Short chain fatty acid compounds and uses thereof

Abstract

The present disclosure describes methods comprising obtaining a level of a biomarker in a subject and based on the level of the biomarker in the subject, continuing a short chain fatty acid therapy. The disclosed methods can comprise administering a composition comprising at least one short chain fatty acid. The disclosed methods can be used to treat an inflammatory condition, a skin disorder, or an autoimmune disorder.

Description

SHORT CHAIN FATTY ACID COMPOUNDS AND USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 614,709 filed on December 26, 2023, and U.S. Provisional Application No. 63 / 661,161 filed on June 18, 2024, each of which are incorporated herein by reference in their entirety.BACKGROUND

[0002] Short chain fatty acids (SCFAs) are saturated aliphatic acids consisting of one polar carboxylic acid moiety and hydrophobic hydrocarbon chain. Among these, acetate (C2), propionate (C3) and butyrate (C4) are the most common and well-studied molecules.INCORPORATION BY REFERENCE

[0003] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.SUMMARY OF THE DISCLOSURE

[0004] Disclosed herein is a method comprising: (a) obtaining a level of a biomarker in a subject, wherein the biomarker is an anti-inflammatory cytokine, wherein the subject is undergoing a regimen of short chain fatty acid therapy for an inflammatory condition; and (b) based on the level of the biomarker in the subject, continuing the short chain fatty acid therapy, wherein the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 40% over a period of about four to five days.

[0005] Disclosed herein is a method comprising: (a) administering a therapeutically-effective amount of a short chain fatty acid therapy for an inflammatory condition to a subject in need thereof; (b) after the administering, obtaining a level of a biomarker in a subject, wherein the biomarker is an anti-inflammatory cytokine; and (c) based on the level of the biomarker in the subject, continuing the short chain fatty acid therapy wherein the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 40% over a period of about four to five days.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 shows IL- 10 levels for each subject prior to administration of a SCFA treatment (Visit 1) and following treatment with the SCFA (as Visit 4 or Visit 5).

[0007] FIG. 2 shows representative images from a psoriasis patient undergoing a SCFA treatment regimen from the patient’s feet before and after treatment.

[0008] FIG. 3 shows representative images from a psoriasis patient undergoing a SCFA treatment regimen from the patient’s neck before and after treatment.

[0009] FIG. 4 shows representative images from a psoriasis patient undergoing a SCFA treatment regimen from the patient’s foot before and after treatment.

[0010] FIG. 5 shows representative images from a psoriasis patient undergoing a SCFA treatment regimen from the patient’s arm before and after treatment.

[0011] FIG. 6 shows representative images from a psoriasis patient undergoing a SCFA treatment regimen from the patient’s knee before and after treatment.

[0012] FIG. 7 shows cytokine release of IL- 10 in plasma from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BID p.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0013] FIG. 8 shows cytokine release of IL- 10 in ear skin from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BID p.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0014] FIG. 9 shows cytokine release of IL- 10 in back skin from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BIDp.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0015] FIG. 10 shows cytokine release of IL-23 in plasma from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BID p.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0016] FIG. 11 shows cytokine release of IL-23 in ear skin from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BID p.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0017] FIG. 12 shows cytokine release of IL-23 in back skin from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BID p.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0018] FIG. 13 shows cytokine release of IL-17A in plasma from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BID p.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0019] FIG. 14 shows cytokine release of IL-17A in ear skin from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BIDp.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0020] FIG. 15 shows cytokine release of IL-17A in back skin from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BID p.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0021] FIG. 16 shows cytokine release of TNF-a in ear skin from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BID p.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0022] FIG. 17 shows cytokine release of TNF-a in back skin from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BID p.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0023] FIG. 18 shows cytokine release of IL-22 in ear skin from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BID p.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.

[0024] FIG. 19 shows cytokine release of IL-22 in back skin from healthy control mice (n=4) following administration of vehicle BID p.o., and IMQ-induced psoriasis model mice (n=10) following administration of vehicle BID p.o., 12 mg / kg Otezla® (Apremilast) BID, 25 mg / kg Otezla® (Apremilast) BID, fixed dose SCFA treatment BID p.o., fixed dose SCFA treatment BIDp.o. with 12 mg / kg Apremilast BID, or fixed dose SCFA treatment BID p.o. with 25 mg / kg Apremilast BID.DETAILED DESCRIPTIONShort chain fatty acid (SCFA)

[0025] Short chain fatty acids (SCFAs) are fatty acids with aliphatic tails shorter than aliphatic tails of long chain fatty acids. Short chain fatty acids can be derivatized to provide a salt or ester thereof, for example, pharmaceutically-acceptable salts and esters of fatty acids (e.g., sodium butyrate, arginine butyrate).

[0026] In some embodiments, a composition disclosed herein comprises at least one SCFA. In some embodiments, a composition disclosed herein comprises at least one short chain fatty acid (SCFA), SCFA precursor, SCFA biosynthesis precursor, a derivative thereof, a SCFA moiety, or a combination thereof.

[0027] In some embodiments, a composition disclosed herein comprises at least one SCFA, or a compound comprising a SCFA moiety. In some embodiments, a composition disclosed herein comprises at least two SCFAs. In some embodiments, a composition disclosed herein comprises at least three SCFAs.

[0028] Non-limiting examples of a SCFA or SCFA moiety include: acetic acid, butyric acid (BA), C3-C12 fatty acids, C3-C10 fatty acids, C3-C8 fatty acids, methoxyacetic acid, valproic acid (VP A), propionic acid, 3 -methoxy propionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, N-acetylbutyrate (and other forms of butyrate, e.g., phenylbutyrate, isobutyrate, pivaloyl oxy methyl butyrate, monoacetone glucose 3-butyrate), isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4- hydroxypentanoic acid, 2-ethylhy dracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3- methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3- methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, and a combination thereof.

[0029] Non-limiting examples of a SCFA or a SCFA moiety include: compounds or structures with at least 12 carbon atoms, at least 11 carbon atoms, at least 10 carbon atoms, at least 9 carbon atoms, at least 8 carbon atoms, at least 7 carbon atoms, at least 6 carbon atoms, at least 5 carbon atoms, atleast 4 carbon atoms, at least 3 carbon atoms, and at least 2 carbon atoms. In some embodiments, the SCFA or SCFA moiety includes compounds or structures with no greater than 13 carbon atoms, no greater than 12 carbon atoms, no greater than 11 carbon atoms, no greater than 10 carbon atoms, no greater than 9 carbon atoms, no greater than 8 carbon atoms, or no greater than 7 carbon atoms.

[0030] In some embodiments, a SCFA or SCFA moiety is not a branched fatty acid. In some embodiments, a SCFA or SCFA moiety is a branched fatty acid.

[0031] In some embodiments, short chain fatty acids (SCFAs) modulate a cytokine. Non-limiting examples of cytokines include: TNFa, IFNy, IL-17A, IL-21, IL-22, IL-23, IL-27, IL-31, and MIP- 3a. Additional non-limiting examples of cytokines include: IL-10, IL-2, IL-18, IL-4, IL-12, IL-35, IL-36.

[0032] In some embodiments, the cytokine is a pro-inflammatory cytokine. Non-limiting examples of pro-inflammatory cytokines include: type 1 cytokines, IL-1 (e.g., IL-10), IL-6, IL-8, IL-9, IL-12, IL-15, IL-17, IL-18, IFN-y, and TNF-a. In some embodiments, the cytokine is an anti-inflammatory cytokine. Non-limiting examples of anti-inflammatory cytokines include IL-4, IL- 10, IL-11, and IL- 13.

[0033] In some embodiments, short chain fatty acids (SCFAs) modulate multiple cellular signaling proteins, including, but not limited to, IL-18, TLR3, IFN-y, TNFa, TGF-0, MyD88, PI3K / Akt, JAK / STAT, Smad 2 / 3, Smad 4, IL-10, Notch, hedgehog, Wnt (beta-catenin), matrix metalloproteinases 9 and 10, tissue inhibitor of metalloproteinases, nodal and NF-KB signaling. In some embodiments, the signaling proteins that are modulated by SCFAs modulate biological pathways or processes include, but are not limited to, inflammation, immunity, proliferation, differentiation, apoptosis, oncogenesis, transcription of DNA, cytokine production, cell survival, angiogenesis, fibrogenesis and cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, and ultraviolet irradiation.

[0034] In some embodiments, short chain fatty acids (SCFAs) modulate multiple immune cells, including, but not limited to, macrophages, mast cells, neutrophils, Thl, Thl7, and Th22 lymphocytes.

[0035] In some embodiments, a method disclosed herein comprises treating or reducing a likelihood of developing medical diseases or disorders characterized by elevated levels or abnormal expression of at least one of IL-18, TLR3, IFN-y, TNFa, TGF-0, MyD88, PI3K / Akt, IAK / STAT, Smad 2 / 3,Smad 4 or IL- 10 signaling.

[0036] In some embodiments, a method disclosed herein comprises treating or reducing a likelihood of developing medical diseases or disorders characterized by decreased levels or abnormal expression of NF-KB signaling.

[0037] In some embodiments, administering a composition disclosed herein increases expression of IL- 10 in the subject compared to baseline (e.g., compared to an IL- 10 level prior to administration of the composition). In some embodiments, administering a composition disclosed herein to a subject increases expression of IL-10 in the subject by at least about 3%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more. In some embodiments, the increased expression of the antiinflammatory and immunosuppressive cytokine IL-10 following administration of SCFAs in a subject indicates a reduced inflammatory mechanism in the subject due to the SCFAs.

[0038] In some embodiments, administering a composition disclosed herein decreases expression of IL-23 in the subject compared to baseline (e.g., compared to an IL-23 level prior to administration of the composition). In some embodiments, administering a composition disclosed herein to a subject increases expression of IL-23 in the subject by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more.

[0039] In some embodiments, administering a composition disclosed herein decreases expression of IL-17A in the subject compared to baseline (e.g., compared to an IL-17A level prior to administration of the composition). In some embodiments, administering a composition disclosed herein to a subject increases expression of IL-17A in the subject by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more.

[0040] In some embodiments, administering a composition disclosed herein decreases expression of TNF-a in the subject compared to baseline (e.g., compared to an TNF-a level prior to administration of the composition). In some embodiments, administering a composition disclosed herein to asubject increases expression of TNF-a in the subject by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more.

[0041] In some embodiments, a composition disclosed herein comprises at least one compound comprising a precursor of a SCFA, or a moiety thereof. Non-limiting examples of the precursor include plant cell-wall polysaccharides, dietary nonstarch polysaccharides (NSP) a salt of lactate, a salt of succinate, a salt of formate, 1,2-propenedol, trypamine, indole, indole-3 -acetate, and a combination thereof.

[0042] In some embodiments, a composition disclosed herein comprises at least one compound comprising a biosynthesis precursor of a SCFA, or a moiety thereof. Non-limiting examples of a biosynthesis precursor include acetyl-CoA carboxylase inhibitor, an adenosine monophosphate kinase (AMPK) activator, vitamin D, and a combination thereof.

