiting examples of microbial serological markers include, but are not limited to, an-anti Saccharomyces cerevisiae antibody (ASCA) immune response, an anti-neutrophil cytoplasmic antibody (ANCA) immune response, an anti- / :. coli outer membrane porin protein C (OmpC) immune response, an r\ -Malassezia restricta immune response, an r\ -Malassezia pachydermatis immune response, an a.ni\-Malassezia furfur immune response, an a.ni\-Malassezia globasa immune response, an ^ yi-Cladosporium albicans immune response, an anti-laminaribiose immune response, an anti-chitobioside immune response, an anti-laminarin immune response, anti-chitin immune response, a pANCA immune response, an anti-12 immune response, or an anti-CBIRl flagellin immune response. In some embodiments, the one or more immune responses to microbial antigens include at least one anti-fungus immune response. In some embodiments, the presence or level of at least one anti-fungus immune response includes an anti-yeast immune response. In some embodiments, the anti-yeast immune response includes an anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response, an anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA-IgG) immune response, or a combination thereof. In some embodiments, the presence or level of at least one fungus immune response includes the ASCA-IgG or the ASCA-IgA immune response. In some embodiments, the one or more immune responses to microbial antigens include at least oneanti-bacterial immune response. In some embodiments, the presence or level of at least one anti-bacterial immune response includes an anti-flagellar immune response. In some embodiments, the anti-flagellar immune response includes an anti-FLAX immune response, an anti-CBIR-1 immune response, an anti-FLA2 immune response, or any combination thereof. In some embodiments, the presence or level of at least one bacterial immune response includes the anti-CBIR-1 immune response. In some embodiments, the antibacterial immune response includes an anti- / :. coli OMPC immune response. In some embodiments, the one or more immune response to microbial antigens include the anti-yeast immune response and the anti-flagellar immune response. In some embodiments, the one or more immune response to microbial antigens include the anti-yeast immune response, the anti-flagellar immune response, and the anti-bacterial immune response. In some embodiments, the one or more immune responses to microbial antigens include ASCA-IgA and the anti-CBIR-1 immune response. In some embodiments, the one or more immune responses to microbial antigens include ASCA-IgG and the anti-CBIR-1 immune response. In some embodiments, the one or more immune responses to microbial antigens include ASCA- IgG, ASCA-IgG, and the anti-CBIR-1 immune response. In some embodiments, detecting the presence or level of the one or more immune response to microbial antigens includes detecting the presence or level of one or more antibodies against the microbial antigen (i.e., an anti-microbial antigen antibody).

[0243] In some embodiments, the methods provided herein include detecting the presence or level of one or more immune responses to microbial antigens above a cutoff. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA- IgA) immune response is about 10 units / mL to about 12 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 11.9 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 10.8 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9 units / mL to about 21 units / mL. In some embodiments, the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9.2 units / mL. In some embodiments, the cutoff for the anti- Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 20.4 units / mL. In some embodiments, the cutoff for the anti -OMPC immune response is about 6.0 units / mL. In some embodiments, the cutoff for the anti-FLAX immune response is about 30.0 units / mL to about 37 units / mL. In some embodiments, the cutoff for the anti-FLAXimmune response is about 36.0 units / mL. In some embodiments, the cutoff for the anti- FLAX immune response is about 36.6 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about 35 units / mL to about 54 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about 35.4 units / mL. In some embodiments, the cutoff for the anti-CBIR-1 immune response is about 53.8 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about 32 units / mL to about 39 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about 32.4 units / mL. In some embodiments, the cutoff for the anti-FLA2 immune response is about 38.9 units / mL. In some embodiments, the methods provided herein include detecting the presence or level of one or more immune response to self antigens. In some embodiments, the one or more immune responses to self antigens include an anti-protease immune response, an anti -neutrophil immune response, an anti-integrin immune response, or any combination thereof. In some embodiments, the one or more immune responses to self antigens includes the anti-protease immune response. In some embodiments, the anti-protease immune response includes an anti -proteinase 3 (PR3) immune response. In some embodiments, the one or more immune responses to self antigens include an anti -neutrophil immune response. In some embodiments, the anti-neutrophil immune response includes a perinuclear antineutrophil cytoplasmic antibody (pANCA) immune response. In some embodiments, the one or more immune response to self antigens include the anti-integrin immune response. In some embodiments, the anti-integrin immune response includes an anti-AvB6 integrin immune response. In some embodiments, the one or more immune responses to self antigens includes the anti-PR3 immune response and the anti-integrin immune response. In some embodiments, the one or more immune responses to self antigens includes the pANCA and the anti-integrin immune responses. In some embodiments, detecting the presence or level of the one or more immune response to self antigens includes detecting the presence or level of one or more antibodies against the self antigen (z.e., an autoantibody).

[0244] In some embodiments, the methods provided herein include detecting the presence or level of the one or more immune responses to self antigens above a cutoff. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 2.5 units / mL to about 20.0 units / mL. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 2.5 units / mL. In some embodiments, the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 20.0 units. In some embodiments, the cutoff for the pANCA immune response is about 1 to about 2 on an intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the pANCA immune response is about 2 onan intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the pANCA immune response is about 1 on an intensity scale ranging from 0 to 4. In some embodiments, the cutoff for the anti-integrin immune response is about 3 units / mL to about 5 units / mL. In some embodiments, the cutoff for the anti-integrin immune response is about 5 units / mL. In some embodiments, the cutoff for the anti-integrin immune response is about 3.1 units / mL.

[0245] The one or more immune responses to the microbial antigens and / or the self antigens can be detected by any suitable method known in the art. In some embodiments, the presence or level of the one or more immune responses to microbial antigens and / or self antigens is detected with a hybridization assay, an amplification-based assay, an immunoassay, or an immunohistochemical assay. In some embodiments, detecting the presence or level of the one or more immune responses to microbial and / or self antigens includes detecting the presence or level of an antibody involved in the response to the microbial antigen (i.e., an anti-microbial antigen antibody) and / or the self antigen (i.e., an autoantibody).Statistical Models

[0246] Certain aspects of the disclosure provide for statistical models, the first and second scores can be determined by any suitable statistical model known in the art. The statistical model can include any statistical method or model used to determine relationships between variables.

[0247] In some embodiments, the statistical model used to calculate the first score and / or the second score includes a regression analysis, such as logistic regression or linear regression. For instance, regression analysis can be performed on the presence or level of the one or more immune responses to microbial antigens and / or self antigens to develop a diagnostic score based on the one or more immune responses to the microbial antigens and / or the self antigens. The diagnostic score can then be used to make a determination of the IBD status (IBD vs. non-IBD) or distinguishing of clinical subtypes of IBD (e.g., UC vs. CD) in a subject. In some embodiments, the regression analysis is logistic regression. A logistic regression model (also referred to as a logistic model or a logit model) is used for prediction of the probability of occurrence of an event by fitting data to a logit function logistic curve. In some instances, it is a generalized linear model used for binomial regression.Samples

[0248] Certain aspects of the disclosure provide for samples. Non-limiting examples of suitable samples include, but are not limited to, whole blood, peripheral blood, plasma, serum, saliva, mucus, urine, semen, lymph, fecal extract, cheek swab, cells or other bodily fluid or tissue, including but not limited to tissue obtained through surgical biopsy or surgical resection. In some embodiments, the sample includes nucleic acids and / or proteins. In some embodiments, the sample includes the one or more immune responses to microbial antigens and / or the one or more immune responses to self antigens. In some embodiments, the sample is selected from the group consisting of serum, plasma, whole blood, and stool. In other embodiments, the sample includes a tissue sample (e.g., an intestinal tissue sample).Subjects

[0249] Certain aspects of the disclosure provide for subjects. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.IBP Therapeutic Agents

[0250] Certain aspects of the methods disclosed herein provide for IBD-therapeutic agents. In some embodiments, the IBD-therapeutic agent is a Crohn’s Disease (CD)- therapeutic agent, an Ulcerative Colitis (UC)-therapeutic agent, or an undifferentiated IBD- therapeutic agent. In some embodiments, the IBD-therapeutic agent includes an antibody, a polypeptide, a nucleic acid, a small molecule compound, a cell therapy, a surgery, or a clinical trial.

[0251] In some embodiments, the IBD-therapeutic agent targets at least one pathway selected from an Tumor Necrosis Factor (TNF) pathway, an interleukin- 12 (IL-12) pathway, an interleukin-23 (IL-23) pathway, a sphingosine- 1 -phosphate pathway, or a j anus kinase (JAK) pathway.

[0252] In some embodiments, the IBD-therapeutic agent includes an anti-Tumor Necrosis Factor (TNF) antibody. In some embodiments, the anti-TNF antibody is an anti-TNF alpha antibody. In some embodiments, the anti-TNF antibody includes infliximab (IFX) or adalimumab (ADA), or a biosimilar thereof. In some embodiments, the anti-TNF antibody includes IFX, or a biosimilar thereof. In some embodiments, the IFX is administered at a dose of about 5 to about 10 mg / kg very 4 to 8 weeks. In some embodiments, the anti-TNFantibody includes ADA, or a biosimilar thereof. In some embodiments, the ADA is administered at a dose of about 40 to 80 mg very one to two weeks.

