Short‑chain fatty acid butyrate: A novel shield against chronic gastric ulcer

Zhou,Yan; Ji,Xiawei; Chen,Jiajing; Fu,Yaoyang; Huang,Juewei; Guo,Rui; Zhou,Jinhui; Cen,Jianke; Zhang,Qihao; Chu,Anne; Huang,Yingpeng; Xu,Changlong; Wang,Fangyan

doi:10.3892/etm.2021.9760

Short‑chain fatty acid butyrate: A novel shield against chronic gastric ulcer

Authors:
- Yan Zhou
- Xiawei Ji
- Jiajing Chen
- Yaoyang Fu
- Juewei Huang
- Rui Guo
- Jinhui Zhou
- Jianke Cen
- Qihao Zhang
- Anne Chu
- Yingpeng Huang
- Changlong Xu
- Fangyan Wang
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Affiliations: Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Pathophysiology, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of General Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: February 5, 2021 https://doi.org/10.3892/etm.2021.9760
Article Number: 329
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Butyrate is one of the most abundant short‑chain fatty acids produced by intestinal bacteria. In the present study, the action of butyrate on chronic gastric mucosa lesions was investigated, as well as its underlying mechanism in mice. Male mice from the Institute of Cancer Research were randomly divided into three groups: Sham, model and butyrate groups. Butyrate was administered intragastrically for 7 days to butyrate group mice following the establishment of a gastric ulcer model. Hematoxylin and eosin staining, immunohistochemical analysis, enzyme‑linked immunosorbent assay and quantitative polymerase chain reaction were used to determine the therapeutic effects and molecular mechanism of butyrate treatment. The findings demonstrated that butyrate induced a marked shift in superoxide dismutase and catalase activities, along with a decrease in malondialdehyde levels, thereby attenuating oxidative stress. Furthermore, butyrate decreased the levels of pro‑inflammatory cytokines interleukin‑1β, tumour necrosis factor‑α and leukotriene B4, which helped combat inflammatory responses. Moreover, butyrate treatment exerted remarkable positive influences that mediate an increase in 6‑keto‑PGF‑1α (a degradation product of prostacyclin), trefoil factor 2, MUC5AC and fibroblast growth factor‑7 levels to promote gastric mucosal repair. The expression of specific receptor GPR109A for butyrate was upregulated, with no significant difference noted in the expression of GPR43 or GPR41. Overall, the present findings revealed that butyrate exerted therapeutic effects by upregulating mucosal repair factors and stimulating protective responses against oxidation and inflammation. GPR109A may be the key receptor for butyrate therapy.

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1	Graham DY: History of Helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer. World J Gastroenterol. 20:5191–5204. 2014.PubMed/NCBI View Article : Google Scholar
2	Waldum HL, Kleveland PM and Sordal OF: Helicobacter pylori and gastric acid: An intimate and reciprocal relationship. Therap Adv Gastroenterol. 9:836–844. 2016.PubMed/NCBI View Article : Google Scholar
3	Adeniyi OS, Emikpe BO and Olaleye SB: Accelerated gastric ulcer healing in thyroxine-treated rats: Roles of gastric acid, mucus, and inflammatory response. Can J Physiol Pharmacol. 96:597–602. 2018.PubMed/NCBI View Article : Google Scholar
4	Brzozowski T, Magierowska K, Magierowski M, Ptak-Belowska A, Pajdo R, Kwiecien S, Olszanecki R and Korbut R: Recent advances in the gastric mucosal protection against stress-induced gastric lesions. Importance of renin-angiotensin vasoactive metabolites, gaseous mediators and appetite peptides. Curr Pharm Des. 23:3910–3922. 2017.PubMed/NCBI View Article : Google Scholar
