Use of L-phenylalanine for the preparation of a product for the treatment of enteritis

Abstract

The application discloses application of L-phenylalanine in preparation of an intestinal inflammation treatment product, wherein the L-phenylalanine has a CAS number of 63-91-2, belongs to a natural amino acid, and has high safety; the product is a drug, a food or a feed additive; the application can treat inflammatory bowel disease, reduce intestinal inflammatory reactions, and promote intestinal mucosal repair and maintenance of intestinal mucosal barrier function, so that intestinal inflammation related clinical symptoms are improved.

Description

Technical Field

[0001] This application relates to the field of metabolite application technology, and in particular to the application of L-phenylalanine in the preparation of enteritis treatment products. Background Technology

[0002] Inflammatory bowel disease (IBD) is an idiopathic inflammatory bowel disease affecting the ileum, colon, and rectum. Clinically, it primarily manifests as diarrhea, abdominal pain, and bloody mucus stools; severe cases can be accompanied by various systemic complications. IBD mainly includes ulcerative colitis (UC) and Crohn's disease (CD). Ulcerative colitis is characterized by continuous inflammation of the colonic mucosa and submucosa, typically starting in the rectum and gradually extending proximally to the entire colon. Crohn's disease can affect the entire digestive tract, presenting as discontinuous, full-thickness inflammation, most commonly in the terminal ileum, but can also involve the colon and perianal region.

[0003] The etiology and pathogenesis of inflammatory bowel disease (IBD) are not fully understood. Currently, it is believed that abnormal activation of the intestinal mucosal immune system and the resulting excessive inflammatory response play a key role in IBD development, which is likely due to the combined effects of multiple factors, including environmental, genetic, infectious, and immune factors. Existing treatment strategies mainly include anti-inflammatory drugs, glucocorticoids, immunomodulators, and biologics.

[0004] However, existing treatments for IBD primarily focus on suppressing inflammatory activity itself and often come with certain toxic side effects. Their targeted support for intestinal repair, mucosal regeneration, and barrier function recovery after inflammatory damage remains limited, making it difficult to simultaneously address the dual needs of inflammation control and tissue repair. Especially after intestinal inflammation causes intestinal mucosal damage, there is still a lack of safe, effective, and sustainable interventions that can reduce the inflammatory response while promoting the restoration of structural integrity and functional stability of the damaged intestinal mucosa.

[0005] Therefore, in the treatment of inflammatory bowel diseases, there are common problems such as insufficient intestinal mucosal barrier repair capacity, limited effect of existing interventions on tissue repair, and lack of safe, effective and low-side-effect natural small molecule intervention substances. There is an urgent need to develop new intervention strategies that can both reduce inflammatory response and promote tissue repair in order to achieve effective treatment of the disease. Summary of the Invention

[0006] This application provides the use of L-phenylalanine in the preparation of products for treating inflammatory bowel diseases in mammals, especially humans, and aims to address the problems in the prior art regarding the insufficient recovery capacity of the intestinal mucosal barrier after inflammatory damage, the limited promotion of tissue repair by existing intervention methods, and the lack of safe, effective, and low-side-effect natural small molecule intervention substances in the repair of intestinal inflammatory damage.

[0007] The L-phenylalanine, with CAS number 63-91-2, is a natural amino acid and has high safety. The product is a pharmaceutical, food, or feed additive that can reduce intestinal inflammatory responses, promote intestinal mucosal repair, and / or improve clinical symptoms related to intestinal inflammation.

[0008] In the above scheme, optionally, the intestinal inflammatory disease includes, but is not limited to, inflammatory bowel disease, infectious enteritis, allergic enteritis, drug-induced enteritis, and chemical enteritis; preferably, inflammatory bowel disease, especially ulcerative colitis or Crohn's disease.

[0009] Optionally, the product described in the above scheme is a drug.