[0253] In some embodiments, the IBD-therapeutic agent targets an anti-interleukin- 12 (IL-12) pathway or an anti-interleukin-23 (IL-23) pathway. In some embodiments, the IBD- therapeutic agent includes an anti-interleukin- 12 (IL-12), or an anti-interleukin-23 (IL-23) antibody. In some embodiments, the anti-IL-12 or the anti-IL-23 antibody includes ustekinumab (UST), or a biosimilar thereof. In some embodiments, the UST is administered at a dose of about 90 mg every 4 to 8 weeks. In some embodiments, the anti-IL-12 or the anti-IL-23 antibody includes mirikizumab, or a biosimilar thereof. In some embodiments, the mirikizumab is administered at a dose of about 200 mg every 4 weeks. In some embodiments, the anti-IL-12 or the anti-IL-23 antibody includes guselkimab, or a biosimilar thereof. In some embodiments, the guselkumab is administered at a dose of about 100 mg every 4 to 8 weeks. In some embodiments, the IBD-therapeutic agent targets a sphingosine- 1- phosphate pathway. In some embodiments, the IBD-therapeutic agent includes a sphingosine- 1 -phosphate receptor agonist. In some embodiments, the sphingosine- 1 -phosphate receptor agonist includes ozanimod, or a biosimilar thereof. In some embodiments, the ozanimob is administered at a dose of about 0.92 mg daily. In some embodiments, the sphingosine- 1- phosphate receptor agonist includes etrasimod, or a biosimilar thereof. In some embodiments, the etrasimod is administered at a dose of about 2 mg daily.

[0254] In some embodiments, the IBD-therapeutic agent targets a JAK pathway. In some embodiments, the IBD-therapeutic agent includes JAK inhibitor. In some embodiments, the JAK inhibitor includes upadacitinib, or a biosimilar thereof. In some embodiments, theudapacitinib is administered at a dose of about 15 to 30 mg daily. In some embodiments, the JAK inhibitor includes ivarmacitinib, or a biosimilar thereof. In some embodiments, the ivarmacitinib is administered at a dose of about 4 to 8 mg daily.Methods of Administration

[0255] In some embodiments of the methods provided herein, the method includes administering an IBD-therapeutic agent to a subject. Administration of the IBD-therapeutic agent can be performed by any suitable route of administration. Methods of administration of pharmaceutical compositions described herein are known to those in the art. In some embodiments, the method described herein include administering an IBD-therapeutic agent to the subject orally, pulmonarily, intranasally, parenterally (intravenously, intramuscularly,intraperitoneally, or subcutaneously), rectally, intralymphatically, or topically. In some embodiments, the methods described herein include administering an IBD-therapeutic agent to the subject systemically. In some embodiments, the methods described herein include administering an IBD-therapeutic agent to the subject locally.

[0256] Administration of the IBD-therapeutic agent to the subject can be performed at one time or over a series of administrations and may be administered to the subject at any time from diagnosis of a disease (e.g., IBD). For instance, the IBD-therapeutic agent can be administered as one or more doses over the course of a treatment. The doses can be administered using the same or a different route of administration, and can contain the same amount or a different amount of the IBD-therapeutic agent. The duration of administration can depend on the route of administration of the IBD-therapeutic agent.EXAMPLES

[0257] In order that this disclosure may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the disclosure in any manner.Example 1: Diagnosis and classification of Inflammatory Bowel Diseases based on immune response to self and microbial antigens.

[0258] This example describes the development of a method to diagnose and classify inflammatory bowel disease (IBD) based on the cumulative presence of immune responses to microbial and self antigens.

[0259] Observational data from a cross-sectional study design extracted from AI2 discover was interrogated for the presence or absence of immune response to self and microbial antigens, to establish 1) a differential diagnosis of IBD and interception of seropositive IBD with the intent to treat the patient with such target, and 2) the classification of seropositive IBD into seropositive Crohn’s Disease (CD) or Ulcerative Colitis (UC) of undifferentiated, such target be specific to UC or CD across the repertoire of immune response to self and microbial. The control group in this method consisted of non-IBD (patients with other GI disease including irritable bowel syndrome), in the absence of immune response to microbial and self.

[0260] Table 1 illustrates the composition of immune response to microbial and self- antigenic determinants, while FIG. 1 shows the distribution of immune responses to self and microbial antigens in IBD. A method for diagnosing IBD and selecting the seropositive CDand UC patient was built from a logistic regression analysis, where having IBD (or not), or having CD (vs UC) were the dependent variables, with the antibody titers above their respective cutoff and in combination as the independent predictors (Table 1).Table 1 : Seropositive IBD interception and classification criteria.

[0261] The estimates from the logistic regression analysis for the differential diagnosis of IBD are presented in Tables 2-4, while FIG. 2 shows the output of the logistic regression analysis of the probability of IBD based on immune responses to self and microbial antigens. For the logistic regression analysis, the dependent variables used corresponded to seropositive non IBD (non-IBD = 0) and IBD (IBD = 1).Table 2: Logistic regression estimates for seropositive non-IBD vs IBP based on immune reaction to self antigens.Table 3: Logistic regression estimates for seropositive non-IBD vs IBP based on immune reaction to microbial antigens.Table 4: Logistic regression estimates for seropositive non-IBD vs IBP based on immune reaction to both self and microbial antigens.

[0262] For next generation (NextGen) serology scaling, IBD serologies across the spectrum of immune responses to microbial and self antigens were analyzed by logistic regression (Table 5), with seropositive non IBD (non-IBD = 0) and IBD (IBD = 1) as the dependent variables.Table 5: Logistic regression estimates for NextGen serology scaling and IBP interception.

[0263] FIG. 3 shows the probability of IBD by number of immune responses to microbial and self antigens. In the IBD population included in the analysis, 63% and 60% of UC and CD patients had 2 or more immune response to microbial or self respectively, with 29% and 36% of UC and CD having 3 or more immune response to self and microbial antigens, respectively (Tables 6-8). FIG. 4 shows the NextGen IBD serologies and IBD interception across patient journey.Table 6: Proportion of IBD patients by number of immune responses.Table 7: Number of IBP patients by number of immune responses.Table 8: Interval likelihood ratio analysis of IBP by number of immune response.Note: Analysis used the sum of 8 immune response as the variable, depicting a max of 4, and combining 4 and 5 immune responses to microbial antigens together. The presence or absence of seropositive non-IBP vs. IBP was used as the classification variable.

[0264] Next, an analysis of interception of IBP vs. irritable bowel syndrome was performed using logistic regression (Tables 9-10).Table 9: NextGen IBP serologies across spectrum of immune responses to self and microbial antigens.Table 10: Interval likelihood ratio analysis of IBP by number of immune response.Note: Analysis used the sum of 8 immune response as the variable, depicting a max of 4, and combining 4 and 5 immune responses to microbial antigens together. The presence or absence of irritable bowel syndrome vs. IBP was used as the classification variable.

[0265] FIG. 5 and Table 11 show the positive predictive values (PPVs) for distinguishing IBP vs. irritable bowel syndrome based on immune responses to self and microbial antigens.Table 11 : PPV for IBP vs. irritable bowel syndrome at various pretest values.

[0266] The classification of IBP subtypes based on immune responses to self and microbial antigens was also analyzed by logistic regression, using ulcerative Colitis (UC) and Crohn’s Pisease (CP) as the dependent variables (Tables 12-16).Table 12: Logistic regression estimates for UC vs. CP based on immune reaction to microbial antigens.Table 13: Interval likelihood ratio analysis of IBP subtype by number of immune response to microbial antigens.Note: Analysis used the sum of 3 immune response as the variable. The presence or absence of UC vs. CD was used as the classification variable.Table 14: Logistic regression estimates for UC vs. CD based on immune reaction to microbial antigens.Table 15: Interval likelihood ratio analysis of IBP subtype by number of immune response to microbial antigens.Note: Analysis used the sum of 5 immune response as the variable. The presence or absence of UC vs. CD was used as the classification variable.Table 16: Logistic regression estimates for UC vs. CD based on immune reaction to self and microbial antigens.

[0267] FIGS. 6A-6B and Tables 17-18 show the probability of CD or UC by immune response to self and microbial antigens. The AUC of the ROC was 0.825 in distinguishing CD from UC using the NextGen IBD serology panel of immune response to self (-3, -2, -1,0) and microbial antigens (0,1, 2, 3, 4, 5), which have to be added together (FIG. 7).Table 17: Probability of CD by immune response to self and microbial antigens.Table 18: Probability of UC by immune response to self and microbial antigens.

[0268] FIG. 8 and Table 19 show the frequency of seronegative and undifferentiated IBD in the cohort of patients.Table 19: Seronegative and undifferentiated IBP (total IBP in the cohort n = 709),

[0269] The NextGen serologies across the spectrum of immune responses to self and microbial antigens was also analyzed by logistic regression, with UC and CD as the dependent variables (Tables 20-21). FIG. 9 shows the probability of UC vs. CD based on the number of immune responses to self and microbial antigens.Table 20: Logistic regression estimates for UC vs. CD based on immune responses to microbial antigens.Note: In CD spectrum, 4 and 5 immune responses were combined for the analysis.Table 21 : Interval likelihood ratio analysis of UC vs. CD by number of immune responses to microbial antigens.Note: Analysis used the number of immune responses as the variable. The presence or absence of UC vs. CD was used as the classification variable.