5	Yu LY, Sun LN, Zhang XH, Li YQ, Yu L, Yuan ZQ, Meng L, Zhang HW and Wang YQ: A review of the novel application and potential adverse effects of proton pump inhibitors. Adv Ther. 34:1070–1086. 2017.PubMed/NCBI View Article : Google Scholar
6	Yang X, Li Y, Sun Y, Zhang M, Guo C, Mirza IA and Li YQ: Vonoprazan: A novel and potent alternative in the treatment of acid-related diseases. Dig Dis Sci. 63:302–311. 2018.PubMed/NCBI View Article : Google Scholar
7	Yamamoto O, Okada Y and Okabe S: Effects of a proton pump inhibitor, omeprazole, on gastric secretion and gastric and duodenal ulcers or erosions in rats. Dig Dis Sci. 29:394–401. 1984.PubMed/NCBI View Article : Google Scholar
8	Yoon H and Kim N: Diagnosis and management of high risk group for gastric cancer. Gut Liver. 9:5–17. 2015.PubMed/NCBI View Article : Google Scholar
9	Ang TL and Fock KM: Clinical epidemiology of gastric cancer. Singapore Med J. 55:621–628. 2014.PubMed/NCBI View Article : Google Scholar
10	Yan S, Li B, Bai ZZ, Wu JQ, Xie DW, Ma YC, Ma XX, Zhao JH and Guo XJ: Clinical epidemiology of gastric cancer in hehuang valley of China: A 10-year epidemiological study of gastric cancer. World J Gastroenterol. 20:10486–10494. 2014.PubMed/NCBI View Article : Google Scholar
11	Hansson LE, Nyren O, Hsing AW, Bergström R, Josefsson S, Chow WH, Fraumeni JF Jr and Adami HO: The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med. 335:242–249. 1996.PubMed/NCBI View Article : Google Scholar
12	Tedelind S, Westberg F, Kjerrulf M and Vidal A: Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: A study with relevance to inflammatory bowel disease. World J Gastroenterol. 13:2826–2832. 2007.PubMed/NCBI View Article : Google Scholar
13	Ploger S, Stumpff F, Penner GB, Schulzke JD, Gäbel G, Martens H, Shen Z, Günzel D and Aschenbach JR: Microbial butyrate and its role for barrier function in the gastrointestinal tract. Ann N Y Acad Sci. 1258:52–59. 2012.PubMed/NCBI View Article : Google Scholar
14	Kimura I, Ichimura A, Ohue-Kitano R and Igarashi M: Free fatty acid receptors in health and disease. Physiol Rev. 100:171–210. 2020.PubMed/NCBI View Article : Google Scholar
15	Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, et al: Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 40:128–139. 2014.PubMed/NCBI View Article : Google Scholar
16	Chen G, Ran X, Li B, Li Y, He D, Huang B, Fu S, Liu J and Wang W: Sodium butyrate inhibits inflammation and maintains epithelium barrier integrity in a TNBS-induced inflammatory bowel disease mice model. EBioMedicine. 30:317–325. 2018.PubMed/NCBI View Article : Google Scholar
17	Pirozzi C, Francisco V, Guida FD, Gómez R, Lago F, Pino J, Meli R and Gualillo O: Butyrate modulates inflammation in chondrocytes via GPR43 receptor. Cell Physiol Biochem. 51:228–243. 2018.PubMed/NCBI View Article : Google Scholar
18	Nakajima A, Nakatani A, Hasegawa S, Irie J, Ozawa K, Tsujimoto G, Suganami T, Itoh H and Kimura I: The short chain fatty acid receptor GPR43 regulates inflammatory signals in adipose tissue M2-type macrophages. PLoS One. 12(e0179696)2017.PubMed/NCBI View Article : Google Scholar
19	Lin HV, Frassetto A, Kowalik EJ Jr, Nawrocki AR, Lu MM, Kosinski JR, Hubert JA, Szeto D, Yao X, Forrest G and Marsh DJ: Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One. 7(e35240)2012.PubMed/NCBI View Article : Google Scholar
20	Kim MH, Kang SG, Park JH, Yanagisawa M and Kim CH: Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology. 145:396–406, e391-310. 2013.PubMed/NCBI View Article : Google Scholar
21	Liu J, Wang F, Luo H, Liu A, Li K, Li C and Jiang Y: Protective effect of butyrate against ethanol-induced gastric ulcers in mice by promoting the anti-inflammatory, anti-oxidant and mucosal defense mechanisms. Int Immunopharmacol. 30:179–187. 2016.PubMed/NCBI View Article : Google Scholar
