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Fenchone Ameliorates Constipation-Predominant Irritable Bowel Syndrome via Modulation of SCF/c-Kit Pathway and Gut Microbiota

  • Li Cui (Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine) ;
  • Bin Zhang (Digestive Department, Nanjing Lishui District Hospital of Traditional Chinese Medicine) ;
  • Shuting Zou (Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine) ;
  • Jing Liu (Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine) ;
  • Pingrong Wang (Jinling Clinical Medical College, Nanjing University of Chinese Medicine) ;
  • Hui Li (Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine) ;
  • Zhenhai Zhang (Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine)
  • Received : 2023.08.08
  • Accepted : 2023.10.16
  • Published : 2024.02.28

Abstract

In this study we sought to elucidate the therapeutic effects of fenchone on constipation-predominant irritable bowel syndrome (IBS-C) and the underlying mechanisms. An IBS-C model was established in rats by administration of ice water by gavage for 14 days. Fenchone increased the reduced body weight, number of fecal pellets, fecal moisture, and intestinal transit rate, and decreased the enhanced visceral hypersensitivity in the rat model of IBS-C. In addition, fenchone increased the serum content of excitatory neurotransmitters and decreased the serum content of inhibitory neurotransmitters in the IBS-C rat model. Meanwhile, western blot and immunofluorescence experiments indicated that fenchone increased the expressions of SCF and c-Kit. Furthermore, compared with the IBS-C model group, fenchone increased the relative abundance of Lactobacillus, Blautia, Allobaculum, Subdoligranulum, and Ruminococcaceae_UCG-008, and reduced the relative abundance of Bacteroides, Enterococcus, Alistipes, and Escherichia-Shigella on the genus level. Overall, fenchone ameliorates IBS-C via modulation of the SCF/c-Kit pathway and gut microbiota, and could therefore serve as a novel drug candidate against IBS-C.

Keywords

Acknowledgement

This work was financially supported by the National Natural Science Foundation of China (81403121), Jiangsu Provincial TCM Science and Technology Development Plan Project (MS2021025), Social Development Project of Jiangsu Province (BE2022817), and the central government financial transfer payment for local projects from the National Administration of Traditional Chinese Medicine (2022GJJZDYJS-01).