[0270] FIGS. 10A-10B and Tables 22-23 show the interval likelihood ratio (ILR) for CD and UC.Table 22: Interval likelihood ratios for CD.Table 23: Interval likelihood ratios for UC.

[0271] Using the logistic regression analyses, a IBD disease classification model was (Montreal classification) built based on the following observations: (1) the presence of classified Ulcerative colitis, enrichment in seropositive UC corresponds to those having at least two immune responses to self-antigens, in the absence of immune response to microbial antigens; (2) in the presence of classified Crohn’s disease, enrichment in seropositive CD corresponds to those having at least two immune responses to microbial antigens, in the absence of immune response to self-antigens; (3) in the presence of classified IBD, enrichment in seronegative IBD corresponds to the absence of known immune response to microbial and self-antigens; and (4) the control group corresponds to the absence of immune response to self and microbial antigens, and the absence of disease. FIG. 11 shows the specimen collection across the repertoire of immune responses to self and microbial antigens.

[0272] FIG. 12 shows the immune response classification model of IBD based on a scale determined from the immune response to self and microbial antigens. The model includes: (1) selecting a first set of antibodies resulting from immune response to microbial antigens (with specificity to the CD spectrum of disease), assembled in a scale (having positive value), as the sum of 5 antibody systems directed against Saccharomyces Cerevisiae (ASCA, IgA and IgG) and flagellins (FLA2 IgG, FLAX IgG, CBIR-1 IgG) (range 0-5) owing to their propensity to CD, (2) selecting a second set of antibodies resulting from immune response self-antigens (with specificity to UC spectrum of disease) as the sum of 3 antibody systems directed against pANCA (2+ intensity), PR3 (>2.5 U / mL), and anti-integrins (>5 U / mL) (range -3 to 0), owing to their propensity to UC; and (3) assembling the two adjacent scales where the value of zero corresponds to seronegative IBD or undifferentiated seropositive IBD to establish the seropositive IBD has having an immune response to self and microbial. FIG. 13 shows the classification of IBD based on the model.

[0273] In addition to the diagnosis and treatment of IBD, the developed classification model and related method can be used for selection of patients for clinical trials and as a companion diagnosis tool (FIG. 14).Example 2: Two-tiered framework for diagnosis and classification of Inflammatory Bowel Diseases based on immune response to self and microbial antigens.

[0274] This example describes the development of a two-tiered model to diagnose and classify inflammatory bowel disease (IBD) and IBD subtypes based on the cumulative presence of immune responses to self and microbial antigens.

[0275] A two-tiered model was developed that includes a multi-analyte assay panel developed to facilitate the differential diagnosis of Inflammatory Bowel Diseases (IBD), its interception and stratification as Crohn’s disease (CD) or Ulcerative Colitis (UC) and their respective ileal and colonic involvement. In this example we report the performance of 7 serologies with anti-integrin IgGl-4 and anti-PR3 IgG5 that are all specific for ulcerative colitis and colonic disease. Table 24 includes a list of standard operating practice (SOP) assays used in the study described herein.Table 24: List of SOPs and documentation.Patient Specimens and Cohorts

[0276] The performances characteristics of a two-tiered model for diagnosing and classifying IBD were established from sera collected from consented subjects. All dataspecimens collected from adults’ donors with autoimmune gastrointestinal diseases, inflammatory and non-inflammatory diseases including a control group of normal healthy adults.

[0277] This included 6 antibodies directed against microbial antigens (the microbial antibodies), corresponded to antibodies directed again yeast (anti-saccharomyces cerevisiae IgG and IgA isotypes), flagellins (CBIR-1, FLA2 and FLAX IgG isotypes), and gramnegative Escherichia coli (with outer membrane porin C as OMPC IgA isotype). The antibodies to self-antigens (autoantibodies) consisted of the anti-integrins IgG (avP6), in combination with DNA sensitive perinuclear anti-neutrophil cytoplasmic antibodies (pANCA, all IgG isotypes) in the presence of anti-PR3 (IgG).

[0278] The specimens were allocated to a training set to parameterize the algorithm that distinguishes IBD from non-IBD (normal healthy and non IBD with other gastrointestinal conditions) and two validation set. In order to adequately compare the performance of the two-tiered model with that of the original model, where the specimens processed were assigned to the training and validation set (validation 1) where they originally were employed (training: n=512; validation: n=224). The second validation cohort consisted of all specimens available and not part of the training or validation set defined above (n=1371). Table 25 shows the distribution of specimens assigned to the training and validation set.Table 25: Distribution of specimens assigned to the training set and validation set.

[0279] The training set consisted of all specimens processed originally part of the training set for the original model (n=512 with specimens available for serological profiling). There are two validation sets, a first validation set of 225 specimens available from the original validation report of 437 specimens employed to prepare the reported performances (thus allowing the head-to-head comparison of the two random forests developed), and 2), and a second validation set corresponds to all specimens that were neither from the training nor from the validation set employed but having a random forest estimated (1371).Reference Range from Healthy Individuals

[0280] The cutoffs associated with the normal donor group for the self antigens are reported in Table 26.

[0281] The cutoffs associated with the 95th percentile of normal donor group (n=290), for the microbial antibodies are reported in Table 27. For all autoantibodies (pANCA, PR3, avP6) the manufacturer cutoffs from the package insert are used (pANCA positive, and PR3>20 CU) with the lower calibrator for avP6 (3.1 U / ml) as the cutoff. There are two components, the microbial antibody component (or scale) cumulating the positive microbial antibody status (6 antibodies) and the self-antigen antibody scale cumulating positive reactivity to self-antigens.Table 26: Cutoffs for the individual self-antigen antibodies.Table 27: Cutoffs for the microbial antibodies.Univariate Analysis

[0282] The cumulative presence of the three self-antigen antibodies in associating withIBD is shown in FIG. 15. These antibodies target distinct self-antigens (pANCA: neutrophilcomponents; PR3: serine protease; avP6: epithelial integrin) and the co-expression may reflect a broader autoimmune activation in UC, making their combination biologically meaningful, with very high specificity in the presence of triple positivity.

[0283] The combination of the three self-antigen antibodies can stratify CD subtypes: CD (L2, colonic) shows higher rates (35% avP6, 21% pANCA) and 7% triple positivity; CD (LI, ileal) shows minimal expression (10% avP6, 11% pANCA, 0% triple). This data demonstrate that antibody combinations reflect disease location and phenotype.

[0284] Combining microbial antibodies into a threshold of >3 positive antibodies results in high specificity >90% specificity across all conditions, making it a strong rule-in marker of CD (FIG. 16 and FIG. 17)

[0285] This data indicates that the clinical decision-making can be simplified, helping clinicians stratify patients more easily without needing to interpret each antibody individually. Thus, a two-tiered framework based on the immune responses to self and microbial antigens enables both disease classification and classification through polaritybased regression analysis. The direction (or polarity) of association between variables is intentionally set to enhance interpretability and classification in the multidimensional data of immune profiles in IBD.

[0286] Based on these results, a two-tiered model for classification and classification of IBD was developed (FIG. 22). In the interception scale for the two-tiered model, higher immune response score resulting from the presence of microbial and self-antigen antibodies is associated with a higher likelihood of IBD, (both positive polarity for the microbial and self-antigen antibodies). In the stratification scale two-tiered scale, the combination of two bifurcating branches, a microbial antibody scale (negative polarity) and self-antigen antibody scale (positive polarity) results in the separation of Crohn’s disease from Ulcerative Colitis, respectively, and their separation in ileal and colonic location.Two-tiered Model Classi fication Scale (IBD vs non-IBD)

[0287] The seropositive IBD signature in the interception scale is made of microbial and self-antigen antibody both having positive polarity and directionality to intercept IBD:

[0288] Self-Antigen Antibody Count: A composite of three serological markers — pANCA, PR3, and anti-avP6 with positive cutoff presented in Table 26.

[0289] Microbial Antibody Count: The sum of the six established microbial antibodies associated with IBD, with positive cutoff presented in Table 27.

[0290] Table 28 shows the output of the logistic regression model parameters. The combined model demonstrated the lowest Akaike information criterion (AIC; 418) and highest explained variance (R2m = 0.700), indicating superior model fit and predictive power. The self-antigen model alone showed strong performance (AIC = 454, R2m = 0.661), confirming its value in IBD classification. The microbial-only model had lower explanatory power (R2m=0.047), but contributed meaningfully when combined.Table 28: Output of logistic regression model parameters.

[0291] The final model equation is presented in Table 29 and reflects the positive polarity of both scale in relation to IBD presence, with the self-antigen scale contributing a stronger weight (max 8.8 points in the presence of triple positivity) than the microbial antibody scale (max 3.8 in the presence of the 6 antibodies). Because in the absence of self-antigen antibodies, and presence of two microbial antibodies (Microbes = 2, Self = 0 —> Score = -0.60) a negative test result potentially limits the performance in ileal CD, the model intercept was adjusted to add 0.61 points where specimens with 2 microbial antibodies and no self-antigen antibodies would thus test positive (IBD = +0.01) and be eligible for Tier 2 analysis and the two-tiered model stratification scale.Table 29: Two-tiered Model Interception Scale.Score = -1.88+2.94xSelf- Count +0.64xMicrobial Antibody Count + 0.61

[0292] The model was validated across the training set and two independent validation cohorts, demonstrating robust generalizability and high discriminative performance (AUC > 0.85). The AUC of the interception scale is presented in Table 30 and FIG. 18. There was no statistical difference between the AUC from the training cohort and those from the validation 1 and validation 2 cohorts (p>0.14).Table 30: AUC in training and validation cohorts.