22	Mizuno H, Sakamoto C, Matsuda K, Wada K, Uchida T, Noguchi H, Akamatsu T and Kasuga M: Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology. 112:387–397. 1997.PubMed/NCBI View Article : Google Scholar
23	Toma W, Hiruma-Lima CA, Guerrero RO and Brito AR: Preliminary studies of mammea americana L. (Guttiferae) bark/latex extract point to an effective antiulcer effect on gastric ulcer models in mice. Phytomedicine. 12:345–350. 2005.PubMed/NCBI View Article : Google Scholar
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
25	Liu J, Wang J, Shi Y, Su W, Chen J, Zhang Z, Wang G and Wang F: Short chain fatty acid acetate protects against ethanol-induced acute gastric mucosal lesion in mice. Biol Pharm Bull. 40:1439–1446. 2017.PubMed/NCBI View Article : Google Scholar
26	Kangwan N, Park JM, Kim EH and Hahm KB: Quality of healing of gastric ulcers: Natural products beyond acid suppression. World J Gastrointest Pathophysiol. 5:40–47. 2014.PubMed/NCBI View Article : Google Scholar
27	Tarnawski A, Douglass TG, Stachura J and Krause WJ: Quality of gastric ulcer healing: Histological and ultrastructural assessment. Aliment Pharmacol Ther. 1 (5 Suppl):S79–S90. 1991.PubMed/NCBI View Article : Google Scholar
28	Guilloteau P, Martin L, Eeckhaut V, Ducatelle R, Zabielski R and Van Immerseel F: From the gut to the peripheral tissues: The multiple effects of butyrate. Nutr Res Rev. 23:366–384. 2010.PubMed/NCBI View Article : Google Scholar
29	Bloemen JG, Venema K, van de Poll MC, Olde Damink SW, Buurman WA and Dejong CH: Short chain fatty acids exchange across the gut and liver in humans measured at surgery. Clin Nutr. 28:657–661. 2009.PubMed/NCBI View Article : Google Scholar
30	Gaudier E, Jarry A, Blottiere HM, de Coppet P, Buisine MP, Aubert JP, Laboisse C, Cherbut C and Hoebler C: Butyrate specifically modulates MUC gene expression in intestinal epithelial goblet cells deprived of glucose. Am J Physiol Gastrointest Liver Physiol. 287:G1168–G1174. 2004.PubMed/NCBI View Article : Google Scholar
31	Liang JB, Wang P, Feng YH, Huang YL, Wang FJ and Ren H: Effects of sodium butyrate on intestinal barrier of severe scald mice and the related mechanism. Zhonghua shao shang za zhi. 36:48–53. 2020.PubMed/NCBI View Article : Google Scholar : (In Chinese).
32	Barcenilla A, Pryde SE, Martin JC, Duncan SH, Stewart CS, Henderson C and Flint HJ: Phylogenetic relationships of butyrate-producing bacteria from the human gut. Appl Environ Microbiol. 66:1654–1661. 2000.PubMed/NCBI View Article : Google Scholar
33	Egorin MJ, Yuan ZM, Sentz DL, Plaisance K and Eiseman JL: Plasma pharmacokinetics of butyrate after intravenous administration of sodium butyrate or oral administration of tributyrin or sodium butyrate to mice and rats. Cancer Chemother Pharmacol. 43:445–453. 1999.PubMed/NCBI View Article : Google Scholar
34	Liang X, Wang RS, Wang F, Liu S, Guo F, Sun L, Wang YJ, Sun YX and Chen XL: Sodium butyrate protects against severe burn-induced remote acute lung injury in rats. PLoS One. 8(e68786)2013.PubMed/NCBI View Article : Google Scholar
35	Wong JM, de Souza R, Kendall CW, Emam A and Jenkins DJ: Colonic health: Fermentation and short chain fatty acids. J Clin Gastroenterol. 40:235–243. 2006.PubMed/NCBI View Article : Google Scholar
36	Hijova E and Chmelarova A: Short chain fatty acids and colonic health. Bratisl Lek Listy. 108:354–358. 2007.PubMed/NCBI
37	Wang FY, Liu JM, Luo HH, Liu AH and Jiang Y: Potential protective effects of clostridium butyricum on experimental gastric ulcers in mice. World J Gastroenterol. 21:8340–8351. 2015.PubMed/NCBI View Article : Google Scholar
