Social Stress Affects Colonic Inflammation, the Gut Microbiome, and Short Chain Fatty Acid Levels and Receptors

Objectives: Gastrointestinal disorders, such as inflammatory bowel diseases (IBD) and functional gastrointestinal disorders (FGID), involve disrupted homeostatic interactions between the microbiota and the host. Both disorders are worsened during stress, and in laboratory mice, stress exposure has been shown to change the composition of the gut microbiome. Stress-induced changes to the microbiome exacerbate intestinal inflammation and alter intestinal motility in mice. However, it is not yet known whether microbiota-derived short chain fatty acids (butyrate, propionate, and acetate) and their receptors contribute to this effect. Methods: Mice were exposed to a social disruption (SDR) stress, or left undisturbed as a control. After the first stress exposure, mice were orally challenged with Citrobacter rodentium or with vehicle. The levels of SCFAs were measured using gas chromatography-mass spectrometry. SCFA receptors were measured via real time PCR. Microbial community composition was assessed using 16S rRNA gene sequencing. Results: Stress exposure reduced colonic SCFA levels. However, stress exposure and C. rodentium significantly increased SCFA levels and changed the expression of SCFA receptors. The levels of SCFAs did not correlate with the severity of colonic inflammation, but the colonic expression of the SCFA receptor GPR41 was positively associated with inflammatory cytokines and colonic histopathology scores. The relative abundances of several taxa of colonic bacteria were significantly changed by stress exposure, including SCFA producers. Conclusions: Social stress can have a significant effect on infection-induced colonic inflammation, and stress-induced changes in microbial-produced metabolites and their receptors may be involved. Address correspondence and reprint requests to Ross M. Maltz, M.D., Pediatric Gastroenterology, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205 (e-mail: Ross.Maltz@nationwidechildrens.org). Received 24 April, 2018 Accepted 5 November, 2018 Jeremy Keirsey, jeremy.keirsey@thermofisher.com, 4120 Kilbannon Way Dublin, OH 43016 Sandra C. Kim, Sandra.Kim@chp.edu, 4401 Penn Avenue Pittsburgh, PA 15224 Amy R. Mackos, mackos.3@osu.edu, 034H Newton Hall, 1585 Neil Ave, Columbus, OH 43210 Raad Z. Gharaibeh, rgharaibeh@gmail.com, 2033 Mowry Rd. PO Box 103633 Gainesville, Florida 32610 Cathy C. Moore, CathyMoore@uncc.edu, 9201 University City Blvd Charlotte, NC 28223 Jinyu Xu, Jinyu.Xu@nationwidechildrens.org, 700 Children's Drive Columbus, OH 43205 Arpad Somogyi, somogyi.16@osu.edu, 281 Biomedical Research Tower (BRT), 460 W. 12th Street, Columbus, OH 43210 Michael T. Bailey, Michael.Bailey2@nationwidechildrens.org, 700 Children's Drive Columbus, OH 43205 Conflicts of Interest and Source of Funding: This works was supported by the National Center for Complementary & Integrative Health of the National Institutes of Health under Award Number R01AT006552 (to M.T.B.). The author(s) report no conflict of interests or competing financial interests. Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org). © 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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