[0043] In some embodiments, a composition disclosed herein comprises a salt of a SCFA, or a derivative thereof. Non-limiting examples of a salt of butyric acid include sodium butyrate, magnesium butyrate, and calcium butyrate. In some embodiments, the composition comprises one or more of magnesium butyrate and calcium butyrate.

[0044] In some embodiments, a composition disclosed herein comprises butyric acid or a pharmaceutically-acceptable salt thereof. In some embodiments, a composition disclosed herein comprises propionic acid or a pharmaceutically-acceptable salt thereof. In some embodiments, a composition disclosed herein comprises butyric acid or a pharmaceutically-acceptable salt thereof and propionic acid or a pharmaceutically-acceptable salt thereof.

[0045] In some embodiments, a composition disclosed herein comprises acetic acid or a pharmaceutically-acceptable salt thereof. In some embodiments, a composition disclosed herein comprises butyric acid or a pharmaceutically-acceptable salt thereof, propionic acid or a pharmaceutically-acceptable salt thereof, and acetic acid or a pharmaceutically-acceptable salt thereof.

[0046] In some embodiments, a composition disclosed herein comprises a derivative of a SCFA. In some embodiments, the derivative comprises at least one SCFA moiety linked to at least one additional moiety. In some embodiments, the derivative comprises at least one SCFA moiety linkedto at least one polyethylene glycol (PEG) moiety. In some embodiments, the SCFA moiety linked to the PEG moiety hydrolyzes under a low pH condition to yield a SCFA molecule and a PEG molecule.

[0047] In some embodiments, a composition disclosed herein a combination of SCFAs, and / or derivatives thereof. In some embodiments, the composition is prepared at amounts of at least 10 mM, at least 20 mM, at least 30 mM, at least 40 mM, at least 50 mM, at least 60 mM, at least 70 mM, at least 80 mM, at least 90 mM, at least 100 mM, or more of each or all the compounds of the composition.

[0048] Derivatives of SCFAs, e.g., having substituents on the carbon chain such as OH, SH, NH2, methyl, ethyl, halogen, and other groups that do not interfere with the compound's therapeutic activity can also be used. In some embodiments, a compound disclosed herein comprises at least one SCFA linked to at least one additional moiety, such as OH, SH, NH2, methyl, ethyl, halogen, and other groups that do not interfere with the compound's therapeutic activity. In some embodiments, a SCFA is pegylated.

[0049] In some embodiments, a composition disclosed herein comprises a precursor of a SCFA alone or in combination with one or more SCFAs. Non-limiting examples of precursors of SCFAs include: a salt of formate, a salt of lactate, a salt of succinate, 1,2-propenedol, trypamine, indole, and indole-3 -acetate.

[0050] In some embodiments, a composition disclosed herein comprises a precursor of SCFA biosynthesis alone or in combination with one or more SCFA. Non-limiting examples of precursors of SCFA biosynthesis include: a salt of formate, a salt of lactate, a salt of succinate, acetyl-CoA carboxylase inhibitors, adenosine monophosphate kinase (AMPK) activators, and vitamin D.

[0051] In some embodiments, a compound comprising at least one SCFA, or a compound comprising a SCFA moiety disclosed herein is combined with one or more compounds, such as one or more additional therapeutic agent, for a particular disease or disorder. In some embodiments, the SCFA is in the same composition as one or more additional therapeutic agents. In some embodiments, the composition comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more than 10 additional therapeutic agents.Interleukin-10 (IL-10)

[0052] IL- 10 is a pleiotropic cytokine with effects on numerous cell populations, such as circulating and resident immune cells as well as epithelial cells. IL-10 is produced by monocytes and Th2 cells, mast cells and also in a subset of activated T cells and B cells.

[0053] IL- 10 can exert either immunosuppressive or immunostimulatory effects on a variety of cell types. Non-limiting examples of effects of IL-10 expression include: inhibiting monocyte / macrophage function, suppressing the production of a pro-inflammatory cytokine (e.g., TNF-a, IL- 113, IL-6,MIP-la and IL-8), increasing release of MCP-1, upregulating monocyte expression of an anti-inflammatory cytokine (e.g., IL-IRa), and suppressing the synthesis of superoxide anions and NO by activated monocytes / macrophages.

[0054] IL- 10 is also a growth co-stimulator for thymocytes and mast cells, and an enhancer of cytotoxic T cell development. In some embodiments, the elevated level of IL-10 activates the transcription of genes for mast cell derived proteases. In some embodiments, the elevated level of IL-10 enhances the production of the tissue inhibitor of metalloproteinases of monocytes and tissue macrophages while decreasing metalloproteinase biosynthesis.

[0055] In some embodiments, a method disclosed herein comprises treating or reducing a likelihood of developing a condition characterized by reduced levels or abnormal expression of IL- 10 signaling. In some embodiments, the condition is an inflammatory condition. In some embodiments, the condition is psoriasis. In some embodiments, a method disclosed herein comprises administering SCFAs to elevate the expression of an anti-inflammatory cytokine. In some embodiments, the antiinflammatory cytokine is IL- 10.

[0056] Non-limiting examples of effects of IL-10 include: inhibiting the activity of Thl cells, NK cells, and macrophages, impeding pathogen clearance, and ameliorating immunopathology.

[0057] In some embodiments, an elevated level of IL- 10 exerts anti-psoriatic activity by effects on different cell populations, including but not limited to, antigen presenting cells, T-cells, or a combination thereof. In some embodiments, an elevated level of IL-10 results in attenuating a T- helper (Th)l / Th2 disbalance. In some embodiments, an elevated level of IL-10 results in a type 1 / type 2 cytokine balance shift. Non-limiting examples of effects of a type 1 / type 2 cytokine balance shift include: increasing proportion of IL-4, IL-5, and IL-10 producing T-cells, and selective increase in IgE serum levels.

[0058] In some embodiments, a method disclosed herein comprises obtaining a level of a biomarker in a subject, wherein the biomarker is an anti-inflammatory cytokine, wherein the subject is undergoing a regimen of short chain fatty acid therapy for an inflammatory condition.

[0059] In some embodiments, a method disclosed herein further comprises based on the level of the biomarker in the subject, continuing the short chain fatty acid therapy, wherein the level of the biomarker shows elevated expression of the biomarker in the subject.

[0060] In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject prior to the administering to the subject the short chain fatty acid therapy. In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject during initiation of the administering to the subject the short chain fatty acid therapy. In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject concurrently with the first administering to the subject the short chain fatty acid therapy.

[0061] In some embodiments, the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or greater than about 100% higher in comparison to a predetermined value. In some embodiments, the predetermined value is level of the biomarker determined prior to the administering to the subject a regimen of short chain fatty acid therapy. In some embodiments, the predetermined value is level of the biomarker determined during initiation of the administering to the subject a regimen of short chain fatty acid therapy.

[0062] In some embodiments, the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 0.5-fold, at least about 1-fold, at least about 1.5-fold, at least about 2 fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, at least about 6-fold, at least about 6.5- fold, at least about 7 fold, at least about 7.5-fold, at least about 8-fold, at least about 8.5-fold, at least about 9-fold, at least about 9.5-fold, at least about 10-fold, or greater than about 10-fold higher in comparison to a predetermined value. In some embodiments, the predetermined value is level of the biomarker determined prior to the administering to the subject a regimen of short chain fatty acidtherapy. In some embodiments, the predetermined value is level of the biomarker determined during initiation of the administering to the subject a regimen of short chain fatty acid therapy.

[0063] In some embodiments, the level of the biomarker shows elevated expression of the biomarker in the subject over a period of about three days, about four days, about five days, about six days, about seven days, or greater than about seven days.

[0064] In some embodiments, the level of the biomarker shows elevated expression of the biomarker in the subject over a period of about three days to four days, about four to five days, about five to six days, about six to seven days, or greater than about seven days.

[0065] In some embodiments, a method disclosed herein comprises (a) administering a therapeutically-effective amount of a short chain fatty acid therapy for an inflammatory condition to a subject in need thereof; (b) after the administering, obtaining a level of a biomarker in a subject, wherein the biomarker is an anti-inflammatory cytokine; and (c) based on the level of the biomarker in the subject, continuing the short chain fatty acid therapy.

[0066] In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject prior to the administering to the subject the short chain fatty acid therapy. In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject during initiation of the administering to the subject the short chain fatty acid therapy. In some embodiments, a method disclosed herein further comprises obtaining a level of a biomarker in a subject concurrently with the first administering to the subject the short chain fatty acid therapy.

[0067] In some embodiments, the short chain fatty acid therapy is continued if the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, or greater than about 100% higher in comparison to a predetermined value. In some embodiments, the predetermined value is the level of the biomarker determined prior to the administering to the subject a regimen of short chain fatty acid therapy. In some embodiments, the predetermined value is level of the biomarker determined during initiation of the administering to the subject a regimen of short chain fatty acid therapy.

[0068] In some embodiments, the short chain fatty acid therapy is continued if the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 0.5-fold, at least about 1-fold, at least about 1.5-fold, at least about 2 fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, at least about 6-fold, at least about 6.5-fold, at least about 7 fold, at least about 7.5-fold, at least about 8-fold, at least about 8.5-fold, at least about 9-fold, at least about 9.5-fold, at least about 10-fold, or greater than about 10-fold higher in comparison to a predetermined value. In some embodiments, the predetermined value is level of the biomarker determined prior to the administering to the subject a regimen of short chain fatty acid therapy. In some embodiments, the predetermined value is level of the biomarker determined during initiation of the administering to the subject a regimen of short chain fatty acid therapy.

[0069] In some embodiments, the short chain fatty acid therapy is continued if the level of the biomarker shows elevated expression of the biomarker in the subject over a period of about three days, about four days, about five days, about six days, about seven days, or greater than about seven days.

[0070] In some embodiments, the short chain fatty acid therapy is continued if the level of the biomarker shows elevated expression of the biomarker in the subject over a period of about three days to four days, about four to five days, about five to six days, about six to seven days, or greater than about seven days.Psoriasis

[0071] Psoriasis is a chronic autoimmune disorder affecting the skin. The clinical appearance of psoriasis results from a dysregulated interaction between immune cells (e.g. dendritic cells [DCs] and T cells) and keratinocytes leading to inflammatory processes which drive the disease. The skin inflammation causes a rapid keratinocyte proliferation ending up in scaling of skin's surface, which shows a common phenotype of dry, raised, red skin lesions (plaques) covered with silvery scales.

[0072] Nonlimiting examples of psoriasis include: plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, psoriasis vulgaris, seborrheic psoriasis erythrodermic psoriasis, nail psoriasis, scalp and palmoplantar psoriasis, and psoriatic arthritis.

[0073] In some embodiments, recruitment of innate and adaptive immune cells, which secrete pro-inflammatory cytokines, contribute to the pathogenesis of psoriasis. Cytokines play a critical role in the onset and progression of disease. Non-limiting examples of cytokines that contribute to the pathogenesis of psoriasis include IL-23 and IL- 17.

[0074] Furthermore, Tregs are impaired in suppressive function leading to an altered T-helper 17 / Treg balance. In some embodiments, cytokine antagonists (e.g. anti-TNFs like for instance Etanercept) are used in the treatment of plaque psoriasis (Ps) and psoriatic arthritis (PsA).

