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CN-122005524-A - Use of sodium propionate or a pharmaceutically acceptable salt thereof in the preparation of a medicament for modulating the microbial-intestinal-brain axis treatment of colon cancer-associated depression

CN122005524ACN 122005524 ACN122005524 ACN 122005524ACN-122005524-A

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to application of sodium propionate or pharmaceutically acceptable salt thereof in preparing a medicine for regulating a microorganism-intestine-brain axis to treat colon cancer-related depression, wherein the sodium propionate regulates the microorganism-intestine-brain axis through three synergistic paths, activates GPR41/FFAR3 to promote GLP-1 and PYY to release and regulate central emotion functions through vagus nerves, inhibits HDAC activity to enhance histone acetylation to promote BDNF expression and inhibits pro-inflammatory factors, activates GPR43/FFAR2 to promote Treg differentiation to repair intestinal barriers, and experiments show that the sodium propionate can improve depression-like behaviors of colon cancer-bearing tumor-combining CUMS mice and inhibit tumor growth.

Inventors

  • ZHANG ANWEI
  • DU JUAN

Assignees

  • 宁夏医科大学

Dates

Publication Date
20260512
Application Date
20260410

Claims (10)

  1. 1. The use of sodium propionate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating a microbial-intestinal-brain axis for the treatment of colon cancer-associated depression, characterized in that sodium propionate modulates the intestinal-brain axis by three synergistic pathways, the metabolic-endocrine pathway, i.e. sodium propionate activates the free fatty acid receptor GPR41/FFAR3 on the surface of the endocrine L cells of the intestinal tract, the epigenetic-immune pathway, i.e. sodium propionate inhibits class I and class IIa histone deacetylase activity, and the intestinal immune tolerance pathway, i.e. sodium propionate activates the GPR43/FFAR2 signal.
  2. 2. The use according to claim 1, wherein the pharmaceutical is in the form of an oral formulation selected from the group consisting of an oral solution, an enteric capsule or an enteric tablet.
  3. 3. The use according to claim 1, wherein the sodium propionate is administered in a dose of 100 to 400 mg/kg body weight/day.
  4. 4. The use according to claim 1, wherein the medicament is an enteric formulation, the enteric coating material of which is selected from Eudragit L100-55 acrylic resin.
  5. 5. The use of claim 1, wherein the colon cancer patient exhibits symptoms of depression as one or more of reduced sugar water preference rate, prolonged forced swimming immobility time, and reduced open field exploration behavior.
  6. 6. Use according to claim 1, characterized in that the sodium propionate is used in combination with an antitumor drug selected from 5-fluorouracil, oxaliplatin or capecitabine in the preparation of a medicament.
  7. 7. The use according to claim 1, wherein sodium propionate is used in combination with a selective 5-hydroxytryptamine reuptake inhibitor in the manufacture of a medicament.
  8. 8. The use according to claim 1, wherein the medicament further comprises dietary fiber as an adjunct ingredient.
  9. 9. The use according to claim 1, wherein the administration cycle of sodium propionate is not less than 4 weeks of continuous administration.
  10. 10. The use according to claim 1, wherein the medicament is a sodium propionate sustained-release microsphere formulation, wherein the mass ratio of sodium propionate to polylactic acid-glycolic acid copolymer is from 1:2 to 1:4.

Description

Use of sodium propionate or a pharmaceutically acceptable salt thereof in the preparation of a medicament for modulating the microbial-intestinal-brain axis treatment of colon cancer-associated depression Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to application of sodium propionate or pharmaceutically acceptable salt thereof in preparation of a medicine for regulating microorganism-intestinal-brain axis to treat colon cancer-related depression. Background Colorectal cancer is the third malignancy with the third global incidence rate, and more than 55 thousands of colorectal cancer cases are newly increased in China every year. Epidemiological studies have shown that colon cancer patients have a proportion of up to 20% to 47% of their concomitant depression, significantly higher than the level of morbidity in the general population. A multicenter prospective study involving 6000 more intestinal disease patients found that the incidence of depression symptoms in the first year after diagnosis of colon cancer patients was about 2.4 times that of the general population, and that the severity of depression symptoms was positively correlated with tumor stage. Colon cancer-associated depression not only severely reduces the quality of life of the patient, but also accelerates tumor progression and recurrence by impairing the immune monitoring function of natural killer cells and cytotoxic T lymphocytes, reducing the patient's therapeutic compliance with surgical and chemotherapeutic regimens, forming a tumor-depressive malignancy cycle. Meta-analysis data shows that five-year survival rate of colon cancer patients with depression is reduced by about 25% compared with that of colon cancer patients without depression, which indicates that depression state itself becomes an independent risk factor for influencing prognosis of colon cancer. In recent years, the discovery of the microorganism-Gut-Brain Axis (Microbiota-glut-Brain Axis, MGBA) provides a completely new perspective for understanding the co-morbid relationship of colon cancer and depression. The gut microbiota communicates bi-directionally with the central nervous system through a number of pathways, including the vagal pathway, the immunomodulatory pathway, the neuroendocrine pathway, and the microbial metabolite pathway. In the vagus nerve channel, after the endocrine cells of the intestinal tract sense the microbial metabolites in the cavity, 5-hydroxytryptamine, glucagon-like peptide-1 and other signal molecules are released, and the vagus nerve afferent fibers are activated to transmit signals to central emotion regulating and controlling areas such as solitary nucleus, blue spot nucleus, marginal system and the like. In the immunomodulating pathway, the impaired intestinal barrier results in bacterial lipopolysaccharide and pro-inflammatory factors (e.g., TNF-alpha, IL-6, IL-1 beta) entering the blood via the portal vein, activating microglial cells across the blood brain barrier to trigger neuroinflammation, interfering with monoamine neurotransmitter synthesis and signal transduction. Among the microbial metabolite pathways, short chain fatty acids (Short-CHAIN FATTY ACIDS, SCFAS) are the most interesting mediator molecules. Short chain fatty acids are the major metabolites produced by the intestinal flora fermenting dietary fiber, with about 60% acetic acid, about 25% propionic acid, and about 15% butyric acid. SCFAs play a key role in maintaining intestinal barrier integrity, modulating immune responses, and affecting central nervous system function. In the intestinal tract, SCFAs activate downstream signaling pathways by binding to G-protein coupled receptors GPR41 (FFAR 3) and GPR43 (FFAR 2) on the surface of colonic epithelial cells, promoting mucus secretion and tight junction protein expression, enhancing intestinal barrier function. In the immune system, propionic acid and butyric acid regulate the differentiation and function of regulatory T cells (tregs) by inhibiting Histone Deacetylase (HDAC) activity, establishing intestinal immune tolerance. In the central nervous system, SCFAs in circulating blood can cross the blood brain barrier, affecting neuronal function and synaptic plasticity through epigenetic regulation and neuroprotective factor expression. The research shows that the intestinal microbiota composition of colon cancer patients is obviously changed, the abundance of short-chain fatty acid-producing flora (such as bacteroides, ross and faecalis) is obviously reduced, and the level of protective metabolites such as propionic acid, butyric acid and the like in the intestinal tract is reduced. Such dysbacteriosis induces or aggravates depression symptoms by means of intestinal-brain axis conduction to the central nervous system through the pathways of increased inflammatory factor release, increased intestinal permeability, disturbed neurotransmitter metabolism,