[0293] The performances characteristics of the interception scale of the two-tiered model in the combined validation cohorts (n=1596, n=1039 IBD and 557 non IBD) is presented across a range of pre-test probabilities (1% to 50%) demonstrated that the two-tiered model interception scale meaningfully shifts post-test probabilities. At a 10% pre-test probability, a positive test increases the post-test probability to 30%, while a negative test reduces it to 3%. At a 20% pre-test probability, a positive test yields and 49% post-test probability, and a negative test reduces it to 6% (FIG. 19).

[0294] The model demonstrated robust diagnostic performance, with a sensitivity of 80.3% and specificity of 79.4% (Tables 31-32). The positive likelihood ratio (LR+) was 3.9 (95% CI: 3.3-4.6), and the negative likelihood ratio (LR-) was 0.25 (95% CI: 0.22-0.28), yielding a diagnostic odds ratio (DOR) of 15.6 (95% CI: 12.1-20.2). The Youden Index was 0.596, indicating a strong balance between sensitivity and specificity.Table 31 : Performance characteristics in validation cohorts.Table 32: Two-tiered model and predictive value.

[0295] Sensitivity and specificity were evaluated at multiple cutoff points (Table 33). A threshold of -0.6 provided 71% and specificity = Specificity: 88%. Higher thresholds (e.g., 1.96) increased specificity (up to 99%) but reduced sensitivity (to 37%), making them suitable for confirmatory testing.Table 33: Sensitivity and Specificity.

[0296] The performance at the interval likelihood ratio is presented (validation cohorts) and show that higher two-tiered model scores (>4) are associated with very high likelihood ratios, strongly confirming IBD (Tables 34-35). Conversely, scores below 0 are associated with low LR, helping to exclude disease.Table 34: Interval likelihood ratio for Two-tiered model Interception scale (7 intervals).Table 35: Interval likelihood ratio for Two-tiered model Interception scale (3 intervals).Two-tiered Model Strati fication Scale (UC vs. CD)

[0297] In the two-tiered model stratification scale, the combination of two bifurcating branches, the microbial antibody scale (negative polarity) and self-antigen antibody scale (positive polarity) results in the separation of Crohn’s disease from Ulcerative Colitis, respectively, and their ileal and colonic location. This stratification scale can be applied in two contexts, 1) following the two-tiered model interception scale positive test results (Tier 1 positive specimens), or 2) once the patient has been diagnosed with IBD with need for confirmation for either CD or UC.

[0298] This scale leverages the regional specificity of immune responses, where Selfantigen antibodies (e.g., pANCA, PR3, avP6) are predominantly associated with colonic involvement and UC. While Microbial antibodies (e.g., ASCA, OmpC, CBirl) are more frequently elevated in ileal CD. Colonic or ileal colonic CD is associated with a combination of microbial antibodies and self-antigen antibodies.

[0299] The two-tiered model stratification scale is the output of multivariate logistic regression with the microbial component, and the self-component each associated with their respective coefficient (Tables 36-37).Table 36: Output of logistic regression model parameters.Table 37: Two-tiered model IBP stratification scale.

[0300] The performances characteristics of the two-tiered model stratification scale is presented in Table 38 and FIG. 20. There was no statistical difference between the AUC from the training cohort and those from the validation 1 and validation 2 cohorts (p>0.8). The two-tiered model stratification scale provides a regionally informed immunological signature that, distinguishes UC from CD with high accuracy and reflects the biological divergence between colonic and ileal immune responses.Table 38: AUC in training and validation cohorts.scalescalescale

[0301] The performances characteristics of the two-tiered model UC / CD stratification scale in the combined validation cohorts (n=1039, n=479 UC and 560 CD) is presented in FIG. 21 and Table 39-41Table 39: Performance characteristics in validation cohorts.Table 40: Performances at various cutoffs.Table 41 : Interval Likelihood ratio for two-tiered model UC / CD stratification.Two-tiered Model for IBP Classification and Stratification

[0302] The self-antigen and microbial antibody profiles used in the two-tiered model of IBD interception and stratification are only meaningful in the context of IBD. In non-IBD patients, these markers may be absent or non-specific, and thus do not reflect the regional and positive immune polarization that the UC / CD scale is designed to capture. The two-tier model is designed as a two-tiered diagnostic algorithm.

[0303] A schematic of the two-tiered model of IBD classification and classification is shown in FIG. 22The two-tiered model parameters are as follows:Tier 1: Initial Screening

[0304] Initial screening with the Tier 1 scale identifies patients with a seropositive IBD signature. A positive result triggers Tier 2 stratification, while a negative result stops further testing due to lack of IBD-consi stent serology.• Negative Result: Pattern not consistent with IBD —> Stop testing.• Positive Result: Pattern consistent with seropositive IBD —> Proceed to Tier 2.• Key markers: pANCA / PR3 / av|J6, ASCAIgA, ASCAIgG, anti-CBIRl IgG, anti-FLA2 IgG, anti-FLAX IgG and anti-OmpC IgA)Tier 2: Scaling Based on Antibody Profiles

[0305] Tier 2 uses two scales based on the type of immune response:1. Self- Antigen Antibody Scale• Positive polarity and suggestive of Ulcerative Colitis (UC).• Associated with colonic involvement in CD and UC.• Key markers: pANCA / PR3 / av|J62. Microbial Antibody Scale• Negative polarity suggests Crohn’s Disease (CD).• In the absence of self-antibody marker, associated with ileal only involvement in CD.• Key marker: Microbial antibodies: yeast (ASCAIgAand IgG), flagellins (CBIR1 IgG, FLA2 IgG, FLAX IgG) and E. colt (anti-OmpC IgA)

[0306] The performances characteristics of the two-tiered model stratification scale in the combined validation cohorts (including 840 IBD testing positive for the two-tiered model interception scale), yielded the performance for UC and CD stratification shown in Table 42 and FIG. 24.Table 42: AUC for Tier 2 UC and CD stratification in the classification Tier 1 positives.

[0307] The performances in the validation cohorts shown in Tables 43-44 were observed when the patient specimen test positive for the two-tiered model interception scale (tier 1 positive) and is CD or UC. This corresponded to a total of 834 subjects (n=420 UC and n=414 CD). Performance with all 1039 IBD patient specimens is also provided.Table 43: Performance characteristics in validation cohorts (Two-tiered model Interception positive).Table 44: ILR for IBP stratification scale (3 categories).

[0308] The two scales and their respective intervals are combined and classified using the two tables, interception and stratification. Table 45 illustrates the distribution of IBD in the subjects in Tier 1.Table 45: ILR for Two-tiered model Interception scale (3 intervals).

[0309] Table 46-48 illustrates the distribution of IBD in the subjects testing positive in Tier 1 and broken down by a positive or negative for two-tiered model stratification. UC (Ulcerative Colitis) becomes increasingly dominant as the Tier 1 likelihood and tier 2 positivity increase. CD especially ileal and ileocolonic types, are more prevalent in the Tier 1 medium likelihood negative tier 2 group. CD is more likely in the tier 1 medium likelihood, negative tier 2 group. UC is strongly associated with tier 2 positivity, especially in the tier 1 higher likelihood group. The higher tier 1 likelihood, negative tier 2 group is inconclusive, with a near-even split. Ileal involvement is dominant in the tier 1 medium likelihood, negative tier 2 group. Colonic involvement is strongly associated with tier 2 positivity. The higher likelihood, negative tier 2 group again appears mixed, suggesting diagnostic uncertainty.Table 46: Distribution of IBP type by Interception / Stratification,Table 47: Distribution of UC and CD by Intercept! on / Stratificati on.Table 48: Distribution of location by Intercept! on / Stratificati on.

[0310] An exemplary test report is shown in Table 49. Diagnosis and stratification can be further confirmed with ultrasound or colonoscopy.Table 49: Exemplary test report.

[0311] The two scales and their respective intervals are combined and classified using Tables 46-47, corresponding to interception and stratification. Exemplary distribution is shown in Table 48 specimen reporting for IBD results determined by the two-tiered model are shown in Tables 49-50.Microbial Antibodies and CD Complications

[0312] Microbial antibodies such as ASCA and OmpC have been implicated in the pathogenesis and progression of Crohn’s disease (CD). The relationship between antibody count (ASCA, IgG, ASCA IgG and OMPC IgA positives) and complications (stricturing or penetration behavior) was examined. The prognostic significance of microbial antibody profiles in relation to complication in CD and UC was evaluated, demonstrating a correlation between the number of the three microbial antibodies and the likelihood of complicated CD disease (FIG. 24).EQUIVALENTS AND SCOPE, INCORPORATION BY REFERENCE

[0313] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. It is understood that modifications which do not substantially affect the activity of the various embodiments of this disclosure are also provided within the description of the disclosure provided herein. The scope of the present disclosure is not intended to be limited to the above description, but rather is as set forth in the appended claims.

[0314] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure also includes embodiments in which more than one, or all of the group members, are present in, employed in, or otherwise relevant to a given product or process.

[0315] Furthermore, it is to be understood that the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the claims or from relevant portions of the description is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Furthermore, where the claims recite a composition, it is to be understood that methods of using the composition for any of the purposes disclosed herein are included, and methods of making the composition according to any of the methods of making disclosed herein or other methods known in the art areincluded, unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise.