[0075] The IL-23 / IL- 17 immune axis can drive skin inflammation in psoriasis, which results from the interplay between keratinocytes and immune cells, such as Thl7 cells. In some embodiments, pharmacological blockade of the IL-23 / IL-17 immune axis results in clinical efficacy in psoriasis. In some embodiments, pharmacological modulation of the IL-23 / IL-17 immune axis is evaluated by different drug modalities and administration (e.g., topical and systemic).

[0076] Human Thl7 differentiation requires IL-10, IL-6 and TGF-0 and IL-23 to sustain production of IL-17 and IL-22 from Thl7 cells. IL-17 induces expression of other pro-inflammatory mediators in keratinocytes, such as IL-17C, IL-19 and IL-36 that, together with IL-17 and IL-22, contribute to keratinocyte activation and epidermal hyperplasia, associated with expression of Keratin- 16 and S100A7. In addition, increased levels of IFN-y in psoriatic skin by activation of skin-resident Thl cells contribute to the inflammatory activation of keratinocytes.

[0077] An autoimmune disease or disorder can include an immune response against a self-antigen that results in inflammation or destruction of healthy tissue in a subject, for example, a mammal, such as a human. Non-limiting examples of autoimmune diseases include arthritis (e.g., rheumatoid arthritis such as acute arthritis, chronic rheumatoid arthritis, gouty arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, vertebral arthritis, and juvenile-onset rheumatoid arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronica primaria, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gutatte psoriasis, pustular psoriasis, psoriasis vulgaris, inverse psoriasis, erythrodermic psoriasis, seborrheic psoriasis and psoriasis of the nails, dermatitis including contact dermatitis, chronic contact dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, and atopic dermatitis, x-linked hyper IgM syndrome, urticaria such as chronic allergic urticaria and chronic idiopathic urticaria, including chronic autoimmune urticaria, polymyositis / dermatomyositis,juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma (including systemic scleroderma), sclerosis such as systemic sclerosis, multiple sclerosis (MS) such as spino-optical MS, primary progressive MS (PPMS), and relapsing remitting MS (RRMS), progressive systemic sclerosis, sclerosis disseminata, and ataxic sclerosis, inflammatory bowel disease (IBD) (for example, Crohn's disease, autoimmune-mediated gastrointestinal diseases, colitis such as ulcerative colitis, colitis ulcerosa, microscopic colitis, collagenous colitis, colitis polyposa, necrotizing enterocolitis, and transmural colitis, and autoimmune inflammatory bowel disease), pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, episcleritis, respiratory distress syndrome, including adult or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, an autoimmune hematological disorder, rheumatoid spondylitis, sudden hearing loss, IgE-mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis such as Rasmussen's encephalitis and limbic and / or brainstem encephalitis, uveitis, such as anterior uveitis, acute anterior uveitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, or autoimmune uveitis, glomerulonephritis (GN) with and without nephrotic syndrome such as chronic or acute glomerulonephritis such as primary GN, immune-mediated GN, membranous GN (membranous nephropathy), idiopathic membranous GN or idiopathic membranous nephropathy, membrane- or membranous proliferative GN (MPGN), including Type I and Type II, and rapidly progressive GN, allergic conditions, allergic reaction, eczema including allergic or atopic eczema, asthma such as asthma bronchiale, bronchial asthma, and auto-immune asthma, conditions involving infiltration of T cells and chronic inflammatory responses, chronic pulmonary inflammatory disease, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE) or systemic lupus erythematodes such as cutaneous SLE, subacute cutaneous lupus erythematosus, neonatal lupus syndrome (NLE), lupus erythematosus disseminatus, lupus (including nephritis, cerebritis, pediatric, non-renal, extra-renal, discoid, alopecia), juvenile onset (Type I) diabetes mellitus, including pediatric insulin-dependent diabetes mellitus (IDDM), adult onset diabetes mellitus (Type II diabetes), autoimmune diabetes, idiopathic diabetes insipidus, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T- lymphocytes, tuberculosis, sarcoidosis, granulomatosis including lymphomatoid granulomatosis, Wegener's granulomatosis, agranulocytosis, vasculitides, including vasculitis (including large vessel vasculitis (including polymyalgia rheumatica and giant cell (Takayasu's) arteritis), medium vesselvasculitis (including Kawasaki's disease and polyarteritis nodosa), microscopic polyarteritis, CNS vasculitis, necrotizing, cutaneous, or hypersensitivity vasculitis, systemic necrotizing vasculitis, and ANCA-associated vasculitis, such as Churg-Strauss vasculitis or syndrome (CSS)), temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs positive anemia, Diamond Blackfan anemia, hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia (anemia perniciosa), Addison's disease, pure red cell anemia or aplasia (PRC A), Factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, CNS inflammatory disorders, multiple organ injury syndrome such as those secondary to septicemia, trauma or hemorrhage, antigen-antibody complex- mediated diseases, anti-glomerular basement membrane disease, anti-phospholipid antibody syndrome, allergic neuritis, Bechet's or Behcet's disease, Castleman's syndrome, Goodpasture's syndrome, Reynaud's syndrome, Sjogren's syndrome, Stevens- Johnson syndrome, pemphigoid such as pemphigoid bullous and skin pemphigoid, pemphigus (including pemphigus vulgaris, pemphigus foliaceus, pemphigus mucus-membrane pemphigoid, and pemphigus erythematosus), autoimmune polyendocrinopathies, Reiter's disease or syndrome, immune complex nephritis, antibody-mediated nephritis, neuromyelitis optica, polyneuropathies, chronic neuropathy such as IgM polyneuropathies or IgM-mediated neuropathy, thrombocytopenia (as developed by myocardial infarction patients, for example), including thrombotic thrombocytopenic purpura (TTP) and autoimmune or immune- mediated thrombocytopenia such as idiopathic thrombocytopenic purpura (ITP) including chronic or acute ITP, autoimmune disease of the testis and ovary including autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, autoimmune endocrine diseases including thyroiditis such as autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis), or subacute thyroiditis, autoimmune thyroid disease, idiopathic hypothyroidism, Grave's disease, polyglandular syndromes such as autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), paraneoplastic syndromes, including neurologic paraneoplastic syndromes such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man or stiff-person syndrome, encephalomyelitis such as allergic encephalomyelitis or encephalomyelitis allergica and experimental allergic encephalomyelitis (EAE), myasthenia gravis such as thymoma- associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus myoclonus syndrome (QMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan'ssyndrome, lymphoid interstitial pneumonitis, bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, primary biliary cirrhosis, pneumonocirrhosis, autoimmune enteropathy syndrome, Celiac disease, Coeliac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia, amylotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear disease such as autoimmune inner ear disease (AIED), autoimmune hearing loss, opsoclonus myoclonus syndrome (OMS), polychondritis such as refractory or relapsed polychondritis, pulmonary alveolar proteinosis, amyloidosis, scleritis, a non-cancerous lymphocytosis, a primary lymphocytosis, which includes monoclonal B cell lymphocytosis (e.g., benign monoclonal gammopathy and monoclonal gammopathy of undetermined significance, MGUS), peripheral neuropathy, paraneoplastic syndrome, channel opathies such as epilepsy, migraine, arrhythmia, muscular disorders, deafness, blindness, periodic paralysis, and channelopathies of the CNS, autism, inflammatory myopathy, focal segmental glomerulosclerosis (FSGS), endocrine ophthalmopathy, uveoretinitis, chorioretinitis, fibromyalgia, multiple endocrine failure, Schmidt's syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases, diabetic nephropathy, Dressier's syndrome, alopecia areata, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), male and female autoimmune infertility, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent abortion, farmer's lung, erythema multiforme, post-cardiotomy syndrome, Cushing's syndrome, bird-fancier's lung, allergic granulomatous angiitis, benign lymphocytic angiitis, Alport's syndrome, alveolitis such as allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reaction, leprosy, malaria, leishmaniasis, kypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sampter's syndrome, Caplan's syndrome, dengue, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial lung fibrosis, idiopathic pulmonary fibrosis, fibrosis of any organ or tissue, cystic fibrosis, endophthalmitis, erythema elevatum et diutinum, erythroblastosis fetalis, eosinophilic faciitis, Shulman's syndrome, Felty's syndrome, flariasis, cyclitis such as chronic cyclitis, heterochronic cyclitis, iridocyclitis, or Fuch's cyclitis, Henoch-Schonlein purpura, human immunodeficiency virus (HIV) infection, echovirus infection, cardiomyopathy, Alzheimer's disease, parvovirus infection, rubella virus infection, post-vaccination syndromes, congenital rubella infection, Epstein-Barr virusinfection, mumps, Evan's syndrome, autoimmune gonadal failure, Sydenham's chorea, poststreptococcal nephritis, thromboangitis ubiterans, thyrotoxicosis, tabes dorsalis, chorioiditis, giant cell polymyalgia, endocrine ophthamopathy, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemia-reperfusion injury, retinal autoimmunity, joint inflammation, bronchitis, chronic obstructive airway disease, silicosis, aphthae, aphthous stomatitis, arteriosclerotic disorders, aspermiogenese, autoimmune hemolysis, Boeck's disease, cryoglobulinemia, Dupuytren's contracture, endophthalmia phacoanaphylactica, enteritis allergica, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, Hamman-Rich's disease, sensoneural hearing loss, haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, leucopenia, mononucleosis infectiosa, traverse myelitis, primary idiopathic myxedema, nephrosis, ophthalmia symphatica, orchitis granulomatosa, pancreatitis, polyradiculitis acuta, pyoderma gangrenosum, Quervain's thyreoiditis, acquired spenic atrophy, infertility due to antispermatozoan antibodies, non-malignant thymoma, vitiligo, SCID and Epstein- Barr virus-associated diseases, acquired immune deficiency syndrome (AIDS), parasitic diseases such as Leishmania, toxic-shock syndrome, food poisoning, conditions involving infiltration of T cells, leukocyte-adhesion deficiency, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, diseases involving leukocyte diapedesis, multiple organ injury syndrome, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathies, oophoritis, primary myxedema, autoimmune atrophic gastritis, sympathetic ophthalmia, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, poly endocrine failure, peripheral neuropathy, autoimmune polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), alopecia totalis, dilated cardiomyopathy, epidermolisis bullosa acquisita (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, purulent or nonpurulent sinusitis, acute or chronic sinusitis, ethmoid, frontal, maxillary, or sphenoid sinusitis, an eosinophil-related disorder such as eosinophilia, pulmonary infiltration eosinophilia, eosinophiliamyalgia syndrome, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, or granulomas containing eosinophils, anaphylaxis, seronegative spondyloarthritides, polyendocrine autoimmune disease, sclerosingcholangitis, sclera, episclera, chronic mucocutaneous candidiasis, Bruton's syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, ataxia telangiectasia, autoimmune disorders associated with collagen disease, rheumatism, neurological disease, ischemic re-perfusion disorder, reduction in blood pressure response, vascular dysfunction, antgiectasis, tissue injury, cardiovascular ischemia, hyperalgesia, cerebral ischemia, and disease accompanying vascularization, allergic hypersensitivity disorders, glomerulonephritides, reperfusion injury, reperfusion injury of myocardial or other tissues, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system inflammatory disorders, ocular and orbital inflammatory disorders, granulocyte transfusion-associated syndromes, cytokine-induced toxicity, acute serious inflammation, chronic intractable inflammation, pyelitis, pneumonocirrhosis, diabetic retinopathy, diabetic large-artery disorder, endarterial hyperplasia, peptic ulcer, valvulitis, and endometriosis.