[0010] Optionally, in the above scheme, the product is a food containing L-phenylalanine, including human food and animal food. The human food is a beverage, solid food, dietary supplement, or medical nutrition food; the animal food is feed or feed additive.

[0011] Optionally, in the above scheme, the product is a feed additive.

[0012] In the above scheme, the target of treatment is a mammal, especially a human.

[0013] Compared with the prior art, this application has at least the following beneficial effects: Based on further analysis and research of existing technologies, this application identifies several shortcomings in the treatment of inflammatory bowel diseases. These include insufficient recovery capacity of the intestinal mucosal barrier after inflammatory damage, limited promotion of tissue repair and mucosal regeneration by existing interventions, and a lack of safe, effective, and low-side-effect natural small-molecule intervention substances. To address these issues, this application utilizes L-phenylalanine in the preparation of products for treating inflammatory bowel diseases, allowing it to directly participate in the regulation of intestinal inflammation as an active ingredient. The L-phenylalanine is a natural amino acid with high safety profile, which helps reduce potential side effects during intervention.

[0014] Since intestinal inflammatory diseases are not only about the inflammatory response itself, but also accompanied by pathological changes such as intestinal mucosal damage, decreased barrier function, and damaged colon tissue morphology, when L-phenylalanine is used in the above-mentioned products, it can alleviate intestinal inflammation and reduce the continuous damage of the inflammatory state to intestinal tissues. On the other hand, it can promote intestinal mucosal repair and improve the phenomenon of colon shortening, thereby promoting the transformation of damaged intestinal tissues from a damaged state to a repaired state. Furthermore, the repair of intestinal mucosa and the improvement of colon morphology are further conducive to the improvement of intestinal barrier integrity and intestinal function.

[0015] Therefore, by giving L-phenylalanine the use of treating inflammatory bowel diseases, this application achieves synergistic intervention in the regulation of inflammatory responses and the repair of damaged tissues, thereby making up for the shortcomings of existing technologies in simultaneously addressing inflammation control and tissue repair. Attached Figure Description

[0016] Figure 1 This is a schematic diagram of the chemical formula of L-phenylalanine provided in one embodiment of this application; Figure 2 A schematic diagram showing the changes in body weight of mice after DSS according to one embodiment of this application; Figure 3 A macroscopic result diagram of mouse colon length provided in one embodiment of this application; Figure 4 A graph showing the statistical results of mouse colon length provided in one embodiment of this application; Figure 5 HE staining image of the colon of a DSS control group mouse provided in one embodiment of this application (400×). Figure 6 HE staining image of the colon of mice in the DSS experimental group provided in one embodiment of this application (400×). Figure 7 A statistical graph of colonic pathology results provided in one embodiment of this application; Figure 8 A graph showing the fecal occult blood score results of experimental dogs in a routine diet group before and after two weeks of treatment, as provided in an embodiment of this application; Figure 9 A graph showing the fecal occult blood score results of experimental dogs in the L-phenylalanine diet group before and after two weeks of treatment, as provided in an embodiment of this application; Figure 10 This is a graph showing the CIBDAI scores of experimental dogs in a standard diet group before and after two weeks of treatment, as provided in one embodiment of this application. Figure 11 CIBDAI score results of experimental dogs in the L-phenylalanine diet group before and after two weeks of treatment, as provided in one embodiment of this application; Figure 12A comparison chart of CIBDAI scores of experimental dogs in a routine diet group and an L-phenylalanine diet group provided in one embodiment of this application; Figure 13 This is a colonoscopy image of an experimental dog in a routine diet group after two weeks of treatment, as provided in one embodiment of this application. Figure 14 This is a colonoscopy image of an experimental dog after two weeks of treatment with an L-phenylalanine diet, provided in one embodiment of this application. Figure 15 This is a schematic diagram of the colonoscopy scoring results of the routine diet group and the L-phenylalanine diet group of experimental dogs provided in one embodiment of this application. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of this application clearer, the following detailed description is provided in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application.