38	Lin Y, Fang ZF, Che LQ, Xu SY, Wu D, Wu CM and Wu XQ: Use of sodium butyrate as an alternative to dietary fiber: Effects on the embryonic development and anti-oxidative capacity of rats. PLoS One. 9(e97838)2014.PubMed/NCBI View Article : Google Scholar
39	Xing X, Jiang Z, Tang X, Wang P, Li Y, Sun Y, Le G and Zou S: Sodium butyrate protects against oxidative stress in HepG2 cells through modulating Nrf2 pathway and mitochondrial function. J Physiol Biochem. 73:405–414. 2016.PubMed/NCBI View Article : Google Scholar
40	Inan MS, Rasoulpour RJ, Yin L, Hubbard AK, Rosenberg DW and Giardina C: The luminal short-chain fatty acid butyrate modulates NF-kappaB activity in a human colonic epithelial cell line. Gastroenterology. 118:724–734. 2000.PubMed/NCBI View Article : Google Scholar
41	Yin L, Laevsky G and Giardina C: Butyrate suppression of colonocyte NF-kappa B activation and cellular proteasome activity. J Biol Chem. 276:44641–44646. 2001.PubMed/NCBI View Article : Google Scholar
42	Luhrs H, Gerke T, Muller JG, Melcher R, Schauber J, Boxberge F, Scheppach W and Menzel T: Butyrate inhibits NF-kappaB activation in lamina propria macrophages of patients with ulcerative colitis. Scand J Gastroenterol. 37:458–466. 2002.PubMed/NCBI View Article : Google Scholar
43	Aziz RS, Siddiqua A, Shahzad M, Shabbir A and Naseem N: Oxyresveratrol ameliorates ethanol-induced gastric ulcer via downregulation of IL-6, TNF-α, NF-kB, and COX-2 levels, and upregulation of TFF-2 levels. Biomed Pharmacother. 110:554–560. 2019.PubMed/NCBI View Article : Google Scholar
44	He H, Feng M, Xu H, Li X, He Y, Qin H, Zhang Y, Tang H and Zou K: Total triterpenoids from the fruits of chaenomeles speciosa exerted gastroprotective activities on indomethacin-induced gastric damage via modulating microRNA-423-5p-mediated TFF/NAG-1 and apoptotic pathways. Food Funct. 11:662–679. 2020.PubMed/NCBI View Article : Google Scholar
45	Longman RJ, Douthwaite J, Sylvester PA, Poulsom R, Corfield AP, Thomas MG and Wright NA: Coordinated localisation of mucins and trefoil peptides in the ulcer associated cell lineage and the gastrointestinal mucosa. Gut. 47:792–800. 2000.PubMed/NCBI View Article : Google Scholar
46	Katoh M: Trefoil factors and human gastric cancer (review). Int J Mol Med. 12:3–9. 2003.PubMed/NCBI
47	Chen J, Zhao KN and Vitetta L: Effects of intestinal microbial(-)elaborated butyrate on oncogenic signaling pathways. Nutrients. 11(1026)2019.PubMed/NCBI View Article : Google Scholar
48	Bultman SJ: Interplay between diet, gut microbiota, epigenetic events, and colorectal cancer. Mol Nutr Food Res. 61(10)2017.PubMed/NCBI View Article : Google Scholar
49	Davie JR: Inhibition of histone deacetylase activity by butyrate. J Nutr. 133 (7 Suppl):2485S–2493S. 2003.PubMed/NCBI View Article : Google Scholar
50	Eslami M, Sadrifar S, Karbalaei M, Keikha M, Kobyliak NM and Yousefi B: Importance of the microbiota inhibitory mechanism on the warburg effect in colorectal cancer cells. J Gastrointest Cancer. 51:738–747. 2020.PubMed/NCBI View Article : Google Scholar
51	Hanson J, Gille A, Zwykiel S, Lukasova M, Clausen BE, Ahmed K, Tunaru S, Wirth A and Offermanns S: Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. J Clin Invest. 120:2910–2919. 2010.PubMed/NCBI View Article : Google Scholar
52	Benyo Z, Gille A, Kero J, Csiky M, Suchánková MC, Nüsing RM, Moers A, Pfeffer K and Offermanns S: GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest. 115:3634–3640. 2005.PubMed/NCBI View Article : Google Scholar
53	Tarnawski AS: Cellular and molecular mechanisms of gastrointestinal ulcer healing. Dig Dis Sci. 50 (Suppl 1):S24–S33. 2005.PubMed/NCBI View Article : Google Scholar