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KR-102961289-B1 - Prevention or treatment of Western diet-induced inflammatory bowel disease by inhibiting expression and activation of gut-taste receptor TAS1R3

KR102961289B1KR 102961289 B1KR102961289 B1KR 102961289B1KR-102961289-B1

Abstract

The present invention provides a method for screening a composition for treating inflammatory bowel disease or a drug for treating inflammatory bowel disease that includes a substance that reduces TAS1R3 gene expression or inhibits protein activity as an active ingredient. When a TAS1R3 expression inhibitor or a TAS1R3 protein activity inhibitor is used according to the present invention, it has the advantage of effectively preventing, improving, or treating inflammatory bowel disease by altering the intestinal microbial community, strengthening tight junctions between intestinal cells, and inhibiting the secretion of inflammatory cytokines. This can be usefully applied for the treatment of inflammatory bowel disease in Asians, which is rapidly increasing due to Western diets, for which no appropriate treatment has been developed to date.

Inventors

  • 신동미
  • 손우정

Assignees

  • 서울대학교산학협력단

Dates

Publication Date
20260507
Application Date
20230120
Priority Date
20220124

Claims (14)

  1. A pharmaceutical composition for the prevention or treatment of inflammatory bowel disease comprising a TAS1R3 expression inhibitor or a TAS1R3 protein activity inhibitor as an active ingredient, wherein the TAS1R3 expression inhibitor is a TAS1R3-specific antisense oligonucleotide, siRNA, shRNA, or miRNA, and the TAS1R3 protein activity inhibitor is a TAS1R3-specific antibody, aptamer, or antagonist.
  2. delete
  3. delete
  4. A pharmaceutical composition according to claim 1, characterized in that the inflammatory bowel disease is an inflammatory bowel disease induced by a Western diet.
  5. In claim 1, the pharmaceutical composition is (i) Changes in the gut microbiome; (ii) Strengthening tight junctions between cells in the intestine; and/or (iii) A pharmaceutical composition characterized by preventing or treating inflammatory bowel disease by inducing an increase in the expression of antimicrobial peptide secretion genes.
  6. A pharmaceutical composition according to claim 5, characterized in that the change in the intestinal microbiome is the expansion of intestinal anaerobic butyrate bacteria and/or inhibition of intestinal harmful bacteria.
  7. A food composition for preventing or improving inflammatory bowel disease comprising a TAS1R3 expression inhibitor or a TAS1R3 protein activity inhibitor as an active ingredient, wherein the TAS1R3 expression inhibitor is a TAS1R3-specific antisense oligonucleotide, siRNA, shRNA, or miRNA, and the TAS1R3 protein activity inhibitor is a TAS1R3-specific antibody, aptamer, or antagonist.
  8. delete
  9. delete
  10. A food composition according to claim 7, characterized in that the inflammatory bowel disease is an inflammatory bowel disease induced by a Western diet.
  11. In claim 7, the above food composition is (i) Changes in the gut microbiome; (ii) Strengthening tight junctions between cells in the intestine; and/or (iii) A food composition characterized by preventing or improving inflammatory bowel disease by inducing an increase in the expression of antimicrobial peptide secretion genes.
  12. A food composition according to claim 11, characterized in that the change in the intestinal microbiome is the expansion of intestinal anaerobic butyrate bacteria and/or the inhibition of intestinal harmful bacteria.
  13. Screening method for inflammatory bowel disease treatments including the following steps: (a) a step of treating a candidate substance to a cell or tissue in which TAS1R3 is expressed or the TAS1R3 protein is active; (b) A step of selecting the above candidate substance as a therapeutic agent for inflammatory bowel disease when TAS1R3 expression is inhibited or TAS1R3 protein activity is inhibited.
  14. A method according to claim 13, characterized in that the inflammatory bowel disease is an inflammatory bowel disease caused by a Western diet.