[0018] Prolonged intestinal inflammation can lead to persistent damage to the intestinal mucosal barrier, clinically manifesting as recurrent episodes of symptoms such as abdominal pain and rectal bleeding. In severe cases, it can progress to intestinal perforation, stenosis, or even cancer. The loss of barrier function not only causes local pathological damage but can also lead to the translocation of toxins into the bloodstream, inducing extraintestinal complications such as joint and skin problems. Furthermore, long-term malabsorption and psychological stress can seriously impair the patient's health and life.

[0019] To address the aforementioned clinical challenges, this invention is the first to discover the significant efficacy of the natural amino acid compound L-phenylalanine in treating inflammatory bowel diseases. Currently, there are no reports of L-phenylalanine's application in treating inflammatory bowel diseases, both domestically and internationally, indicating significant potential for clinical development. To solve the above-mentioned technical problems, in one embodiment, such as Figure 1 The illustration provides the use of L-phenylalanine in the manufacture of products for treating intestinal inflammatory diseases in mammals, particularly humans. The L-phenylalanine, CAS number 63-91-2, is a natural amino acid with high safety profile, which helps reduce potential side effects during intervention. The product is a pharmaceutical, food, or feed additive, and its application can alleviate intestinal inflammatory responses, promote intestinal mucosal repair, and / or improve colonic atrophy.

[0020] The L-phenylalanine in this embodiment can be obtained from commercial sources, such as L-phenylalanine powder with a purity of 99%.

[0021] In this embodiment, "preparing a product for treating intestinal inflammatory diseases in mammals, especially humans" refers to adding L-phenylalanine as the active ingredient to a product system suitable for human or mammalian intake. This allows the product to exert a therapeutic effect by regulating the inflammatory response when intestinal inflammation occurs in humans or mammals. The therapeutic effect is not only reflected in the reduction of the inflammatory response but also includes the repair of intestinal tissue damage and the restoration of function resulting from the improvement of inflammation. The above effects do not refer to changes in a single indicator but include multiple interrelated improvements, such as reduced inflammation severity, improved weight recovery, reduced colonic shortening, improved intestinal mucosal morphology, reduced histopathological damage, and the resulting improvement in colonic function. In practice, the therapeutic effect of the product can be comprehensively evaluated based on the above indicators.

[0022] This embodiment evaluates the therapeutic effect of L-phenylalanine in a mouse DSS-induced colitis model (ulcerative colitis model). For example, healthy SPF-grade C57BL / 6J female mice were used. Colitis was induced by replacing normal drinking water with a 2% DSS solution. After DSS treatment ended and the inflammation was still active, L-phenylalanine was administered orally. In this embodiment, L-phenylalanine was dissolved in sterile saline to form a solution with a concentration of 6 mg / mL. The experimental group received 200 μL per mouse via gavage, while the control group received an equal volume of saline. Mouse weight changes were recorded during administration, and colon length was measured after sacrifice. Simultaneously, the distal colon tissue was stained with hematoxylin and eosin (HE) to evaluate the therapeutic effect of L-phenylalanine on inflammatory bowel disease.

[0023] This embodiment evaluates the therapeutic effect of L-phenylalanine in a beagle canine acetic acid-induced colitis model (ulcerative colitis model). Exemplarily, beagle dogs can be used to establish an intestinal inflammation model. While the inflammation remains active after modeling, dogs are fed a regular diet and a diet containing L-phenylalanine for two consecutive weeks. During this period, clinical indicators such as fecal condition, fecal occult blood score, frequency of defecation, vomiting, appetite, and mental status are recorded. After feeding, the degree of intestinal inflammation and disease activity are evaluated using colonoscopy and CIBDAI scoring. This large animal implementation further illustrates the therapeutic efficacy and applicability of L-phenylalanine in different animal models of intestinal inflammatory diseases and provides experimental evidence for its application in mammals, especially humans.