References

  1. Sedky AA, Magdy Y. 2020. Tadalafil versus linaclotide in gastrointestinal dysfunction and depressive behavior in constipation-predominant irritable bowel syndrome. Life Sci. 256: 117960.
  2. Ling X, Peng S, Zhong J, Guo L, Xu Y, Jin X, et al. 2022. Effects of Chang-Kang-Fang formula on the microbiota-gut-brain axis in rats with irritable bowel syndrome. Front. Pharmacol. 13: 778032.
  3. Mishima Y, Ishihara S. 2021. Enteric microbiota-mediated serotonergic signaling in pathogenesis of irritable bowel syndrome. Int. J. Mol. Sci. 22: 10235.
  4. Siddiqui S, Cash BD. 2020. Tenapanor for constipation-predominant irritable bowel syndrome. Drugs Today (Barc) 56: 203-210.
  5. Sonu I, Triadafilopoulos G, Gardner JD. 2016. Persistent constipation and abdominal adverse events with newer treatments for constipation. BMJ Open Gastroenterol. 3: e000094.
  6. Qiu Z, Dai X, Fan C, Cao Y, Lv Z, Liang X, et al. 2023. A new regioselective synthesis of the cysteine-rich peptide linaclotide. Molecules 28: 10007.
  7. Annahazi A, Schemann M. 2022. Contribution of the enteric nervous system to autoimmune diseases and irritable bowel syndrome. Adv. Exp. Med. Biol. 1383: 1-8.
  8. Huang Z, Lin Z, Lin C, Chu H, Zheng X, Chen B, et al. 2022. Transcutaneous electrical acustimulation improves irritable bowel syndrome with constipation by accelerating colon transit and reducing rectal sensation using autonomic mechanisms. Am. J. Gastroenterol. 117: 1491-1501.
  9. Mokhtar NM, Jaafar NM, Alfian E, Mohd Rathi ND, Abdul Rani R, Raja Ali RA. 2021. Clinical assessment and cytokines level in constipation-predominant irritable bowel syndrome participants treated with Lactobacillus-containing cultured milk drink. Acta Gastroenterol. Belg. 84: 585-591.
  10. Cheng CH, Liu YC, Yang YSH, Lin KJ, Wu D, Liu YR, et al. 2023. Plasmon-activated water as a therapeutic strategy in Alzheimer's disease by altering gut microbiota. Aging (Albany NY) 15: 3715-3737.
  11. Ma M, Wang Y, Fan S, Huang Y, Su X, Lu C. 2023. Urolithin A alleviates colitis in mice by improving gut microbiota dysbiosis, modulating microbial tryptophan metabolism, and triggering AhR activation. J. Agric. Food Chem. 71: 7710-7722.
  12. Wu L, Gao L, Jin X, Chen Z, Qiao X, Cui X, et al. 2023. Ethanol extract of Mao Jian green tea attenuates gastrointestinal symptoms in a rat model of irritable bowel syndrome with constipation via the 5-hydroxytryptamine signaling pathway. Foods 12: 1101.
  13. Lim YJ, Jamaluddin R, Hazizi AS, Chieng JY. 2018. Effects of synbiotics among constipated adults in Serdang, Selangor, Malaysia-A Randomised, double-blind, placebo-controlled trial. Nutrients 10: 824.
  14. DuPont AW, Jiang ZD, Harold SA, Snyder N, Galler GW, Garcia-Torres F, et al. 2014. Motility abnormalities in irritable bowel syndrome. Digestion 89: 119-123.
  15. Foong D, Zhou J, Zarrouk A, Ho V, O'Connor MD. 2020. Understanding the biology of human interstitial cells of Cajal in gastrointestinal motility. Int. J. Mol. Sci. 21: 4540.
  16. Feng J, Gao J, Zhou S, Liu Y, Zhong Y, Shu Y, et al. 2017. Role of stem cell factor in the regulation of ICC proliferation and detrusor contraction in rats with an underactive bladder. Mol. Med. Rep. 16: 1516-1522.
  17. Valdivieso-Ugarte M, Gomez-Llorente C, Plaza-Diaz J, Gil A. 2019. Antimicrobial, antioxidant, and immunomodulatory properties of essential oils: a systematic review. Nutrients 11: 2786.
  18. Bordbar G, Miri MB, Omidi M, Shoja S, Akhavan M. 2020. Efficacy and safety of a novel herbal medicine in the treatment of irritable bowel syndrome: a randomized double-blinded clinical trial. Gastroenterol. Res. Pract. 2020: 8213082.
  19. Di Vito M, Bellardi MG, Sanguinetti M, Mondello F, Girolamo A, Barbanti L, et al. 2020. Potent in vitro activity of Citrus aurantium essential oil and Vitis vinifera hydrolate against gut yeast isolates from irritable bowel syndrome patients-the right mix for potential therapeutic use. Nutrients 12: 1329.
  20. Pittler MH, Ernst E. 1998. Peppermint oil for irritable bowel syndrome: a critical review and metaanalysis. Am. J. Gastroenterol. 93: 1131-1135.
  21. Kim T, Song B, Cho KS, Lee IS. 2020. Therapeutic potential of volatile terpenes and terpenoids from forests for inflammatory diseases. Int. J. Mol. Sci. 21: 2187.
  22. Slavchev I, Dobrikov GM, Valcheva V, Ugrinova I, Pasheva E, Dimitrov V. 2014. Antimycobacterial activity generated by the amide coupling of (-)-fenchone derived aminoalcohol with cinnamic acids and analogues. Bioorg. Med. Chem. Lett. 24: 5030-5033.
  23. Keskin I, Gunal Y, Ayla S, Kolbasi B, Sakul A, Kilic U, et al. 2017. Effects of Foeniculum vulgare essential oil compounds, fenchone and limonene, on experimental wound healing. Biotech. Histochem. 92: 274-282.
  24. Pessoa MLS, Silva LMO, Araruna MEC, Serafim CAL, Junior EBA, Silva AO, et al. 2020. Antifungal activity and antidiarrheal activity via antimotility mechanisms of (-)-fenchone in experimental models. World J. Gastroenterol. 26: 6795-6809.