[0078] In some embodiments, a method disclosed herein comprises treating a condition. In some embodiments the condition is a skin disorder. In some embodiments, the condition is psoriasis. In some embodiments, treating comprises causing disappearance of a psoriatic lesion in the subject in need thereof. In some embodiments, treating comprises causing a reduction in area of one or more psoriatic lesions in the subject in need thereof. In some embodiments, treating comprises causing a reduction in intensity of redness, thickness, and / or scaling of one or more psoriatic lesions in the subject in need thereof.

[0079] In some embodiments, treating comprises causing a psoriasis area and severity index (PASI) treatment score of at least PASI 75. In some embodiments, treating comprises causing a PASI treatment score of at least PASI 80. In some embodiments, treating comprises causing a PASI treatment score of at least PASI 85. In some embodiments, treating comprises causing a PASI treatment score of at least PASI 90. In some embodiments, treating comprises causing a PASI treatment score of at least PASI 95. In some embodiments, treating comprises causing a PASI treatment score of PASI 100.

[0080] In some embodiments, a method disclosed herein comprising a SCFA disclosed herein reduces epidermal / dermal separation. In some embodiments, a method disclosed herein comprising a SCFA disclosed herein reduces a likelihood of degradation of the skin after inflammation.Conditions

[0081] The present disclosure describes methods and systems for treating conditions comprising administering a pharmaceutical composition comprising at least one short chain fatty acid (SCFA), a SCFA precursor, a SCFA biosynthesis precursor, a compound comprising a SFCA moiety, a derivative thereof, and a combination thereof. In some embodiments, the condition is a skin disorder. In some embodiments, the condition is psoriasis. In some embodiments, the condition is an autoimmune disorder.

[0082] Disclosed herein is a method for the treatment or reducing a likelihood of developing at least one disease or disorder in a subject, comprising administering to the subject at least one composition comprising a SCFA or a compound comprising a SCFA, optionally in combination with at least one additional agent or therapy.

[0083] In some embodiments, a composition disclosed herein increases the number of disease-free days, reduce the severity of a disease or disorder, reduce the risk of developing a disease or disorder, reduce the risk of recurrence of a disease or disorder, or a combination thereof in the subject. In some embodiments, a composition disclosed herein increase the number of disease-free days by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% or more in the subject as compared to a subject who is not receiving treatment. In some embodiments, a composition disclosed herein reduce the severity of a disease or disorder by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% or more in the subject as compared to a subject who is not receiving treatment. In some embodiments, a composition disclosed herein reduce the risk of developing a disease or disorder by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least58%, at least 59%, at least 60% or more in the subject as compared to a subject who is not receiving treatment. In some embodiments, a composition disclosed herein reduce the risk of recurrence of a disease or disorder by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% or more in the subject as compared to a subject who is not receiving treatment.

[0084] Non-limiting examples of diseases and disorders that are treated, reduced in likelihood, or ameliorated include: inflammatory diseases and various cancer diseases. Non-limiting examples of inflammatory diseases and disorders include: asthma, arthritis, allergic rhinitis, psoriasis, atopic dermatitis, inflammatory bowel diseases, Crohn's disease, an allergic or autoimmune disease or disorder associated with C-section delivery of a neonate, uveitis, and vasculitis.Skin Disorders

[0085] In some embodiments, a SCFA disclosed herein is effective in the treatment of a skin disorder. In some embodiments, a combination of at least one SCFA with at least one other skin disorder treatment can be effective as a therapeutic approach for the treatment of a skin disorder.

[0086] Disclosed herein is a method for treatment, inhibition, prevention, or reduction of a skin disease or disorder by administering a composition comprising a SCFA, as disclosed herein, to a subject in need thereof, optionally in combination with at least one additional agent or therapy. Nonlimiting examples of skin diseases and disorders include: psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, psoriasis vulgaris, seborrheic psoriasis, erythrodermic psoriasis, nail psoriasis, scalp and palmoplantar psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE) rash, scleroderma (systemic sclerosis), diabetes related skin conditions, rheumatoid arthritis and associated skin rashes (rheumatoid vasculitis), melanoma, vitiligo, eczema (atopic dermatitis), dyshidrotic eczema, rosacea, hives, impetigo, cellulitis, contact dermatitis, canker sores, acne, Lichen planus, actinic keratosis, ichthyosis vulgaris, dermatomyositis, and pemphigoid.

[0087] Disclosed herein is a method for treatment, inhibition, prevention, or reduction of a skindisease or disorder, comprising administering a composition comprising a SCFA, as disclosed herein, to a subject in need thereof.

[0088] In some embodiments, a subject suffering from a skin disorder is a human. In some embodiments, a subject suffering from a skin disorder is a non-human animal.

[0089] In some embodiments, a composition disclosed herein comprises at least one SCFA and at least one second compound for use as a therapeutic for the treatment of skin disorders. In some embodiments, a SCFA comprises one or more of formic acid, acetic acid, propionic acid, isobutyric acid, butyric acid, tributyrin, N-acetylbutyrate (and other forms of butyrate), isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, and dodecanoic acid. In some embodiments, a second compound comprises one or more of a PDE4 inhibitor, an anti-inflammatory compound, a disease-modifying antirheumatic drug (DMARD), an immunosuppressant, a biologic agent, and a Cox-2 inhibitor.

[0090] In some embodiments, a composition for use in methods of treating skin disorders comprises an amount of a form of a butyrate salt, wherein the amount is therapeutically equivalent to about 1200 mg of a salt of butyrate, for example, a sodium, calcium, or magnesium salt, an amount of a form of a propionate salt, wherein the amount is therapeutically equivalent to about 39 mg of a salt of propionate, for example, a sodium, calcium, or magnesium salt, about 7 mg of a source of magnesium, for example, magnesium chloride or magnesium hydroxide, and about 0.1 mg of a vitamin D, for example, vitamin D3.

[0091] In some embodiments, a composition for use in methods of treating skin disorders comprises an amount of a form of a butyrate salt, wherein the amount is therapeutically equivalent to about 800 mg of a salt of butyrate, for example, a sodium, calcium, or magnesium salt, an amount of a form of a propionate salt, wherein the amount is therapeutically equivalent to about 50 mg of a salt of propionate, for example, a sodium, calcium, or magnesium salt, about 10 mg of a source of magnesium, for example, magnesium chloride or magnesium hydroxide, and about 40 IU of a vitamin D, for example, vitamin D3.

[0092] In some embodiments, a composition for use in methods of treating skin disorders comprises an amount of a form of a butyrate salt, wherein the amount is therapeutically equivalent to about 900 mg of a salt of butyrate, for example, a sodium, calcium, or magnesium salt, an amount of a form of a propionate salt, wherein the amount is therapeutically equivalent to about 100 mg of a salt ofpropionate, for example, a sodium, calcium, or magnesium salt, about 10 mg of a source of magnesium, for example, magnesium chloride or magnesium hydroxide, and about 50 IU of a vitamin D, for example, vitamin D3. In some embodiments, the composition further comprises about 10 mg apremilast. In some embodiments, the composition is co-administered with a unit dosage form of about 10 mg apremilast.

[0093] In some embodiments, an example of a daily oral dosage for use in methods of treating skin disorders comprises an amount of a form of butyric acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 3600 mg of butyric acid or a pharmaceutically-acceptable salt, for example, a sodium, calcium, or magnesium salt, an amount of a form of a propionate acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 400 mg of a salt of propionate, for example, a sodium, calcium, or magnesium salt, about 40 mg of a source of magnesium, for example, magnesium chloride or magnesium hydroxide, and about 200 IU of a vitamin D, for example, vitamin D3.

[0094] In some embodiments, an example of a dosage for use in methods of treating skin disorders comprises a form of butyric acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 700 mg to about 1,800 mg of butyric acid or a pharmaceutically-acceptable salt thereof, for example, a sodium, calcium, or magnesium salt, an amount of a form of a propionate acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 200 mg to about 300 mg of a salt of propionate, for example, a sodium, calcium, or magnesium salt, about 5 mg to about 20 mg of a source of magnesium, for example, magnesium chloride or magnesium hydroxide, and about 200 IU of a vitamin D, for example, Vitamin D3 administered 1-4 times daily.

[0095] In some embodiments, a composition is administered 1-4 times daily for at least 1 week, at least 2 weeks, at least 3 weeks or for more than 3 weeks.

[0096] In some embodiments, an example dosage for use in methods of treating skin disorders comprises an amount of a form of butyric acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 1 to about 2 g of butyric acid or a pharmaceutically-acceptable salt thereof, for example, a sodium, calcium, or magnesium salt, an amount of a form of a propionate acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 100 mg of propionic acid or a pharmaceutically-acceptable salt thereof, for example, a sodium, calcium, or magnesium salt, about 10 mg to about 15 mg Otezla, about 10 mg to about 20 mg of a source of magnesium, for example, magnesium chloride or magnesium hydroxide, and about 80 to aboutlOO IU of a vitamin D, for example, Vitamin D3.

[0097] In some embodiments, a composition comprising at least one SCFA is an enteric coated, extended release, and sustained release capsule.

[0098] In some embodiments, a method of treating skin disorders comprises administration of an oral formulation of a SCFA in combination with a topical ointment. An example of a topical ointment for use in treating skin disorder comprises about 40% clobetazol (0.05%) cream, about 20% calcipotriene (vit D, 0.005%) cream, about 20% vit E (0.5%) cream, and about 20% salicylic acid (10%) cream. Another example of a topical ointment for use in treating skin disorder comprises about 40% clobetazol (0.05%) cream, about 20% calcipotriene (vit D, 0.005%) cream, about 20% vit E (0.5%) cream, and about 20% zinc cream. In some embodiments, zinc is used together with salicylic acid in a topical ointment.Dosing and Administration

[0099] In practicing the methods or use provided herein, therapeutically-effective amounts of the compounds described herein are administered to a subject having a disease or condition to be treated. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. Subjects can be, for example, humans, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, or neonates. A subject can be a patient.

[0100] The particular dosage of a compound required to treat the condition can depend on the severity of the condition, the route of administration, and related factors that can be decided by the attending physician.

[0101] A therapeutically-effective amount of a compound of the present disclosure can be expressed as mg of the compound per kg of subject body mass. In some embodiments, a therapeutically- effective amount is 1-1,000 mg / kg, 1-500 mg / kg, 1-250 mg / kg, 1-100 mg / kg, 1-50 mg / kg, 1-25 mg / kg, or 1-10 mg / kg. In some embodiments, a therapeutically-effective amount is about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg,about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1,000 mg / kg.