[0316] Where elements are presented as lists, e.g., in Markush group format, it is to be understood that each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should be understood that, in general, where the disclosure, or aspects of the embodiments, is / are referred to as that includes particular elements, features, steps, etc., certain embodiments of the disclosure or aspects of the embodiments consist, or consist essentially of, such elements, features, steps, etc. Thus, for each embodiment of the disclosure that includes one or more elements, features, steps, etc., the disclosure also provides embodiments that consist or consist essentially of those elements, features, steps, etc.

[0317] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and / or the understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. It is also to be understood that unless otherwise indicated or otherwise evident from the context and / or the understanding of one of ordinary skill in the art, values expressed as ranges can assume any subrange within the given range, wherein the endpoints of the subrange are expressed to the same degree of accuracy as the tenth of the unit of the lower limit of the range.

[0318] In addition, it is to be understood that any particular embodiment of the present disclosure may be explicitly excluded from any one or more of the claims. Where ranges are given, any value within the range may explicitly be excluded from any one or more of the claims. Any embodiment, element, feature, application, or aspect of the compositions and / or methods of the disclosure, can be excluded from any one or more claims. For purposes of brevity, all of the embodiments in which one or more elements, features, purposes, or aspects is excluded are not set forth explicitly herein.

[0319] Throughout this disclosure various publications, patents, and sequence database entries are mentioned. The disclosures of these publications, patents, and sequence database entries, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0320] Although the disclosure has been described with reference to the examples provided above, it should be understood that various modifications can be made without departing from the scope of the disclosure. Accordingly, the above examples are intended to illustrate but not limit the present disclosure.

Claims

CLAIMSWhat is claimed is:

1. A method of diagnosing inflammatory bowel disease (IBD) in a subject, the method comprising: a. in a sample obtained from the subject, i. detecting the presence or level of one or more immune response to microbial antigens, wherein the one or more immune response to microbial antigens include two or more of at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response, and ii. detecting the presence or level of one or more immune response to self antigens; b. determining (i) a first score based on the presence or level of the one or more immune response to microbial antigens, and (ii) a second score based on the presence or level of the one or more immune response to self antigens; c. diagnosing the subject with IBD based on the first and second scores.

2. The method of claim 1, wherein the one or more immune response to microbial antigens comprises at least one anti-yeast immune response and at least one anti- flagellar immune response.

3. The method of claim 1, wherein the one or more immune response to microbial antigens comprises at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response.

4. The method of any one of claims 1-3, wherein the presence or level of at least one anti-yeast immune response comprises an anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response, an anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response, or a combination thereof.

5. The method of any one of claims 1-4, wherein the presence or level of at least one anti-flagellar immune response comprises an anti-FLAX immune response, an anti- CBIR-1 immune response, an anti-FLA2 immune response, or any combination thereof.

6. The method of claim 5, wherein the presence or level of at least one anti-flagellar immune response comprises the anti-CBIR-1 immune response.

7. The method of any one of claims 1-6, wherein the presence or level of at least one anti-bacterial immune response comprises an anti-E. coli OMPC immune response.

8. The method of any one of claims 1-8, wherein the presence or level of the one or more immune response to microbial antigens is above a cutoff.

9. The method of claim 8, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 11.9 units / mL.

10. The method of claim 8, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 10.8 units / mL.

11. The method of claim 8, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9.2 units / mL.

12. The method of claim 8, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 20.4 units / mL.

13. The method of claim 8, wherein the cutoff for the anti-OMPC immune response is about 6.0 units / mL14. The method of claim 8, wherein the cutoff for the anti-FLAX immune response is about 36.0 units / mL.

15. The method of claim 8, wherein the cutoff for the anti-FLAX immune response is about 36.6 units / mL.

16. The method of claim 8, wherein the cutoff for the anti-CBIR-1 immune response is about 35.4 units / mL.

17. The method of claim 8, wherein the cutoff for the anti-CBIR-1 immune response is about 53.8 units / mL.

18. The method of claim 8, wherein the cutoff for the anti-FLA2 immune response is about 32.4 units / mL.

19. The method of claim 8, wherein the cutoff for the anti-FLA2 immune response is about 38.9 units / mL.

20. The method of any one of claims 1-19, wherein the one or more immune response to self antigens comprises at least one of an anti -proteinase 3 (anti-PR3) immune response, a perinuclear anti-neutrophil cytoplasmic antibody (pANCA) immune response, an anti-integrin immune response or any combination thereof.

21. The method of claim 20, wherein the one or more immune response to self antigens comprises the anti-PR3 immune response, and the anti-integrin immune response.

22. The method of claim 20, wherein the one or more immune response to self antigens comprises the pANCA immune response, and the anti-integrin immune response.

23. The method of any one of claims 20-22, wherein the presence or level of the one or more immune response to self antigens is above a cutoff.

24. The method of claim 23, wherein the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 2.5 units / mL.

25. The method of claim 23, wherein the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 20.0 units.

26. The method of claim 23, wherein the cutoff for the pANCA immune response is about 2 on an intensity scale ranging from 0 to 4.

27. The method of claim 23, wherein the cutoff for the pANCA immune response is about 1 on an intensity scale ranging from 0 to 4.

28. The method of claim 23, wherein the cutoff for the anti-integrin immune response is about 5 units / mL.

29. The method of claim 23, wherein the cutoff for the anti-integrin immune response is about 3.1 units / mL.

30. The method of any one of claims 1-29, wherein the first score is calculated on a scale of 0 to 5 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

31. The method of any one of claims 1-30, wherein the second score is calculated on a scale of 0 to -3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

32. The method of any one of claims 1-31, wherein the subject is not diagnosed with IBD if the first score and the second score have a value of 0.

33. The method of any one of claims 1-31, wherein the subject is diagnosed with IBD if the first score and / or the second score are different than 0.

34. The method of any one of claims 1-33, further comprising diagnosing the subject with a clinical subtype of IBD.

35. The method of claim 34, wherein the subject is diagnosed with Crohn’s disease (CD) if the first score is different than 0, and the second score has a value greater than 0.

36. The method of claim 35, wherein the first score is at least 2.

37. The method of claim 35, wherein the first score is at least 3.

38. The method of claim 34, wherein the subject is diagnosed with ulcerative Colitis (UC) if the second score is different than 0, and the first score has a value of lesser than 0.

39. The method of claim 38, wherein the second score is at least -2.

40. The method of claim 38, wherein the second score is -3.

41. The method of claim 34, wherein the subject is diagnosed with undifferentiated IBD if the first score and the second score are different than 0.

42. The method of any one of claims 1-41, wherein the method further comprises determining a composite score based on the first and the second scores.

43. The method of claim 42, wherein determining the composite score comprises the addition of the first and the second scores.

44. The method of claim 42 or 43, wherein the subject is diagnosed with seronegative IBD or undifferentiated seropositive IBD if the composite score is 0.

45. The method of any one of claims 1-29, wherein the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

46. The method of any one of claims 1-29 and 45, wherein the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

47. The method of claim 45 or 46, wherein the method further comprises determining an interception score based on the first and the second scores.

48. The method of claim 47, wherein determining the interception score comprises the addition of the first and the second scores.

49. The method of claim 48, wherein the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0.

50. The method of claim 48, wherein the subject is diagnosed as having medium likelihood of IBD if the interception score has a value of 0 to 2.

51. The method of claim 48, wherein the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12.

52. The method of any one of claims 45-51, further comprising diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD.

53. The method of claim 52, wherein the method comprises adding the negative value of the first score and the second score to determine a stratification score.

54. The method of claim 53, wherein the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1.

55. The method of claim 53, wherein the subject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1.

56. The method of claim 53, wherein the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1.

57. The method of claim 53, wherein the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1.

58. The method of claim 53, wherein the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4.

59. A method of classifying a clinical subtype of inflammatory bowel disease (IBD) in a subject having IBD, the method comprising: a. in a sample from the subject, i. detecting the presence or level of one or more immune response to microbial antigens, wherein the one or more immune response to microbial antigens include two or more of at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response, and ii. detecting the presence or level of one or more immune response to self antigens; b. calculating (i) a first score based on the presence or level of the one or more immune response to microbial antigens, and (ii) a second score based on the presence or level of the one or more immune response to self antigens; c. classifying a clinical subtype of IBD in the subject based on the first and second scores.

60. The method of claim 59, wherein the one or more immune response to microbial antigens comprises at least one anti-yeast immune response and at least one anti- flagellar immune response.

61. The method of claim 59, wherein the one or more immune response to microbial antigens comprises at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response.

62. The method of any one of claims 59-61, wherein the clinical subtype of IBD is Ulcerative Colitis (UC), Crohn’s disease (CD), or undifferentiated IBD.

63. The method of any one of claims 59-62, wherein the presence or level of at least one anti-yeast immune response comprises an anti-Saccharomyces cerevisiaeimmunoglobulin IgA (ASCA-IgA) immune response, an anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response, or a combination thereof.

64. The method of any one of claims 59-63, wherein the presence or level of at least one anti-flagellar immune response comprises an anti-FLAX immune response, an anti- CBIR-1 immune response, an anti-FLA2 immune response, or any combination thereof.