  25. Filippone A, Ardizzone A, Bova V, Lanza M, Casili G, Cuzzocrea S, et al. 2022. A combination of xyloglucan, pea protein and Chia seed ameliorates intestinal barrier integrity and mucosa functionality in a rat model of constipation-predominant irritable bowel syndrome. J. Clin. Med. 11: 7073.
  26. Hao M, Song J, Zhai X, Cheng N, Xu C, Gui S, et al. 2023. Improvement of loperamide-hydrochloride-induced intestinal motility disturbance by Platycodon grandiflorum polysaccharides through effects on gut microbes and colonic serotonin. Front. Cell Infect. Microbiol. 13: 1105272.
  27. Gershon MD, Margolis KG. 2021. The gut, its microbiome, and the brain: connections and communications. J. Clin. Invest. 131: e143768.
  28. Gershon MD. 2013. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr. Opin. Endocrinol. Diabetes Obes. 20: 14-21.
  29. Chen L, Zhang J, Suo H, Wang W, Wang H, Zhang Y, et al. 2019. Preventive effects of different fermentation times of shuidouchi on diphenoxylate-induced constipation in mice. Foods 8: 86.
  30. Qian Y, Suo H, Du M, Zhao X, Li J, Li GJ, et al. 2015. Preventive effect of Lactobacillus fermentum Lee on activated carbon-induced constipation in mice. Exp. Ther. Med. 9: 272-278.
  31. Li T, Hu M, Jiang C, Zhang D, Gao M, Xia J, et al. 2021. Laxative effect and mechanism of Tiantian Capsule on loperamide-induced constipation in rats. J. Ethnopharmacol. 266: 113411.
  32. Zhang J, Gao N, Jiang H, Li H, Cui X, Tang S, et al. 2022. Comparative study on alleviating effect of kiwi berry (Actinidia arguta) polysaccharide and polyphenol extracts on constipated mice. Food Res. Int. 162: 112037.
  33. Hu M, Fang C, Liu Y, Gao M, Zhang D, Shi G, et al. 2021. Comparative study of the laxative effects of konjac oligosaccharides and konjac glucomannan on loperamide-induced constipation in rats. Food Funct. 12: 7709-7717.
  34. Wen Y, Li J, Long Q, Yue CC, He B, Tang XG. 2020. The efficacy and safety of probiotics for patients with constipation-predominant irritable bowel syndrome: a systematic review and meta-analysis based on seventeen randomized controlled trials. Int. J. Surg. 79: 111-119.
  35. Shang X, E FF, Guo KL, Li YF, Zhao HL, Wang Y, et al. 2022. Effectiveness and safety of probiotics for patients with constipation-predominant irritable bowel syndrome: a systematic review and meta-analysis of 10 randomized controlled trials. Nutrients 14: 2482.
  36. Quigley EMM, Markinson L, Stevenson A, Treasure FP, Lacy BE. 2023. Randomised clinical trial: efficacy and safety of the live biotherapeutic product MRx1234 in patients with irritable bowel syndrome. Aliment. Pharmacol. Ther. 57: 81-93.
  37. Polansky O, Sekelova Z, Faldynova M, Sebkova A, Sisak F, Rychlik I. 2015. Important metabolic pathways and biological processes expressed by chicken cecal microbiota. Appl. Environ. Microbiol. 82: 1569-1576.
  38. Zhou W, Liu P, Xu W, Ran L, Yan Y, Lu L, et al. 2023. A purified fraction of polysaccharides from the fruits of Lycium barbarum L. improves glucose homeostasis and intestinal barrier function in high-fat diet-fed mice. Food Funct. 14: 5311-5325.
  39. van Muijlwijk GH, van Mierlo G, Jansen P, Vermeulen M, Bleumink-Pluym NMC, Palm NW, et al. 2021. Identification of Allobaculum mucolyticum as a novel human intestinal mucin degrader. Gut Microbes 13: 1966278.
  40. Wang Y, Zhang N, Kan J, Zhang X, Wu X, Sun R, et al. 2019. Structural characterization of water-soluble polysaccharide from Arctium lappa and its effects on colitis mice. Carbohydr. Polym. 213: 89-99.
  41. Cui L, Guan X, Ding W, Luo Y, Wang W, Bu W, et al. 2021. Scutellaria baicalensis Georgi polysaccharide ameliorates DSS-induced ulcerative colitis by improving intestinal barrier function and modulating gut microbiota. Int. J. Biol. Macromol. 166: 1035-1045.
  42. Ji M, Huang H, Lan X. 2022. Correlation between intestinal microflora in irritable bowel syndrome and severity. Dis. Markers 2022: 1031844.
  43. Wang L, Alammar N, Singh R, Nanavati J, Song Y, Chaudhary R, et al. 2020. Gut microbial dysbiosis in the irritable bowel syndrome: a systematic review and meta-analysis of case-control studies. J. Acad. Nutr. Diet 120: 565-586.
  44. Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, et al. 2017. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol. Aging 49: 60-68.
  45. Grant CV, Loman BR, Bailey MT, Pyter LM. 2021. Manipulations of the gut microbiome alter chemotherapy-induced inflammation and behavioral side effects in female mice. Brain Behav. Immun. 95: 401-412.
  46. Parker BJ, Wearsch PA, Veloo ACM, Rodriguez-Palacios A. 2020. The genus alistipes: gut bacteria with emerging implications to inflammation, cancer, and mental health. Front. Immunol. 11: 906.
  47. Hasan R, Bose S, Roy R, Paul D, Rawat S, Nilwe P, et al. 2022. Tumor tissue-specific bacterial biomarker panel for colorectal cancer: bacteroides massiliensis, Alistipes species, Alistipes onderdonkii, Bifidobacterium pseudocatenulatum,Corynebacterium appendicis. Arch. Microbiol. 204: 348.