[0102] A compound described herein can be present in a composition in a range of from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, from about 45 mg to about 50 mg, from about 50 mg to about 55 mg, from about 55 mg to about 60 mg, from about 60 mg to about 65 mg, from about 65 mg to about 70 mg, from about 70 mg to about 75 mg, from about 75 mg to about 80 mg, from about 80 mg to about 85 mg, from about 85 mg to about 90 mg, from about 90 mg to about 95 mg, from about 95 mg to about 100 mg, from about 100 mg to about 125 mg, from about 125 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 225 mg, from about 225 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 325 mg, from about 325 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 425 mg, from about 425 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 525 mg, from about 525 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 625 mg, from about 625 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 725 mg, from about 725 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 825 mg, from about 825 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 925 mg, from about 925 mg to about 950 mg, from about 950 mg to about 1000 mg, from about 1000 mg to about 1025 mg, from about 1025 mg to about 1050 mg, from about 1050 mg to about 1100 mg, from about 1100 mg to about 1125 mg, from about 1125 mg to about 1150 mg, from about 1150 mg to about 1200 mg, from about 1200 mg to about 1225 mg, from about 1225 mg to about 1250 mg, from about 1250 mg to about 1300 mg, from about 1300 mg to about 1325 mg, from about 1325 mg to about 1350 mg, from about 1350 mg to about 1400 mg, from about 1400 mg to about 1425 mg, from about 1425 mg to about 1450 mg, from about 1450 mg to about 1500 mg, from about 1500 mg to about 1525 mg, from about 1525 mg to about 1550 mg, from about 1550 mg to about 1600 mg, from about 1600 mg to about 1625 mg, from about 1625 mg to about 1650 mg, from about 1650 mg to about 1700 mg, from about 1700 mg to about 1725 mg, from about 1725 mg to about 1750 mg, from about 1750 mg to about 1800 mg, from about 1800 mg to about 1825 mg, from about 1825 mg to about 1850 mg, from about 1850 mg to about1900 mg, 1900 mg to about 1925 mg, from about 1925 mg to about 1950 mg, or from about 1950 mg to about 2000 mg.

[0103] A compound described herein can be present in a composition in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg about 1925 mg, about 1950 mg, about 1975 mg, or about 2000 mg.

[0104] In some embodiments, a therapeutically-effective amount can be administered 1-35 times per week, 1-14 times per week, or 1-7 times per week. In some embodiments, a therapeutically- effective amount can be administered 1-10 times per day, 1-5 times per day, 1 time, 2 times, or 3 times per day.

[0105] In some embodiments, a number of doses for a therapeutically-effective amount can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10.

[0106] In some embodiments, a compound disclosed herein can be administered in therapeutically- effective amounts by various forms and routes including, for example, by intravenous, intravitreal, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, intraocular, and topical administration. Non-limiting examples of parenteral or systemic administration include subcutaneous, intravenous, intraperitoneal, and intramuscular injections.

[0107] In some embodiments, a pharmaceutical composition disclosed herein is generally formulated for oral or topical (i.e., skin, ocular and mucosal surfaces) administration, with the most suitable route in any given case depending on the nature and severity of the condition being treated and on the nature of the particular active agent which is being used.

[0108] Topical Formulations

[0109] In some embodiments, a pharmaceutical composition, composition, or compound disclosed herein, can be administered topically, and thus be formulated in a form suitable for topical administration, i.e. as a pH balanced cream preparation. An obstacle for topical administration of pharmaceuticals is the stratum comeum layer of the epidermis. The stratum corneum is a highly resistant layer comprised of protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes cornified and living cells. One of the factors that limit the penetration rate (flux) of a compound through the stratum comeum is the amount of the active substance that can be loaded or applied onto the skin surface. The greater the amount of active substance which is applied per unit of area of the skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, and in turn the greater the diffusion force of the active substance through the skin. Therefore, a formulation containing a greater concentration of the active substance is more likely to result in penetration of the active substance through the skin at a more consistent rate, than a formulation having a lesser concentration, all other things being equal.

[0110] Formulations suitable for topical administration include, but are not limited to, liquid or semi liquid preparations such as liniments, lotions, oil in water or water in oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Further, formulations suitable for topical administration can be in the form of cremes and liquids including, for example, syrups, suspensions or emulsions, inhalants, sprays, mousses, oils, gels, and solids. Topically administrable formulations can, for example, comprise from about 1% to about 10% (w / w) active ingredient. Although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration can further comprise one or more of the additional ingredients described herein.[OHl] Enhancers of permeation can be used. These materials increase the rate of penetration of drugs across the skin. Non-limiting examples of enhancers include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), and dimethylsulfoxide. Other enhancers include oleicacid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, and N-methyl-2-pyrrolidone.

[0112] In some embodiments, the topically active pharmaceutical composition is combined with other ingredients such as adjuvants, anti-oxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifying agents, viscosifiers, buffering agents, or preservatives. In some embodiments, a permeation or penetration enhancer is included in the composition and is effective in improving the percutaneous penetration of the active ingredient into and through the stratum comeum with respect to a composition lacking the permeation enhancer. Non-limiting examples of permeation enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone. In some embodiments, the composition further comprises a hydrotropic agent, which functions to increase disorder in the structure of the stratum corneum, and thus allows increased transport across the stratum comeum. Non-limiting examples of hydrotropic agents include isopropyl alcohol, propylene glycol, and sodium xylene sulfonate.

[0113] The topically active pharmaceutical composition should be applied in an amount effective to effect desired changes. In some embodiments, an active compound is present in an amount of from about 0.0001% to about 15% by weight volume of the composition, from about 0.0005% to about 5% of the composition, or from about 0.001% to about 1% of the composition.

[0114] Oral Formulations

[0115] In some embodiments, a pharmaceutical composition, composition, or compound disclosed herein, is administered orally, and thus be formulated in a form suitable for oral administration, i.e. as a solid or a liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, and pellets. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, and oils. If formulated as a capsule, the compositions disclosed herein comprise, in addition to the active compound and the inert carrier or diluent, a hard gelating capsule. In some embodiments, a formulation for oral administration is an enteric coated, time release capsule.

[0116] Formulations suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such formulations can be prepared by anysuitable method of pharmacy, which includes bringing into association the active compound and a suitable carrier (which can contain one or more accessory ingredients as noted above). In general, the formulations disclosed herein are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet can be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free- flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and / or surface active / dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.

[0117] The delayed release dosage units can be coated with the delayed release polymer coating using conventional techniques, e.g., using a conventional coating pan, an airless spray technique, fluidized bed coating equipment (with or without a Wurster insert).

[0118] An example method for preparing extended release tablets is by compressing a drugcontaining blend, e.g., blend of granules, prepared using a direct blend, wet-granulation, or drygranulation process. Extended release tablets can also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant. However, tablets are manufactured using compression rather than molding. A method for forming extended release drugcontaining blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and colorants. As an alternative to direct blending, a drug-containing blend can be prepared by using wet-granulation or dry-granulation processes. Beads containing the active agent can also be prepared by any one of a number of techniques, starting from a fluid dispersion. For example, a method for preparing drug-containing beads involves dispersing or dissolving the active agent in a coating suspension or solution containing pharmaceutical excipients such as polyvinylpyrrolidone, methylcellulose, talc, metallic stearates, silicone dioxide, or plasticizers. The admixture is used to coat a bead core such as a sugar sphere having a size of approximately 60 to 20 mesh.

[0119] An alternative procedure for preparing drug beads is by blending drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, a disintegrant, etc., extruding the blend,spheronizing the extrudate, drying and optionally coating to form the immediate release beads.

[0120] Delayed release formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, and soluble in the neutral environment of small intestines. The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drugcontaining composition can be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. Examples of coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and / or enzymatically degradable polymers, and can be enteric polymers. Enteric polymers become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Non-limiting examples of coating materials for effecting delayed release include cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, e.g., formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit®, including Eudragit® L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit®. L- 100 (soluble at pH 6.0 and above), Eudragit®. S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and Eudragits®. NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum, zein, and shellac. Combinations of different coating materials can be used. Multi-layer coatings using different polymers can be applied.

[0121] The coating composition can include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A plasticizer reduces the fragility of the coating and canbe represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer. Non-limiting examples of plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil, and acetylated monoglycerides. A stabilizing agent is used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants can reduce sticking effects during film formation and drying and can represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates can be used. Pigments such as titanium dioxide can be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), can be added to the coating composition.

[0122] In addition to a therapeutic or diagnostic agent (or possibly other desired molecules for delivery), the particles can include excipients such as a sugar, such as lactose, a protein, such as albumin, and / or a surfactant.

[0123] In some embodiments, a treatment regimen comprises daily oral administration of a short chain fatty acid. In some embodiments, an amount of a form of butyric acid or a pharmaceutically- acceptable salt thereof, wherein the amount is therapeutically equivalent to about 600 mg of butyric acid or a pharmaceutically-acceptable salt thereof, such as sodium butyrate, calcium butyrate, or magnesium butyrate, is administered 3 times per day (a total of about 1800 mg / day) for at least one week. In some embodiments, a treatment regimen comprises oral administration of two capsules, each containing an amount of a form of butyric acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 600 mg of butyric acid or a pharmaceutically-acceptable salt thereof, such as sodium butyrate, calcium butyrate, or magnesium butyrate, 3 times per day (a total of about 3,600 mg / day) for at least one week. In some embodiments, a treatment regimen comprises oral administration of two capsules, each containing an amount of a form of butyric acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 600 mg of butyric acid or a pharmaceutically-acceptable salt thereof, such as sodium butyrate, calcium butyrate, or magnesium butyrate, 3 times per day (a total of about 3,600 mg / day) for at least one week followed thereafter by oral administration of capsules, each containing an amount of a form of butyric acid or a pharmaceutically-acceptable salt thereof, wherein the amount is therapeutically equivalent to about 600 mg of butyric acid or apharmaceutically-acceptable salt thereof, such as sodium butyrate calcium butyrate, or magnesium butyrate, 3 times per day (a total of about 1800 mg / day) for at least one week.

[0124] Compounds of the present disclosure, whether administered alone, or in combination with a modulator of oxidative stress can be administered to a subject in need of such administration, for example a human or animal patient.Pharmaceutical Compositions

[0125] A pharmaceutical composition can be a combination of any compounds described herein with other chemical components, such as pharmaceutically acceptable carriers, stabilizers, binders, diluents, dispersing agents, suspending agents, thickening agents, solubilizing agents, or excipients. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions, or solutions. The pharmaceutical composition facilitates administration of the compound to an organism.

[0126] Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.

[0127] In some embodiments, the pharmaceutical composition provided herein comprises a buffer as an excipient. Non-limiting examples of buffers include potassium phosphate, sodium phosphate, phosphate buffer, citrate buffer, saline sodium citrate buffer (SSC), acetate, saline, physiological saline, phosphate buffer saline (PBS), 4-2-hy droxy ethyl- 1 -piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), and piperazine-N,N'-bis(2- ethanesulfonic acid) buffer (PIPES), citric acid monohydrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and any combination thereof.