65. The method of claim 64, wherein the presence or level of at least one anti-flagellar immune response comprises the anti-CBIR-1 immune response.

66. The method of any one of claims 59-65, wherein the presence or level of at least one anti-bacterial immune response comprises an anti-E. coli OMPC immune response.

67. The method of any one of claims 59-66, wherein the presence or level of the one or more immune response to microbial antigens is above a cutoff.

68. The method of claim 67, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 11.9 units / mL.

69. The method of claim 67, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 10.8 units / mL.

70. The method of claim 67, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9.2 units / mL.

71. The method of claim 67, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 20.4 units / mL.

72. The method of claim 67, wherein the cutoff for the anti-OMPC immune response is about 6.0 units / mL73. The method of claim 67, wherein the cutoff for the anti-FLAX immune response is about 36.0 units / mL.

74. The method of claim 67, wherein the cutoff for the anti-FLAX immune response is about 36.6 units / mL.

75. The method of claim 67, wherein the cutoff for the anti-CBIR-1 immune response is about 35.4 units / mL.

76. The method of claim 67, wherein the cutoff for the anti-CBIR-1 immune response is about 53.8 units / mL.

77. The method of claim 67, wherein the cutoff for the anti-FLA2 immune response is about 32.4 units / mL.

78. The method of claim 67, wherein the cutoff for the anti-FLA2 immune response is about 38.9 units / mL.

79. The method of any one of claims 59-78, wherein the one or more immune response to self antigens comprises at least one of an anti -proteinase 3 (anti-PR3) immune response, an perinuclear anti-neutrophil cytoplasmic immune response (pANCA), and an anti-integrin immune response, or any combination thereof.

80. The method of claim 79, wherein the one or more immune response to self antigens comprises the anti-PR3 immune response, and the anti-integrin immune response.

81. The method of claim 80, wherein the one or more immune response to self antigens comprises the pANCA immune response, and the anti-integrin immune response.

82. The method of any one of claims 79-81, wherein the presence or level of the one or more immune response to self antigens is above a cutoff.

83. The method of claim 82, wherein the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 2.5 units / mL.

84. The method of claim 82, wherein the cutoff for the anti-proteinase 3 (anti-PR3) immune response is about 20.0 units85. The method of claim 82, wherein the cutoff for the perinuclear anti-neutrophil cytoplasmic immune response (pANCA) is about 2 on an intensity scale ranging from 0 to 4.

86. The method of claim 82, wherein the cutoff for the pANCA immune response is about 1 on an intensity scale ranging from 0 to 4.

87. The method of claim 82, wherein the cutoff for the anti-integrin immune response is about 5 units / mL.

88. The method of claim 82, wherein the cutoff for the anti-integrin immune response is about 3.1 units / mL.

89. The method of any one of claims 59-88, wherein the first score is calculated on a scale of 0 to 5 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

90. The method of any one of claims 59-89, wherein the second score is calculated on a scale of 0 to -3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

91. The method of any one of claims 59-90, wherein the IBD is classified as Crohn’s disease (CD) if the first score is different than 0, and the second score has a value of 0.

92. The method of claim 91, wherein the first score is at least 2.

93. The method of claim 91, wherein the first score is at least 3.

94. The method of any one of claims 59-93, wherein the IBD is classified as Ulcerative Colitis (UC) if the second score is different than 0, and the first score has a value of 0.

95. The method of claim 94, wherein the second score is at least -2.

96. The method of claim 94, wherein the second score is -3.

97. The method of any one of claims 69-96, wherein the IBD is classified as undifferentiated IBD if the first score and the second score are different than 0.

98. The method of any one of claims 59-97, wherein the method further comprises determining a composite score based on the first and the second scores.

99. The method of claim 98, wherein determining the composite score comprises the addition of the first and the second scores.

100. The method of claim 98 or 99, wherein the subject is diagnosed with seronegative IBD or undifferentiated seropositive IBD if the composite score is 0.

101. The method of any one of claims 59-88, wherein the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

102. The method of any one of claims 59-88 and 101, wherein the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

103. The method of claim 101 or 102, wherein the method further comprises determining an interception score based on the first and the second scores.

104. The method of claim 103, wherein determining the interception score comprises the addition of the first and the second scores.

105. The method of claim 104, wherein the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0.

106. The method of claim 104, wherein the subject is diagnosed as having medium likelihood of IBD if the interception score has a value of 0 to 2.

107. The method of claim 104, wherein the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12.

108. The method of any one of claims 101-107, further comprising diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD.

109. The method of claim 108, wherein the method comprises adding the negative value of the first score and the second score to determine a stratification score.

110. The method of claim 109, wherein the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1.

111. The method of claim 109, wherein the subject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1.

112. The method of claim 109, wherein the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1.

113. The method of claim 109, wherein the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1.

114. The method of claim 109, wherein the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4.

115. A method of treating a subject having inflammatory bowel disease (IBD), the method comprising: a. in a sample from the subject, i. detecting the presence or level of one or more immune response to microbial antigens, wherein the one or more immune response to microbial antigens include two or more of at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response, and ii. detecting the presence or level of one or more immune response to self antigens; b. calculating (i) a first score based on the presence or level of the one or more immune response to microbial antigens, and (ii) a second score based on the presence or level of the one or more; and c. administering an IBD-therapeutic agent to the subject based on the first and second scores.

116. The method of claim 115, wherein the one or more immune response to microbial antigens comprises at least one anti-yeast immune response and at least one anti-flagellar immune response.

117. The method of claim 115, wherein the one or more immune response to microbial antigens comprises at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response.

118. The method of any one of claims 115-117, wherein the IBD is Ulcerative Colitis (UC), Crohn’s disease (CD), or undifferentiated IBD.

119. The method of any one of claim 115-118, wherein the presence or level of at least one anti-yeast immune response comprises an anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response, an anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response, or a combination thereof.

120. The method of any one of claims 115-119, wherein the presence or level of at least one anti-flagellar immune response comprises an anti-FLAX immune response, an anti-CBIR-1 immune response, an anti-FLA2 immune response, or any combination thereof.

121. The method of claim 120, wherein the presence or level of at least one anti- flagellar immune response comprises the anti-CBIR-1 immune response.

122. The method of any one of claims 115-121, wherein the presence or level of at least one anti-bacterial immune response comprises an anti- / :. coli OMPC immune response.

123. The method of any one of claims 115-122, wherein the presence or level of the one or more immune response to microbial antigens is above a cutoff.

124. The method of claim 123, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 11.9 units / mL.

125. The method of claim 123, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 10.8 units / mL.

126. The method of claim 123, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9.2 units / mL.

127. The method of claim 123, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 20.4 units / mL.

128. The method of claim 123, wherein the cutoff for the anti-OMPC immune response is about 6.0 units / mL129. The method of claim 123, wherein the cutoff for the anti-FLAX immune response is about 36.0 units / mL.

130. The method of claim 123, wherein the cutoff for the anti-FLAX immune response is about 36.6 units / mL.

131. The method of claim 123, wherein the cutoff for the anti-CBIR-1 immune response is about 35.4 units / mL.

132. The method of claim 123, wherein the cutoff for the anti-CBIR-1 immune response is about 53.8 units / mL.

133. The method of claim 123, wherein the cutoff for the anti -FL A2 immune response is about 32.4 units / mL.

134. The method of claim 123, wherein the cutoff for the anti-FLA2 immune response is about 38.9 units / mL.

135. The method of any one of claims 115-134, wherein the one or more immune response to self antigens comprises at least one of an anti-proteinase 3 (anti-PR3) immune response, an perinuclear anti-neutrophil cytoplasmic immune response (pANCA), an anti-integrin immune response, or any combination thereof.

136. The method of claim 135, wherein the one or more immune response to self antigens comprises the anti-PR3 immune response, and the anti-integrin immune response.

137. The method of claim 135, wherein the one or more immune response to self antigens comprises the pANCA immune response, and the anti-integrin immune response.

138. The method of any one of claims 135-137, wherein the presence or level of the one or more immune response to self antigens is above a cutoff.

139. The method of claim 138, wherein the cutoff for the anti-proteinase 3 (anti- PR3) immune response is about 2.5 units / mL.

140. The method of claim 138, wherein the cutoff for the anti-proteinase 3 (anti- PR3) immune response is about 20.0 units.

141. The method of claim 138, wherein the cutoff for the perinuclear antineutrophil cytoplasmic immune response (pANCA) is about 2 on an intensity scale ranging from 0 to 4.

142. The method of claim 138, wherein the cutoff for the pANCA immune response is about 1 on an intensity scale ranging from 0 to 4.

143. The method of claim 138, wherein the cutoff for the anti-integrin immune response is about 5 units / mL.

144. The method of claim 138, wherein the cutoff for the anti-integrin immune response is about 3.1 units / mL.

145. The method of any one of claims 115-144, wherein the first score is calculated on a scale of 0 to 5 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

146. The method of any one of claims 115-145, wherein the second score is calculated on a scale of 0 to -3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

147. The method of any one of claims 115-146, wherein the subject is administered a Crohn’s disease (CD)-therapeutic agent if the first score is different than 0, and the second score has a value of 0.

148. The method of claim 147, wherein the first score is at least 2.

149. The method of claim 147, wherein the first score is at least 3.

150. The method of any one of claims 115-144, wherein the subject is administered an Ulcerative Colitis (UC)-therapeutic agent if the second score is different than 0, and the first score has a value of 0.