[0024] The therapeutic effects of "reducing intestinal inflammation, promoting intestinal mucosal repair, and / or improving intestinal tissue damage" in this embodiment can be demonstrated by multiple results. In mouse experiments, on the third day after L-phenylalanine administration, the experimental group showed better weight recovery than the control group; anatomical observation on the fourth day showed that the experimental group had a less severe colonic shortening; HE staining results showed that the experimental group had better colonic pathological evaluation than the control group. In canine experiments, the fecal occult blood score, CIBDAI score, and endoscopic bleeding points and ulcers were reduced in the L-phenylalanine-containing diet group, the intestinal mucosa was smoother, and the endoscopic score was correspondingly lower.

[0025] This embodiment utilizes L-phenylalanine in the preparation of a product for treating inflammatory bowel diseases, allowing it to directly participate in the regulation of bowel inflammation as an active ingredient. This application can alleviate bowel inflammatory responses and reduce the associated damage to bowel tissues caused by inflammation, thereby exerting a therapeutic effect. Simultaneously, it can promote intestinal mucosal repair, improve colonic shortening and pathological damage, and improve fecal occult blood, clinical scores, and endoscopic findings, further contributing to the recovery of bowel function.

[0026] In this embodiment, the product is a drug. In this embodiment, L-phenylalanine can be prepared and used according to the concept of pharmaceutical formulation, so as to serve as an active ingredient in a drug for the treatment of mammalian, especially human, inflammatory bowel diseases.

[0027] In some embodiments, the product can be a drug, which facilitates accurate and standardized administration of L-phenylalanine, enabling it to reduce inflammatory responses, promote intestinal mucosal repair, and improve colonic damage during the treatment of intestinal inflammation, thereby enhancing the feasibility of this use in therapeutic products.

[0028] In this embodiment, the product is a feed additive. L-phenylalanine can be used not only as an active ingredient in pharmaceuticals but also as a functional additive in feed systems. In feed additive form, L-phenylalanine can be added to a food matrix or feed matrix in a predetermined ratio, allowing mammals or humans to ingest it during their daily diet. This approach is particularly suitable for applications requiring continuous intervention, mild intervention, or long-term nutritional support.

[0029] In practice, L-phenylalanine in feed additive form can be directly added to food ingredients, feed ingredients, or their mixtures, and after thorough mixing, an ingestible product containing L-phenylalanine can be obtained. In existing canine examples, the L-phenylalanine-containing growth diet used in the L-phenylalanine diet group can be considered as an implementation of adding L-phenylalanine as a food additive to an edible matrix. The effects of L-phenylalanine in feed additive form can be evaluated through continuous feeding combined with fecal occult blood score, CIBDAI score, and colonoscopy observation.

[0030] This embodiment enables L-phenylalanine to be incorporated into ingestible products as a feed additive, thereby broadening the product forms of L-phenylalanine in the treatment of intestinal inflammatory diseases. This form facilitates continuous intake, which is beneficial for supporting the treatment of intestinal inflammatory diseases without relying on strict drug administration procedures, and improving fecal occult blood, clinical status, and intestinal mucosal manifestations.

[0031] In this embodiment, the food is a human food or an animal food containing L-phenylalanine.

[0032] The food described in this embodiment is a human food or animal feed containing L-phenylalanine. As a specific implementation, the animal food can be feed containing L-phenylalanine. Food containing L-phenylalanine can be obtained by adding L-phenylalanine to conventional food or feed ingredients and mixing them thoroughly; alternatively, it can be obtained through a substitution feeding method, allowing humans or mammals to continuously ingest food or feed containing L-phenylalanine. The human food can be a functional food or nutritional supplement, and the animal feed is particularly suitable for companion animals such as dogs and cats, as well as other animals suitable for feeding and management.