[0128] In some embodiments, the pharmaceutical composition provided herein comprises an alcohol as an excipient. Non-limiting examples of alcohols include ethanol, propylene glycol, glycerol, polyethylene glycol, chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol, threitol,arabitol, ribitol, mannitol, galactilol, fucitol, lactitol, and any combination thereof.

[0129] Pharmaceutical preparations can be formulated with polyethylene glycol (PEG). PEGs with molecular weights ranging from about 300 g / mol to about 10,000,000 g / mol can be used. Nonlimiting examples of PEGs include PEG 200, PEG 300, PEG 400, PEG 540, PEG 550, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000, PEG 10,000, and PEG 20,000.

[0130] Further excipients that can be used in a composition described herein include, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, dehydroacetic acid, ethylenediamine, ethyl vanillin, glycerin, hypophosphorous acid, phenol, phenylethyl alcohol, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, sodium bisulfite, sodium metabisulfite, sorbic acid, thimerasol, acetic acid, aluminum monostearate, boric acid, calcium hydroxide, calcium stearate, calcium sulfate, calcium tetrachloride, cellulose acetate pthalate, microcrystalline celluose, chloroform, citric acid, edetic acid, and ethylcellulose.

[0131] In some embodiments, the pharmaceutical composition provided herein comprises an aprotic solvent as an excipient. Non-limiting examples of aprotic solvents include perfluorohexane, a,a,a- trifluorotoluene, pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane, carbon tetrachloride, freon-11, benzene, toluene, carbon disulfide, diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl acetate, 1,2-dimethoxy ethane, 2-methoxy ethyl ether, tetrahydrofuran, methylene chloride, pyridine, 2-butanone, acetone, N-methylpyrrolidinone, nitromethane, dimethylformamide, acetonitrile, sulfolane, dimethyl sulfoxide, and propylene carbonate.

[0132] The amount of the excipient in a pharmaceutical composition described herein can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% by mass of a compound in the pharmaceutical formulation.

[0133] The amount of the excipient in a pharmaceutical composition described herein can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% by mass or by volume of the unit dosage form.

[0134] In some embodiments, the addition of an excipient to a pharmaceutical composition described herein can increase or decrease the viscosity of the composition by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the addition of an excipient to a pharmaceutical composition described herein can increase or decrease the viscosity of the composition by no greater than 5%, no greater than 10%, no greater than 15%, no greater than 20%, no greater than 25%, no greater than 30%, no greater than 35%, no greater than 40%, no greater than 45%, no greater than 50%, no greater than 55%, no greater than 60%, no greater than 65%, no greater than 70%, no greater than 75%, no greater than 80%, no greater than 85%, no greater than 90%, no greater than 95%, or no greater than 99%.

[0135] A composition disclosed herein can be used as a complete food product, as a component of a food product, as a dietary supplement, as part of a dietary supplement, or as a feed additive, and can be either in liquid, semisolid or solid form. A composition disclosed herein can be in the form of a pharmaceutical composition. The compositions, dietary supplements, food products, baby food products, feed additives, and / or pharmaceutical compositions disclosed herein can advantageously be utilized in methods for promoting the health of an individual.

[0136] A composition disclosed herein can be in liquid, semisolid, or solid form. For example, the compositions can be administered as tablets, gel packs, capsules, gelatin capsules, flavored drinks, as a powder that can be reconstituted into such a drink, cooking oil, salad oil or dressing, sauce, syrup, mayonnaise, or margarine. Non-limiting examples of the food product and dietary supplements can include dairy products, baby food, baby formula, beverages, bars, a powder, a food topping, a drink,a cereal, an ice cream, a candy, a snack mix, a baked food product, and a fried food product. Nonlimiting examples of beverages include energy drinks, nutraceutical drinks, smoothies, sports drinks, orange juice, and other fruit drinks. Non-limiting examples of a bar include a meal replacement, a nutritional bar, a snack bar, an energy bar, and an extruded bar. Non-limiting examples of a dairy product include yogurt, yogurt drinks, cheese, and milk.

[0137] In some embodiments, a food products or dietary supplements can further comprise herbals, herbal extracts, fungal extracts, enzymes, fiber sources, minerals, and vitamins. In some embodiments, a microalgal oils and microalgal biomass can be used in the compositions disclosed herein for both therapeutic and non-therapeutic uses. Thus, the compositions, food products, and animal feed additives disclosed herein can be used for therapeutic or non-therapeutic purposes.

[0138] In some embodiments, a method disclosed herein comprises treating a condition. In some embodiments the condition is a skin disorder. In some embodiments, the condition is psoriasis. In some embodiments, treating comprises causing disappearance of a psoriatic lesion in the subject in need thereof. In some embodiments, a method disclosed herein reduces epidermal / dermal separation. In some embodiments, a method disclosed herein reduces or prevents degradation of the skin after inflammation.

[0139] In some embodiments, a therapeutically-effective amount can be an amount effective in treating a condition, treating a skin disorder, treating psoriasis, or treating an autoimmune disorder. In some embodiments, a therapeutically-effective amount can be an amount effective in causing disappearance of a psoriatic lesion in the subject in need thereof. The disappearance of a psoriatic lesion can be by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99%.

[0140] In some embodiments, a therapeutically-effective amount can be an amount effective in reduces epidermal / dermal separation in the skin. The epidermal / dermal separation can be reduced in size by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99%.

[0141] In some embodiments, a therapeutically-effective amount can be an amount effective in prevents degradation of the skin after inflammation.Pharmaceutically-A cceptable Salts.

[0142] The present disclosure provides the use of pharmaceutically-acceptable salts of any compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a baseaddition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically- acceptable salt is a metal salt.

[0143] Metal salts can arise from the addition of an inorganic base to a compound described herein. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0144] In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0145] Ammonium salts can arise from the addition of ammonia or an organic amine to a compound described herein. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N- methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, piprazole, imidazole, or pyrazine.

[0146] In some embodiments, an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N- methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a piprazole salt, an imidazole salt, or a pyrazine salt.

[0147] Acid addition salts can arise from the addition of an acid to a compound described herein. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrousacid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

[0148] In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt.Combinations

[0149] In some embodiments, a method disclosed herein further comprises administering a therapeutically-effective amount of a second therapy. In some embodiments, the second therapy exhibits synergy with a short chain fatty acid, for example as provided herein, or a pharmaceutically- acceptable salt thereof. In some embodiments, the second therapy exhibits an additive therapeutic effect to the short chain fatty, for example as provided herein, acid or a pharmaceutically-acceptable salt thereof. In some embodiments, the short chain fatty acid, for example as provided herein, or a pharmaceutically-acceptable salt thereof exhibits an additive therapeutic effect to the second therapy.

[0150] In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a therapeutically-effective amount of a short chain fatty acid, for example as provided herein, or a pharmaceutically-acceptable salt thereof and a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective for treating the condition in combination with the therapeutically-effective amount of the short chain fatty acid, for example as provided herein, or a pharmaceutically-acceptable salt thereof, and wherein the reduced amount of the second therapy is less than an amount of the second therapy that is therapeutically effective for the condition in absence of the therapeutically-effective amount of the short chain fatty acid, for example as provided herein, or a pharmaceutically-acceptable salt thereof.

[0151] In some embodiments, a combination can be in a single formulation or can be separate and administered in sequence (either a composition comprising at least one SCFA, for example as provided herein, or a molecule comprising a SCFA moiety, first and then a composition comprising an additional agent, or a composition comprising an additional agent first and then a composition comprising at least one SCFA, for example as provided herein, or a molecule comprising a SCFA moiety). In some embodiments, the SCFA, for example as provided herein, or a molecule comprising a SCFA moiety, can be administered to the subject about 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 0.25 hours, 0.5 hours, 0.75 hours, 1 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks before the composition comprising at least one additional agent is administered to the subject. In other embodiments, the composition comprising at least one additional agent can be administered to the subject about 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 0.25 hours, 0.5 hours, 0.75 hours, 1 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks before the composition comprising at least one SCFA, for example as provided herein, or a molecule comprising a SCFA moiety, is administered to the subject.

[0152] PDE4 Inhibitors

[0153] In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, for example as provided herein, or a biologically-active derivative or precursor thereof, in combination with one or more phosphodiesterase 4 (PDE4) inhibitors. Non-limiting examples of PDE4 inhibitors include Apremilast (Otezla®), roflumilast (Daxas®), Crisaborole (5-(4-Cyanophenoxy)-2,3-dihydro-l- hydroxy-2,l-benzoxaborole, AN-2728, Eucrisa®), Pefcalcitol (M5181), and HFP034 (butyl 2-[2-(2- fluorophenyl) acetamido] benzoate). In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, for example as provided herein, or a biologically-active derivative or precursor thereof, and additionally one or more PDE4 inhibitors. In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, for example as provided herein, or a biologically-active derivative or precursor thereof, in combination with a composition comprising one or more PDE4 inhibitor.

[0154] Biologic Agents

[0155] In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically-active derivative or precursor thereof, in combination with one or more biologic drugs. Nonlimiting biologic drugs include: etanercept (Enbrel®), infliximab (Remicade®), Apremilast (Otezla®), and adalimumab (Humira®). Additional nonlimiting examples of biologic drugs include: ustekinumab, secukinumab, ixekizumab, guselkumab, and risankizumab.

[0156] In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, for example as provided herein, or a biologically-active derivative or precursor thereof, and additionally one or more biologic agent. In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, for example as provided herein, or a biologically-active derivative or precursor thereof, in combination with a composition comprising one or more biologic agent.

[0157] Magnesium, Vitamin D, and Vitamin E

[0158] In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, for example as provided herein, or a biologically-active derivative or precursor thereof, and additionally one or more of magnesium or a source of magnesium, vitamin D (e.g., vitamin D3), and vitamin E (e.g., d-a-tocopherol acetate). Magnesium is a co-factor for more than 300 enzymes that regulate diverse biochemical reactions including regulation of blood glucose levels, detoxification, and others. Vitamin D3 deficiency is frequent in patients with immune disorders. Vitamin E has antioxidant activities. Non-limiting examples of a source of magnesium include magnesium chloride, magnesium hydroxide, magnesium carbonate, magnesium bicarbonate, magnesium sulfate, magnesium phosphate, and magnesium acetate.

[0159] In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, for example as provided herein, or a biologically-active derivative or precursor thereof, and additionally one or more of a source of magnesium, vitamin D (e.g., vitamin D3), and vitamin E. In some embodiments, a method disclosed herein comprises administering to a subject in need thereof a composition comprising at least one SCFA, for example as provided herein, or a biologically-active derivative or precursor thereof, in combination with a composition comprising one or more of a source of magnesium, vitamin D (e.g., vitamin D3), and vitamin E.

[0160] In some embodiments, a composition disclosed herein comprises a source of magnesium. In some embodiments, a composition disclosed herein comprises an inorganic magnesium salt such as magnesium chloride, magnesium carbonate, or magnesium phosphate. In some embodiments, a composition disclosed herein comprises vitamin D (e.g., vitamin D3). In some embodiments, a composition disclosed herein comprises vitamin E.