151. The method of claim 150, wherein the second score is at least -2.

152. The method of claim 150, wherein the second score is -3.

153. The method of any one of claims 115-144, wherein the subject is administered an undifferentiated IBD-therapeutic agent if the first score and the second score are different than 0.

154. The method of any one of claims 115-153, further comprising stopping treatment of the subject with the IBD-therapeutic agent if the first score and second score have a value of 0.

155. The method of any one of claims 115-154, wherein the method further comprises determining a composite score based on the first and the second scores.

156. The method of claim 155, wherein determining the composite score comprises the addition of the first and the second scores.

157. The method of claim 155 or 156, the administering of the IBD therapeutic agent is based on the composite score.

158. The method of any one of claims 115-144, wherein the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

159. The method of any one of claims 115-144 and 158, wherein the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

160. The method of claim 158 or 159, wherein the method further comprises determining an interception score based on the first and the second scores.

161. The method of claim 160, wherein determining the interception score comprises the addition of the first and the second scores.

162. The method of claim 161, wherein the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0.

163. The method of any one of claim 161, wherein the subject is diagnosed as having medium likelihood of IBD if the interception score has a value of 0 to 2.

164. The method of claim 161, wherein the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12.

165. The method of claim 163 or 164, wherein the subject is administered an IBD- therapeutic agent.

166. The method of any one of claims 158-165, further comprising diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD.

167. The method of claim 166, wherein the method comprises adding the negative value of the first score and the second score to determine a stratification score.

168. The method of claim 167, wherein the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1.

169. The method of claim 167, wherein the subject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1.

170. The method of claim 167, wherein the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1.

171. The method of claim 167, wherein the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1.

172. The method of claim 167, wherein the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4.

173. The method of any one of claims 169-171, wherein the subject is administered a Crohn’s disease (CD)-therapeutic agent.

174. The method of claim 172, wherein the subject is administered an Ulcerative Colitis (UC)-therapeutic agent.

175. The method of claim 168, wherein the subject is administered an undifferentiated IBD-therapeutic agent176. The method of any one of claims 165 and 173-175, further comprising stopping treatment of the subject with the therapeutic agent if the interception score has a value of 0 or lower.

177. The method of any one of claims 115-176, wherein the IBD-therapeutic agent targets at least one pathway selected from an Tumor Necrosis Factor (TNF) pathway, an interleukin- 12 (IL-12) pathway, an interleukin-23 (IL-23) pathway, a sphingosine- 1 -phosphate pathway, or a j anus kinase (JAK) pathway.

178. The method of any one of claims 115-177, wherein the IBD therapeutic agent comprises infliximab (IFX), adalimumab (ADA), ustekinumab (UST), mirikizumab, guselkumab, ozanimod, etrasimod, upadacitinib, ivarmacitinib, or a biosimilar thereof.

179. A method for selecting a subject having inflammatory bowel disease (IBD) for treatment with an IBD-therapeutic agent, the method comprising: a. in a sample from the subject, i. detecting the presence or level of one or more immune response to microbial antigens, wherein the one or more immune response to microbial antigens include two or more of at least one anti-yeastimmune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response, and ii. detecting the presence or level of one or more immune response to self antigens; b. calculating (i) a first score based on the presence or level of the one or more immune response to microbial antigens, and (ii) a second score based on the presence or level of the one or more; and c. selecting the subject for treatment with the IBD-therapeutic agent based on the first and second scores.

180. The method of claim 179, wherein the one or more immune response to microbial antigens comprises at least one anti-yeast immune response and at least one anti-flagellar immune response.

181. The method of claim 179, wherein the one or more immune response to microbial antigens comprises at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response..

182. The method of any one of claims 179-181, wherein the IBD is Ulcerative Colitis (UC), Crohn’s disease (CD), or undifferentiated IBD.

183. The method of any one of claims 179-182, wherein the presence or level of at least one anti-yeast immune response comprises an anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response, an anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response, or a combination thereof.

184. The method of any one of claims 179-183, wherein the presence or level of at least one anti-flagellar immune response comprises an anti-FLAX immune response, an anti-CBIR-1 immune response, an anti-FLA2 immune response, or any combination thereof.

185. The method of claim 184, wherein the presence or level of at least one anti- flagellar immune response comprises the anti-CBIR-1 immune response.

186. The method of any one of claims 179-185, wherein the presence or level of at least one anti-bacterial immune response comprises an anti- / :. coli OMPC immune response.

187. The method of any one of claims 179-186, wherein the presence or level of the one or more immune response to microbial antigens is above a cutoff.

188. The method of claim 187, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 11.9 units / mL.

189. The method of claim 187, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 10.8 units / mL.

190. The method of claim 187, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9.2 units / mL.

191. The method of claim 187, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 20.4 units / mL.

192. The method of claim 187, wherein the cutoff for the anti-OMPC immune response is about 6.0 units / mL193. The method of claim 187, wherein the cutoff for the anti -FLAX immune response is about 36.0 units / mL.

194. The method of claim 187, wherein the cutoff for the anti -FLAX immune response is about 36.6 units / mL.

195. The method of claim 187, wherein the cutoff for the anti-CBIR-1 immune response is about 35.4 units / mL.

196. The method of claim 187, wherein the cutoff for the anti-CBIR-1 immune response is about 53.8 units / mL.

197. The method of claim 187, wherein the cutoff for the anti-FLA2 immune response is about 32.4 units / mL.

198. The method of claim 187, wherein the cutoff for the anti -FL A2 immune response is about 38.9 units / mL.

199. The method of any one of claims 179-198, wherein the one or more immune response to self antigens comprises at least one of an anti-proteinase 3 (anti-PR3) immune response, an perinuclear anti-neutrophil cytoplasmic immune response (pANCA), an anti-integrin immune response, or any combination thereof.

200. The method of claim 199, wherein the one or more immune response to self antigens comprises the anti-PR3 immune response, and the anti-integrin immune response.

201. The method of claim 199, wherein the one or more immune response to self antigens comprises the pANCA immune response, and the anti-integrin immune response.

202. The method of any one of claims 199-201, wherein the presence or level of the one or more immune response to self antigens is above a cutoff.

203. The method of claim 202, wherein the cutoff for the anti-proteinase 3 (anti- PR3) immune response is about 2.5 units / mL.

204. The method of claim 202, wherein the cutoff for the anti-proteinase 3 (anti- PR3) immune response is about 20.0 units.

205. The method of claim 202, wherein the cutoff for the perinuclear antineutrophil cytoplasmic immune response (pANCA) is about 2 on an intensity scale ranging from 0 to 4.

206. The method of claim 202, wherein the cutoff for the pANCA immune response is about 1 on an intensity scale ranging from 0 to 4.

207. The method of claim 202, wherein the cutoff for the anti-integrin immune response is about 5 units / mL.

208. The method of claim 202, wherein the cutoff for the anti-integrin immune response is about 3.1 units / mL.

209. The method of any one of claims 179-208, wherein the first score is calculated on a scale of 0 to 5 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

210. The method of any one of claims 179-209, wherein the second score is calculated on a scale of 0 to -3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

211. The method of any one of claims 179-210, wherein the subject is selected for treatment with the IBD therapeutic agent if the first score and second score are different than 0.

212. The method of any one of claims 209-211, wherein the subject is selected for treatment with a Crohn’s disease (CD) therapeutic agent if the first score is different than 0, and the second score has a value of 0.

213. The method of claim 212, wherein the first score is at least 2.

214. The method of claim 212, wherein the first score is at least 3.

215. The method of any one of claims 209-211, wherein the subject is selected for treatment with an Ulcerative Colitis (UC) therapeutic agent if the second score is different than 0, and the first score has a value of 0.

216. The method of claim 215, wherein the second score is at least -2.

217. The method of claim 215, wherein the second score is -3.

218. The method of any one of claims 209-211, wherein the subject is selected for treatment with the IBD therapeutic agent if the first score and the second score are different than 0.

219. The method of any one of claims 179-218, wherein the subject is not selected for treatment with the IBD therapeutic agent if the first score and second score have a value of 0.

220. The method of any one of claims 179-219, wherein the method further comprises determining a composite score based on the first and the second scores.

221. The method of claim 220, wherein determining the composite score comprises the addition of the first and the second scores.

222. The method of claim 220-221, wherein the subject is selected for treatment with the IBD therapeutic agent based on the composite score.

223. The method of any one of claims 179-208, wherein the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

224. The method of any one of claims 179-208 and 223, wherein the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

225. The method of claim 223 or 224, wherein the method further comprises determining an interception score based on the first and the second scores.

226. The method of claim 225, wherein determining the interception score comprises the addition of the first and the second scores.

227. The method of claim 226, wherein the subject is diagnosed as having low likelihood of IBD if the interception score has a value of 0.

228. The method of claim 226, wherein the subject is diagnosed as having medium likelihood of IBD if the interception score has a value of 0 to 2.

229. The method of claim 226, wherein the subject is diagnosed as having high likelihood of IBD if the interception score has a value of 2 to 12.

230. The method of claim 228 or 229, wherein the subject is selected for treatment with an IBD-therapeutic agent.

231. The method of any one of claims 223-230, further comprising diagnosing the subject with a clinical subtype of IBD in a subject identified as having a likelihood of IBD.