Description

Prevention or treatment of Western diet-induced inflammatory bowel disease by inhibiting expression and activation of gut-taste receptor TAS1R3 The present invention has identified that inflammatory bowel disease caused by the intake of a Western diet can be prevented or treated by inhibiting the expression and activation of the intestinal taste receptor TAS1R3. The present invention provides a method for screening a composition for treating inflammatory bowel disease or a drug for treating inflammatory bowel disease, wherein the substance inhibiting TAS1R3 gene expression deficiency and the corresponding protein activity is an active ingredient. Inflammatory bowel disease (IBD) is a condition characterized by chronic inflammation of unknown cause within the intestinal tract that alternates between periods of remission and relapse; ulcerative colitis and Crohn's disease are representative examples. According to the U.S. CDC (Centers for Disease Control and Prevention), there are over 4 million IBD patients worldwide, with an estimated 1.4 million patients in the United States alone and over 70,000 new cases reported annually. Consequently, the global market for inflammatory bowel disease treatments reached $11.7 billion in 2014 and is projected to grow to over 19 trillion won by 2023. It is noteworthy that while the incidence of inflammatory bowel disease in Asian countries was low (in fact, it was previously classified as a very rare disease), the number of domestic patients with inflammatory bowel disease has been rapidly increasing over the past decade. According to an analysis of data from the Health Insurance Review and Assessment Service, the number of patients treated for Crohn's disease in Korea in 2015 alone exceeded 18,000, with total medical expenses exceeding 47.3 billion won. Furthermore, the number of new patients more than doubled between 2010 and 2019, and due to the nature of the disease involving repeated remissions and relapses, the number of domestic patients is expected to continue increasing. Changes in environmental factors can be cited as a cause for the sudden increase in incidence in Asia, and in particular, changes in Westernized dietary patterns have been reported to be highly significant in relation to the occurrence of the disease (The role of diet in the aetiopathogenesis of inflammatory bowel disease. Nature Review Gastroenterology Hepatology , 2018, 15:525-535). Inflammatory bowel disease places a significant emotional burden on patients due to its nature as a 'disease directly related to physiological phenomena,' including intermittent abdominal pain. Currently, biological cytokine inhibitors such as anti-TNF agents, anti-integrin agents, and IL-12/23 inhibitors are the dominant treatments for inflammatory bowel disease. However, in the case of anti-TNF agents, 50 to 60 percent of patients do not respond or the response disappears within one year. As a result, there is a high demand for the development of new treatments, as many patients fail to respond to existing standard drug treatments (5-Aminosalicylic acid (5-ASA) agents, steroids, immunomodulators, etc.) or undergo surgery due to side effects. Furthermore, since currently marketed treatments and methods are typically targeted at Westerners such as those in the United States and Europe, research results have reported that their effectiveness is actually significantly lower for inflammatory bowel disease in Asians, whose incidence has rapidly increased due to Westernized dietary habits (Treatment of inflammatory bowel disease in Asia. Intest Res , 2016, 14(3):231-239; Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia, Intest Res , 2019, 17(3):285-310). Accordingly, the inventors, noting that there are no separate therapeutic agents or treatment methods targeting the pathogenesis of inflammatory bowel disease induced by environmental factors such as the intake of a Western diet, made diligent efforts to develop a therapeutic agent specific to inflammatory bowel disease occurring particularly in the Asian region. As a result, they confirmed that long-term intake of a Western diet actually induces severe inflammation in the intestines, and that the intestinal taste receptor TAS1R3 can act as an important mediator in mediating such intestinal inflammation. Furthermore, they discovered that knocking out TAS1R3 significantly increases the transcription factor PPAR-γ within intestinal cells, which i) increases the expression of genes involved in tight junction reinforcement and antimicrobial peptide secretion, thereby enhancing the intestinal mucosal defense system and strengthening the protective mechanism against Western diet-induced intestinal inflammation; additionally, the increased PPAR-γ ii) creates a hypoxic state in the intestinal lumen, thereby [addressing] anaerobic butyrate bacteria The present invention was completed by verifying that intestinal inflammation