[0033] In practice, after modeling, experimental animals can be divided into a conventional diet group and a diet containing L-phenylalanine. The conventional diet group is given a standard growth diet, while the other group is given a growth diet containing L-phenylalanine. During the feeding period, fecal condition, fecal occult blood score, frequency of defecation, vomiting, appetite, and mental state are recorded. After feeding, colonoscopy and CIBDAI scores are performed. The canine example has shown that feeding with a diet containing L-phenylalanine improves relevant clinical and endoscopic evaluation indicators.

[0034] In some embodiments, the food can be a feed containing L-phenylalanine, allowing L-phenylalanine to continuously enter the animal's body through daily feeding, thus making it more suitable for forming a continuous and stable intervention process. This embodiment is beneficial for improving fecal occult blood, clinical scores, and colonoscopy findings during intestinal inflammatory diseases, and is particularly suitable for practical applications in the animal field.

[0035] In practice, the mouse examples can provide a reference for determining the dosage range.

[0036] Mice weighing approximately 19-20g were given a gavage volume of 200μL and an L-phenylalanine solution concentration of 6mg / mL. Therefore, each mouse ingested approximately 1.2mg of L-phenylalanine, which translates to over 60mg / kg. For feed formulations, the amount of L-phenylalanine added can be pre-calculated based on the animal's weight and daily feed intake. The specific conversion is as follows: In cross-species dose conversion, the body surface area normalization method can be used for estimation: based on a mouse dose of approximately 60 mg / kg, common conversion factors are used for estimation: when the conversion factor is 9.1, the human equivalent dose is approximately 6.6 mg / kg; for a 60 kg adult, the total daily dose is approximately 396 mg. When the FDA-recommended conversion factor of 12.3 is used, the human equivalent dose is approximately 4.9 mg / kg; for a 60 kg adult, the total daily dose is approximately 294 mg. These results indicate that L-phenylalanine has potential human application value within a reasonable dosage range and can provide a reference for subsequent clinical dosage design.

[0037] The purpose of this embodiment is to provide an application of natural small molecule amino acids in the treatment of inflammatory bowel diseases. These natural small molecule amino acids can significantly reduce intestinal inflammation, promote intestinal repair after colitis, and improve intestinal tissue damage.

[0038] In this embodiment, the natural small molecule amino acid is L-phenylalanine.

[0039] This embodiment provides the application of L-phenylalanine in the preparation of drugs for the treatment of inflammatory bowel diseases in mammals, especially humans.

[0040] The product can be a pharmaceutical, food, or feed additive. Specifically, in the pharmaceutical embodiment, L-phenylalanine can be used to prepare drugs for the prevention or treatment of inflammatory bowel diseases and to promote bowel repair; in the food or feed additive embodiment, it can be used for continuous intervention through daily intake.

[0041] In this embodiment, the metabolite L-phenylalanine was purchased commercially from Aladdin Company, catalog number P651996, CAS number: 63-91-2, in 100g 99% pure dry powder form. Healthy SPF-grade C57BL / 6J female mice, 8 weeks old and weighing approximately 19-20g, were selected and divided into an experimental group (L-phenylalanine) and a control group (Vehicle), with 6 mice in each group. After drinking autoclaved deionized water for one day, both groups of mice had their normal drinking water replaced with a 2% DSS solution. The mice's weight changes were recorded daily. After 6 days of DSS drinking, when the mice's weight decreased to approximately 90%, DSS drinking was stopped, and filtered autoclaved deionized water was used instead. After 2 days, when the mice's weight decreased to approximately 85%, the enteritis model was considered successfully established, and L-phenylalanine was administered via gavage. L-Phenylalanine was provided by a commercial supplier and dissolved in sterile physiological saline at a concentration of 6 mg / mL, prepared fresh for immediate use. The experimental group was administered 200 μL of the 6 mg / mL L-phenylalanine aqueous solution by gavage, while the control group was administered an equal volume of physiological saline by gavage. The body weight of the mice was observed.