[0161] Any embodiments disclosed herein can be used in conjunction or individually. For example, any pharmaceutically-acceptable excipient, method, technique, solvent, or compound disclosed herein can be used together with any other pharmaceutically-acceptable excipient, method, technique, solvent, or compound disclosed herein to achieve any therapeutic result. Compounds, excipients, and other formulation components can be present at any amount, ratio, or percentagedisclosed herein in any such formulation, and any such combination can be used therapeutically for any purpose described herein.EXAMPLESEXAMPLE 1: Treatment of Skin Disorders with Short Chain Fatty Acids - assessment of IL10 cytokine response

[0162] Various assays were designed and tested in serum as shown and described for FIG. 1 and Table 1. Assays included evaluations of various cytokines (e.g., IL-10, IL-2, IL-4, IL-5, IL-12, IL- 13, IL-17, IL-lp, IL-6, IL-8, IFN-y, and TNF-a).

[0163] Study design

[0164] Capsules each comprising 800 mg of butyric acid, 50 mg of propionic acid, 40 IU of Vitamin D3, and 10 mg of magnesium chloride were administered orally three times daily to a subject having moderate to severe plaque psoriasis. The subject was orally administered two capsules in the morning, one capsule in the afternoon, and two capsules in the evening. The subject received treatment (e.g., five capsules) daily for five consecutive days until the end of the study.

[0165] Cytokine analysis - Multiplex assay

[0166] Human cytokines released in human serum were quantified using a Cytokine Panel 13 (Quest Diagnostics, test code: 36611).

[0167] Blood samples were collected from the subject at day 1 (study initiation) and at day 4 or day 5 (end of study). Separation was performed to separate serum from cells immediately following blood collection or within two hours of blood collection. For example, separation of plasma / serum from the red blood cells in the blood sample was achieved by centrifuging the blood sample for about 10 minutes at 3000 RPM.

[0168] Serum samples (approximately 0.4 mL to 1 mL serum) were transferred to a transport tube and frozen until analysis was performed. Samples and reference standards were assessed using a quantitative multiplex bead assay. The Cytokine Panel for various cytokines (e.g., IL-10, IL-2, IL-4, IL-5, IL-12, IL-13, IL-17, IL-10, IL-6, IL-8, IFN-y, and TNF-a) was used to assess cytokine release.

[0169] IL-10 is an anti-inflammatory cytokine which downregulates autoimmunity. IL-10 cytokine expression following treatment with SCFAs comprising butyric acid and propionic acid was assessed (FIG. 1) The levels of IL-10 expression of a serum sample for a subject at day 4 or day 5 was compared to the corresponding serum sample of the subject at day 1 (study initiation) (Table 1).Table 1 Expression values of IL-10

[0170] These experiments showed that administration of SCFAs increased IL-10 expression levels over time. The increased expression of the anti-inflammatory and immunosuppressive cytokine IL- 10 following administration of SCFAs in a subject indicated a reduced inflammatory mechanism in the subject due to the SCFAs.EXAMPLE 2: Treatment of Skin Disorders with Short Chain Fatty Acids - assessment of immediate pre- and post-treatment results in patients with scalp and palmoplantar psoriasis

[0171] Study design

[0172] Capsules each comprising 800 mg of butyric acid, 50 mg of propionic acid, 40 IU of Vitamin D3, and 10 mg of magnesium chloride were administered orally three times daily to subjects having moderate to severe plaque psoriasis (e.g., scalp and palmoplantar psoriasis). The subjects were eachorally administered two capsules in the morning, one capsule in the afternoon, and two capsules in the evening. The subjects received treatment (e.g., five capsules) daily for five consecutive days until the end of the study.

[0173] Representative images of immediate pre- and post-treatment results in patients administered the SCFA treatment regime are shown in FIGs. 2-6. In all patients tested, no adverse events were reported. These experiments showed that following administration of SCFAs, the subjects had marked improvement and / or complete resolution of skin lesions.EXAMPLE 3: Treatment of Skin Disorders with Short Chain Fatty Acids - assessment of ex vivo samples

[0174] Various assays were designed and tested in ex vivo samples (e.g., plasma, ear skin, back skin) from mouse imiquimod (IMQ)-induced psoriasis models as shown and described for FIGs. 7- 19. Assays included evaluations of various cytokines (e.g., IL-10, IL-23, IL-17A, TNF-a, and IL- 22).

[0175] Imiquimod (IMQ)-induced psoriasis model

[0176] Topical application of IMQ, a TLR7 / 8 ligand and potent immune activator induced and exacerbated psoriasis in mice. The mouse IMQ-induced psoriasis (IMQ Ps) model was initiated by a repeated topical application of Aldara© cream (containing 5% IMQ) over 6 consecutive days. Female Balb / c mice (9 weeks of age at reception, ordered with 20g, Charles River, Sulzfeld, Germany; n= 10 mice / group, exception healthy controls n= 4) received daily a topical application of 62.5 mg of commercially available IMQ cream (5% Aldara©) on the beforehand (day -1) shaved (~2cm x 3cm), depilated (Pilka© cream) back skin, and 7 mg on the outer right ear skin for 6 consecutive days, translating in a daily dose of approximately 3.5 mg IMQ. Healthy control mice were included in the study and were treated with vehicle cream (Vaseline; Bombastus-Werke AG) only instead of IMQ. Additionally, an IMQ disease control group was also included.

[0177] To evaluate the anti-inflammatory efficacy of the two compounds in mouse IMQ psoriasis, mice are treated twice daily (BID) by oral gavage with one of the following: (1) 12 mg / kg of Apremilast (in 0.5% CMC / 0.025% Tween80 in sterile water; m / m / v) alone, (2) 25 mg / kg of Apremilast (in 0.5% CMC / 0.025% Tween80 in sterile water; m / m / v) alone, (3) fixed dose of SCFA (in ddH2O) alone, (4) 12 mg / kg Apremilast in combination with fixed dose of SCFA, and (5) 25mg / kg Apremilast in combination with fixed dose of SCFA. Healthy and IMQ disease controls were orally treated in parallel with vehicle only. Etanercept (lOmg / kg Q3D s.c.) served as a technical control. All treatments started with a first application of IMQ on day 0.

[0178] In these experiments, the SCFAs administered were 60mg / kg / day of Ca-propionate and 1,100 mg / kg / day mixture of salts (Ca-butyrate and Mg-butyrate).

[0179] IMQ psoriasis is characterized by rapid induction of skin inflammation with pathologic and histologic resemblance to human psoriasis, including skin erythema, skin scaling and epidermal thickening (acanthosis), accompanied with immune cell infiltration.

[0180] Cytokine analysis - Multiplex assay

[0181] Pro-inflammatory cytokines (e.g., IL-10, IL-23, IL-17A, TNF-a, and IL-22) of each mouse were measured by multiplex ELISA in ex vivo samples (e.g., plasma, ear skin, back skin) collected on day 6 after IMQ psoriasis study.

[0182] With regards to observations of animal well-being, SCFA and all tested doses of Apremilast or combination treatments are well tolerated during the study duration.

[0183] For cytokine analysis in plasma, blood samples were collected and separation was performed to separate serum from cells immediately following blood collection or within two hours of blood collection. For example, separation of plasma / serum from the red blood cells in the blood sample was achieved by centrifuging the blood sample for about 10 minutes at 3000 RPM.

[0184] IL- 10

[0185] IL- 10 cytokine expression following treatment with SCFAs comprising butyric acid and propionic acid was assessed (FIGs. 7-9). Treatment with a monotherapy of SCFA increased IL-10 levels in plasma, ear skin, and back skin samples by 32%, 67%, and 58%, respectively, compared to IMQ disease controls. No significant change in IL-10 levels was observed in these samples following treatment with a monotherapy of Apremilast or a combination therapy of SCFA and Apremilast.

[0186] These experiments showed that administration of SCFAs increased IL-10 expression levels over time. The increased expression of the anti-inflammatory and immunosuppressive cytokine IL- 10 following administration of SCFAs in a subject indicated a reduced inflammatory mechanism in the subject due to the SCFAs.

[0187] IL-23

[0188] IL-23 cytokine expression following treatment with SCFAs comprising butyric acid and propionic acid was assessed (FIGs. 10-12). Treatment with a monotherapy of SCFA decreased IL- 23 levels in plasma and ear skin samples by 29% and 13%, respectively, compared to IMQ disease controls. A decrease in IL-23 levels was not observed in plasma and ear skin samples following treatment with a monotherapy of Apremilast. Treatment with a combination therapy of SCFA and Apremilast decreased IL-23 levels by 34% and 37% in plasma samples. However, no significant change in IL-23 levels was observed in ear skin samples.

[0189] IL-17A

[0190] IL-17A cytokine expression following treatment with SCFAs comprising butyric acid and propionic acid was assessed (FIGs. 13-15). Treatment with a monotherapy of SCFA did not significantly change IL-17A levels in plasma and back skin samples, but IL-17A levels were reduced by 26% in ear skin samples. Treatment with a monotherapy of Apremilast or a combination therapy of SCFA and Apremilast reduced IL-17A levels in all sample sources tested (e.g., plasma, ear skin, and back skin).

[0191] TNF-a

[0192] TNF-a cytokine expression following treatment with SCFAs comprising butyric acid and propionic acid was assessed (FIGs. 16-17). All treatments tested, a monotherapy of SCFA, treatment with a monotherapy of Apremilast, and a combination therapy of SCFA and Apremilast, slightly reduced the levels of TNFa in ear skin samples.

[0193] IL-22

[0194] IL-22 cytokine expression following treatment with SCFAs comprising butyric acid and propionic acid was assessed (FIGs. 18-19). IL-22 was not induced in ear skin or back skin samples of IMQ disease controls. In these assays, no treatment effects were observed.EMBODIMENTS

[0196] The following non-limiting embodiments provide illustrative examples of the disclosure, but do not limit the scope of the disclosure.

[0197] Embodiment 1. A method comprising: (a) obtaining a level of a biomarker in a subject, wherein the biomarker is an anti-inflammatory cytokine, wherein the subject is undergoing a regimen of short chain fatty acid therapy for an inflammatory condition; and (b) based on the level of the biomarker in the subject, continuing the short chain fatty acid therapy, wherein the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 40% over a period of about four to five days.

[0198] Embodiment 2. A method comprising: (a) administering a therapeutically-effective amount of a short chain fatty acid therapy for an inflammatory condition to a subject in need thereof; (b) after the administering, obtaining a level of a biomarker in a subject, wherein the biomarker is an anti-inflammatory cytokine; and (c) based on the level of the biomarker in the subject, continuing the short chain fatty acid therapy wherein the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 40% over a period of about four to five days.

[0199] Embodiment 3. The method of any one of embodiments 1-2, wherein the anti-inflammatory cytokine is Interleukin (IL)- 10.

[0200] Embodiment 4. The method of any one of embodiments 1-3, wherein the inflammatory condition is a skin disorder.

[0201] Embodiment 5. The method of any one of embodiments 1-4, wherein the inflammatory condition is an autoimmune disorder.