232. The method of claim 231, wherein the method comprises adding the negative value of the first score and the second score to determine a stratification score.

233. The method of claim 232, wherein the subject is diagnosed as having medium likelihood of an inconclusive IBD subtype if the interception score has a value of 0 to 2, and the stratification score has a value of -1 to 1.

234. The method of claim 232, wherein the subject is diagnosed as having medium likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 0 to 2, and the stratification score has a value of -5 to 1.

235. The method of claim 232, wherein the subject is diagnosed as having high likelihood of Crohn’s disease (CD) with ileal location if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1.

236. The method of claim 232, wherein the subject is diagnosed as having high likelihood of an inconclusive Crohn’s disease (CD) with mixed pattern if the interception score has a value of 2 to 12, and the stratification score has a value of -5 to 1.

237. The method of claim 323, wherein the subject is diagnosed as having high likelihood of Ulcerative Colitis (UC) with colonic location if the interception score has a value of 2 to 12, and the stratification score has a value of 2 to 4.

238. The method of any one of claims 234-236, wherein the subject is selected for treatment with a Crohn’s disease (CD)-therapeutic agent.

239. The method of claim 237, wherein the subject is selected for treatment with an Ulcerative Colitis (UC)-therapeutic agent.

240. The method of claim 233, wherein the subject is selected for treatment with an undifferentiated IBD-therapeutic agent241. The method of any one of claims 179-240, further comprising administering the IBD therapeutic agent to the subject.

242. The method of any one of claims 179-241, wherein the IBD-therapeutic agent targets at least one pathway selected from an Tumor Necrosis Factor (TNF) pathway,an interleukin- 12 (IL-12) pathway, an interleukin-23 (IL-23) pathway, a sphingosine- 1 -phosphate pathway, or a j anus kinase (JAK) pathway.

243. The method of any one of claims 179-242, wherein the IBD therapeutic agent comprises infliximab (IFX), adalimumab (ADA), ustekinumab (UST), mirikizumab, guselkumab, ozanimod, etrasimod, upadacitinib, ivarmacitinib, or a biosimilar thereof.

244. A method for monitoring the effectiveness of an inflammatory bowel disease (IBD)-therapeutic agent in a subject with IBD, the method comprising: a. in a sample from the subject, i. detecting the presence or level of one or more immune response to microbial antigens, wherein the one or more immune response to microbial antigens include two or more of at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response, and ii. detecting the presence or level of one or more immune response to self antigens; b. calculating (i) a first score based on the presence or level of the one or more immune response to microbial antigens, and (ii) a second score based on the presence or level of the one or more; and c. adjusting the amount of IBD therapeutic agent being administered to the subject, based on the first and second scores.

245. The method of claim 244, wherein the one or more immune response to microbial antigens comprises at least one anti-yeast immune response and at least one anti-flagellar immune response.

246. The method of claim 244, wherein the one or more immune response to microbial antigens comprises at least one anti-yeast immune response, at least one anti-flagellar immune response, and at least one anti-bacterial immune response.

247. The method of any one of claims 244-246, wherein the IBD is Ulcerative Colitis (UC), Crohn’s disease (CD), or undifferentiated IBD.

248. The method of any one of claims 244-247, wherein the presence or level of at least one anti-yeast immune response comprises an anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response, an anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response, or a combination thereof.

249. The method of any one of claims 244-248, wherein the presence or level of at least one anti-flagellar immune response comprises an anti-FLAX immune response, an anti-CBIR-1 immune response, an anti-FLA2 immune response, or any combination thereof.

250. The method of claim 249, wherein the presence or level of at least one anti- flagellar immune response comprises the anti-CBIR-1 immune response.

251. The method of any one of claims 244-250, wherein the presence or level of at least one anti-bacterial immune response comprises an anti -A", coli OMPC immune response.

252. The method of any one of claims 244-251, wherein the presence or level of the one or more immune response to microbial antigens is above a cutoff.

253. The method of claim 252, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 11.9 units / mL.

254. The method of claim 252, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgA (ASCA-IgA) immune response is about 10.8 units / mL.

255. The method of claim 252, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 9.2 units / mL.

256. The method of claim 252, wherein the cutoff for the anti-Saccharomyces cerevisiae immunoglobulin IgG (ASCA- IgG) immune response is about 20.4 units / mL.

257. The method of claim 252, wherein the cutoff for the anti-OMPC immune response is about 6.0 units / mL258. The method of claim 252, wherein the cutoff for the anti-FLAX immune response is about 36.0 units / mL.

259. The method of claim 252, wherein the cutoff for the anti-FLAX immune response is about 36.6 units / mL.

260. The method of claim 252, wherein the cutoff for the anti-CBIR-1 immune response is about 35.4 units / mL.

261. The method of claim 252, wherein the cutoff for the anti-CBIR-1 immune response is about 53.8 units / mL.

262. The method of claim 252, wherein the cutoff for the anti-FLA2 immune response is about 32.4 units / mL.

263. The method of claim 252, wherein the cutoff for the anti-FLA2 immune response is about 38.9 units / mL.

264. The method of any one of claims 244-263, wherein the one or more immune response to self antigens comprises at least one of an anti-proteinase 3 (anti-PR3) immune response, an perinuclear anti-neutrophil cytoplasmic immune response (pANCA), an anti-integrin immune response, or any combination thereof.

265. The method of claim 264, wherein the one or more immune response to self antigens comprises the anti-PR3 immune response, and the anti-integrin immune response.

266. The method of claim 264, wherein the one or more immune response to self antigens comprises the pANCA immune response, and the anti-integrin immune response.

267. The method of any one of claims 264-266, wherein the presence or level of the one or more immune response to self antigens is above a cutoff.

268. The method of claim 267, wherein the cutoff for the anti-proteinase 3 (anti- PR3) immune response is about 2.5 units / mL.

269. The method of claim 267, wherein the cutoff for the anti-proteinase 3 (anti- PR3) immune response is about 20.0 units.

270. The method of claim 267, wherein the cutoff for the perinuclear antineutrophil cytoplasmic immune response (pANCA) is about 2 on an intensity scale ranging from 0 to 4.

271. The method of claim 267, wherein the cutoff for the pANCA immune response is about 1 on an intensity scale ranging from 0 to 4.

272. The method of claim 267, wherein the cutoff for the anti-integrin immune response is about 5 units / mL.

273. The method of claim 267, wherein the cutoff for the anti-integrin immune response is about 3.1 units / mL.

274. The method of any one of claims 244-273 wherein the first score is calculated on a scale of 0 to 5 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

275. The method of any one of claims 244-274, wherein the second score is calculated on a scale of 0 to -3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

276. The method of any one of claims 244-275, wherein the amount of the IBD- therapeutic agent being administered to the subject is increased if the first score and second score are different than 0.

277. The method of any one of claims 244-276, wherein the amount of the IBD- therapeutic agent being administered to the subject is decreased if the first score and second score have a value of 0.

278. The method of any one of claims 244-277, wherein the method further comprises determining a composite score based on the first and the second scores.

279. The method of claim 278, wherein determining the composite score comprises the addition of the first and the second scores.

280. The method of claim 278 or 279, wherein the amount of the IBD-therapeutic agent being administered to the subject is increased if the composite score has a value different than 0.

281. The method of any one of claims 244-280, wherein the first score is calculated on a scale of 0 to 6 using a statistical model, wherein a first score of 0 is indicative of the absence of the one or more immune response to microbial antigens.

282. The method of any one of claims 244-280 and 281, wherein the second score is calculated on a scale of 0 to 3 using a statistical model, wherein a second score of 0 is indicative of the absence of the one or more immune response to self antigens.

283. The method of claim 281 or 282, wherein the method further comprises determining an interception score based on the first and the second scores.

284. The method of claim 283, wherein determining the interception score comprises the addition of the first and the second scores.

285. The method of claims 284, wherein the amount of the IBD-therapeutic agent being administered to the subject is maintained or increased if the interception score has a value of 0 to 2.

286. The method of claims 284, wherein the amount of the IBD-therapeutic agent being administered to the subject is increased if the interception score has a value of 2 to 12.

287. The method of claims 284, wherein the amount of the IBD-therapeutic agent being administered to the subject is decreased if the interception score has a value of 0 or lower.

288. The method of any one of claims 244-287, wherein the IBD-therapeutic agent targets at least one pathway selected from a Tumor Necrosis Factor (TNF) pathway, an interleukin- 12 (IL-12) pathway, an interleukin-23 (IL-23) pathway, a sphingosine- 1 -phosphate pathway, or a j anus kinase (JAK) pathway.

289. The method of any one of claims 244-288, wherein the IBD therapeutic agent comprises infliximab (IFX), adalimumab (ADA), ustekinumab (UST), mirikizumab, guselkumab, ozanimod, etrasimod, upadacitinib, ivarmacitinib, or a biosimilar thereof.

290. The method of any one of claims 1-289, wherein the presence or level of the one or more immune response to microbial antigens and / or the one or more immune response to self antigens is detected with a hybridization assay, an amplification-based assay, an immunoassay, or an immunohistochemical assay.

291. The method of any one of claims 1-290, wherein the sample is selected from the group consisting of serum, plasma, whole blood, and stool.

292. The method of any one of claims 1-291, wherein the subject is a human subject.

293. The method of any one of claims 1-292, wherein the statistical model used to calculate the first score and / or the second score comprises logistic regression.

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