[0042] In this embodiment, female beagle dogs around 12 months of age were selected. After modeling with glacial acetic acid, they were randomly divided into a conventional diet group and an L-phenylalanine diet group, with 3 beagle dogs in each group. The diets of the two groups were replaced with conventional growth diet and L-phenylalanine-containing growth diet, respectively. Fecal condition, frequency of defecation, vomiting, appetite, and mental state were recorded daily. Colonoscopy and CIBDAI scoring were performed after 2 weeks.

[0043] Statistical analysis was performed using Prism10 software (GraphPad Software, LaJolla, CA) through multiple... t To compare the changes in body weight between the two groups, the significance level was set at [value missing]. p <0.05. Data are presented as mean ± standard error (Mean ± SEM). Results from mouse experiments showed that, 3 days after oral administration of L-phenylalanine, the weight gain in the experimental group was significantly different from that in the control group. Figure 2 As shown in the image. After euthanizing the mice on day 4, the colons of the two groups were observed. It was found that the colon shortening in the experimental group was significantly better than that in the control group. Figure 3 and Figure 4 As shown in the image. Simultaneously, HE staining was performed on the distal colon of the mice, and the results indicated that the pathological evaluation of the colon in the experimental group was significantly better than that in the control group. Figures 5-7 As shown in the results for experimental dogs, after 2 weeks of feeding a diet containing L-phenylalanine, the fecal occult blood score in the conventional diet group did not change compared to before treatment. Figure 8As shown, the fecal occult blood score in the L-phenylalanine diet group was significantly lower than before treatment. Figure 9 As shown.

[0044] The CIBDAI score of the standard diet group remained unchanged compared to before treatment. Figure 10 As shown, the CIBDAI score of the L-phenylalanine diet group was significantly lower than before treatment, such as... Figure 11 As shown; at the same time, compared with the conventional diet group, the CIBDAI score of the L-phenylalanine diet group was significantly lower, such as Figure 12 As shown. Colonoscopy results indicated that, compared to the conventional diet group, the L-phenylalanine diet group showed fewer bleeding points and ulcers in the colon, and the intestinal mucosa appeared smoother and without protrusions, as shown. Figures 13-14 As shown. Meanwhile, colonoscopy scores showed that the L-phenylalanine group had significantly lower scores compared to the conventional diet group, such as... Figure 15 As shown.

[0045] In conclusion, the above results lay the foundation for the potential application of L-phenylalanine in the treatment of inflammatory bowel diseases in mammals, especially humans.

[0046] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

Claims

1. The application of L-phenylalanine in the preparation of products for the treatment of enteritis, wherein the L-phenylalanine has the CAS number 63-91-2, is a natural amino acid, and has high safety; the product is a drug, food, or feed additive, and the application can treat inflammatory bowel diseases, reduce intestinal inflammatory response, promote intestinal mucosal repair and maintain intestinal mucosal barrier function, thereby improving clinical symptoms related to intestinal inflammation.

2. The application according to claim 1, characterized in that, The clinical symptoms associated with the aforementioned inflammatory bowel disease include one or more of the following: abnormal stool condition, rectal bleeding, diarrhea, abnormal frequency of bowel movements, and decreased appetite.

3. The application according to claim 1, characterized in that, The inflammatory bowel disease includes inflammatory bowel disease, infectious enteritis, allergic enteritis, drug-induced enteritis, and chemical enteritis; preferably inflammatory bowel disease, especially ulcerative colitis or Crohn's disease.

4. The application according to claim 1, characterized in that, The product in question is a medicine.

5. The application according to claim 1, characterized in that, The product is a feed additive.

6. The application according to claim 1, characterized in that, The food products mentioned include human or animal food products containing L-phenylalanine.

7. The application according to claim 1, characterized in that, The treatment targets mammals and humans.

8. The application according to claim 6, characterized in that, The human food products mentioned are beverages, solid foods, dietary supplements, or medical nutrition foods.

9. The application according to claim 6, characterized in that, The animal food is feed or feed additive.

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