[0202] Embodiment 6. The method of any one of embodiments 1-5, wherein the inflammatory condition is psoriasis.

[0203] Embodiment 7. The method of any one of embodiments 1-6, wherein the short chain fatty acid therapy suppresses production of a pro-inflammatory cytokine.

[0204] Embodiment 8. The method of any one of embodiments 1-7, wherein the short chain fatty acid therapy comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises butyric acid or a pharmaceutically-acceptable salt thereof.

[0205] Embodiment 9. The method of embodiment 8, wherein the pharmaceutical composition comprises butyric acid.

[0206] Embodiment 10. The method of embodiment 8, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of butyric acid, wherein the pharmaceutically- acceptable salt of butyric acid is sodium butyrate.

[0207] Embodiment 11. The method of embodiment 8, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of butyric acid, wherein the pharmaceutically- acceptable salt of butyric acid is magnesium butyrate.

[0208] Embodiment 12. The method of embodiment 8, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of butyric acid, wherein the pharmaceutically- acceptable salt of butyric acid is calcium butyrate.

[0209] Embodiment 13. The method of any one of embodiments 8-12, wherein the pharmaceutical composition further comprises propionic acid or a pharmaceutically-acceptable salt thereof.

[0210] Embodiment 14. The method of embodiment 13, wherein the pharmaceutical composition comprises propionic acid.

[0211] Embodiment 15. The method of embodiment 13, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of propionic acid, wherein the pharmaceutically- acceptable salt of propionic acid is sodium propionate.

[0212] Embodiment 16. The method of embodiment 13, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt, wherein the pharmaceutically-acceptable salt of propionic acid is magnesium propionate.

[0213] Embodiment 17. The method of embodiment 13, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt, wherein the pharmaceutically-acceptable salt of propionic acid is calcium propionate.

[0214] Embodiment 18. The method of any one of embodiments 8-17, wherein the pharmaceutical composition further comprises acetic acid or a pharmaceutically-acceptable salt thereof.

[0215] Embodiment 19. The method of embodiment 18, wherein the pharmaceutical composition comprises acetic acid.

[0216] Embodiment 20. The method of embodiment 18, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of acetic acid, wherein the pharmaceutically- acceptable salt of acetic acid is sodium acetate.

[0217] Embodiment 21. The method of embodiment 18, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of acetic acid, wherein the pharmaceutically- acceptable salt of acetic acid is magnesium acetate.

[0218] Embodiment 22. The method of embodiment 18, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of acetic acid, wherein the pharmaceutically- acceptable salt of acetic acid is calcium acetate.

[0219] Embodiment 23. The method of any one of embodiments 1-7, wherein the short chain fatty acid therapy comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises about 100 mg to about 4000 mg of butyric acid or a pharmaceutically-acceptable salt thereof.

[0220] Embodiment 24. The method of any one of embodiments 1-7, wherein the short chain fatty acid therapy comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises about 500 mg to about 3000 mg of butyric acid or a pharmaceutically-acceptable salt thereof.

[0221] Embodiment 25. The method of any one of embodiments 1-7, wherein the short chain fatty acid therapy comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises about 800 mg to about 1800 mg of butyric acid or a pharmaceutically-acceptable salt thereof.

[0222] Embodiment 26. The method of any one of embodiments 23-25, wherein the pharmaceutical composition further comprises about 10 mg to about 500 mg of propionic acid or a pharmaceutically-acceptable salt thereof.

[0223] Embodiment 27. The method of any one of embodiments 23-25, wherein the pharmaceutical composition further comprises about 25 mg to about 250 mg of propionic acid or a pharmaceutically-acceptable salt thereof.

[0224] Embodiment 28. The method of any one of embodiments 23-25, wherein the pharmaceutical composition further comprises about 50 mg to about 200 mg of propionic acid or a pharmaceutically-acceptable salt thereof.

[0225] Embodiment 29. The method of any one of embodiments 8-28, wherein the pharmaceutical composition further comprises vitamin D.

[0226] Embodiment 30. The method of any one of claims 8-28, wherein the pharmaceutical composition further comprises vitamin D3.

[0227] Embodiment 31. The method of any one of claims 8-28, wherein the pharmaceutical composition further comprises vitamin D3 in an amount from about 50 IU to about 200 IU.

[0228] Embodiment 32. The method of any one of claims 8-31, wherein the pharmaceutical composition further comprises a source of magnesium.

[0229] Embodiment 33. The method of any one of claims 8-31, wherein the pharmaceutical composition further comprises an inorganic magnesium salt.

[0230] Embodiment 34. The method of any one of claims 8-31, wherein the pharmaceutical composition further comprises a source of magnesium in an amount of from about 10 mg to about 20 mg.

[0231] Embodiment 35. The method of any one of claims 8-31, wherein the pharmaceutical composition further comprises magnesium chloride.

[0232] Embodiment 36. The method of any one of claims 8-31, wherein the pharmaceutical composition further comprises magnesium chloride in an amount of from about 10 mg to about 20 mg.

[0233] Embodiment 37. The method of any one of claims 8-36, wherein the pharmaceutical composition is a capsule.

[0234] Embodiment 38. The method of any one of claims 8-36, wherein the pharmaceutical composition is an enteric coated, extended-release capsule.

[0235] Embodiment 39. The method of any one of claims 1-38, wherein the level of the biomarker in the subject is obtained from any assay of a tissue of the subject.

[0236] Embodiment 40. The method of claim 39, further comprising performing the assay of the tissue of the subject.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method comprising: a) obtaining a level of a biomarker in a subject, wherein the biomarker is an antiinflammatory cytokine, wherein the subject is undergoing a regimen of short chain fatty acid therapy for an inflammatory condition; and b) based on the level of the biomarker in the subject, continuing the short chain fatty acid therapy, wherein the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 40% over a period of about four to five days.

2. A method comprising: a) administering a therapeutically-effective amount of a short chain fatty acid therapy for an inflammatory condition to a subject in need thereof; b) after the administering, obtaining a level of a biomarker in a subject, wherein the biomarker is an anti-inflammatory cytokine; and c) based on the level of the biomarker in the subject, continuing the short chain fatty acid therapy wherein the level of the biomarker shows elevated expression of the biomarker in the subject by at least about 40% over a period of about four to five days.

3. The method of any one of claims 1-2, wherein the anti-inflammatory cytokine is Interleukin (IL)-10.

4. The method of any one of claims 1-3, wherein the inflammatory condition is a skin disorder.

5. The method of any one of claims 1-4, wherein the inflammatory condition is an autoimmune disorder.

6. The method of any one of claims 1-5, wherein the inflammatory condition is psoriasis.

7. The method of any one of claims 1-6, wherein the short chain fatty acid therapy suppresses production of a pro-inflammatory cytokine.

8. The method of any one of claims 1-7, wherein the short chain fatty acid therapy comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises butyric acid or a pharmaceutically-acceptable salt thereof.

9. The method of claim 8, wherein the pharmaceutical composition comprises butyric acid.

10. The method of claim 8, wherein the pharmaceutical composition comprises thepharmaceutically-acceptable salt of butyric acid, wherein the pharmaceutically-acceptable salt of butyric acid is sodium butyrate.

11. The method of claim 8, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of butyric acid, wherein the pharmaceutically-acceptable salt of butyric acid is magnesium butyrate.

12. The method of claim 8, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of butyric acid, wherein the pharmaceutically-acceptable salt of butyric acid is calcium butyrate.

13. The method of any one of claims 8-12, wherein the pharmaceutical composition further comprises propionic acid or a pharmaceutically-acceptable salt thereof.

14. The method of claim 13, wherein the pharmaceutical composition comprises propionic acid.

15. The method of claim 13, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of propionic acid, wherein the pharmaceutically-acceptable salt of propionic acid is sodium propionate.

16. The method of claim 13, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt, wherein the pharmaceutically-acceptable salt of propionic acid is magnesium propionate.

17. The method of claim 13, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt, wherein the pharmaceutically-acceptable salt of propionic acid is calcium propionate.

18. The method of any one of claims 8-17, wherein the pharmaceutical composition further comprises acetic acid or a pharmaceutically-acceptable salt thereof.

19. The method of claim 18, wherein the pharmaceutical composition comprises acetic acid.

20. The method of claim 18, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of acetic acid, wherein the pharmaceutically-acceptable salt of acetic acid is sodium acetate.

21. The method of claim 18, wherein the pharmaceutical composition comprises the pharmaceutically-acceptable salt of acetic acid, wherein the pharmaceutically-acceptable salt of acetic acid is magnesium acetate.

22. The method of claim 18, wherein the pharmaceutical composition comprises thepharmaceutically-acceptable salt of acetic acid, wherein the pharmaceutically-acceptable salt of acetic acid is calcium acetate.

23. The method of any one of claims 1-7, wherein the short chain fatty acid therapy comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises about 100 mg to about 4000 mg of butyric acid or a pharmaceutically-acceptable salt thereof.

24. The method of any one of claims 1-7, wherein the short chain fatty acid therapy comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises about 500 mg to about 3000 mg of butyric acid or a pharmaceutically-acceptable salt thereof.

25. The method of any one of claims 1-7, wherein the short chain fatty acid therapy comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises about 800 mg to about 1800 mg of butyric acid or a pharmaceutically-acceptable salt thereof.

26. The method of any one of claims 23-25, wherein the pharmaceutical composition further comprises about 10 mg to about 500 mg of propionic acid or a pharmaceutically-acceptable salt thereof.

27. The method of any one of claims 23-25, wherein the pharmaceutical composition further comprises about 25 mg to about 250 mg of propionic acid or a pharmaceutically-acceptable salt thereof.

28. The method of any one of claims 23-25, wherein the pharmaceutical composition further comprises about 50 mg to about 200 mg of propionic acid or a pharmaceutically-acceptable salt thereof.

29. The method of any one of claims 8-28, wherein the pharmaceutical composition further comprises vitamin D.

30. The method of any one of claims 8-28, wherein the pharmaceutical composition further comprises vitamin D3.

31. The method of any one of claims 8-28, wherein the pharmaceutical composition further comprises vitamin D3 in an amount from about 50 IU to about 200 IU.

32. The method of any one of claims 8-31, wherein the pharmaceutical composition further comprises a source of magnesium.

33. The method of any one of claims 8-31, wherein the pharmaceutical composition further comprises an inorganic magnesium salt.

34. The method of any one of claims 8-31, wherein the pharmaceutical composition further comprises a source of magnesium in an amount of from about 10 mg to about 20 mg.

35. The method of any one of claims 8-31, wherein the pharmaceutical composition further comprises magnesium chloride.

36. The method of any one of claims 8-31, wherein the pharmaceutical composition further comprises magnesium chloride in an amount of from about 10 mg to about 20 mg.

37. The method of any one of claims 8-36, wherein the pharmaceutical composition is a capsule.

38. The method of any one of claims 8-36, wherein the pharmaceutical composition is an enteric coated, extended-release capsule.

39. The method of any one of claims 1-38, wherein the level of the biomarker in the subject is obtained from any assay of a tissue of the subject.

40. The method of claim 39, further comprising performing the assay of the tissue of the subject.

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