Resveratrol modulates the gut microbiota to prevent murine colitis development through induction of Tregs and suppression of Th17 cells

• Published in: Journal of leukocyte biology Vol. 106; no. 2; pp. 467 - 480
• Main Authors: Alrafas, Haider Rasheed, Busbee, Philip B., Nagarkatti, Mitzi, Nagarkatti, Prakash S.
• Format: Journal Article
• Language: English
• Published: United States 01-08-2019
• Subjects: 2,4,6‐trinitrobenzenesulfonic acid; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biomarkers; butyrate; Colitis - etiology; Colitis - metabolism; Colitis - pathology; Colitis - prevention & control; Colonoscopy; Disease Models, Animal; Fecal Microbiota Transplantation; fecal transfer; Female; Gastrointestinal Microbiome - drug effects; Gastrointestinal Microbiome - immunology; Humans; Immunomodulation - drug effects; inflammation; Metagenomics - methods; Mice; Resveratrol - pharmacology; short‐chain fatty acid; T helper cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th17 Cells - drug effects; Th17 Cells - immunology; Th17 Cells - metabolism; fecal transfer; T helper cells; short-chain fatty acid; 2,4,6-trinitrobenzenesulfonic acid; butyrate; inflammation
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1002/JLB.3A1218-476RR

Inflammatory diseases of the gastrointestinal tract are often associated with microbial dysbiosis. Thus, dietary interactions with intestinal microbiota, to maintain homeostasis, play a crucial role in regulation of clinical disorders such as colitis. In the current study, we investigated if resveratrol, a polyphenol found in a variety of foods and beverages, would reverse microbial dysbiosis induced during colitis. Administration of resveratrol attenuated colonic inflammation and clinical symptoms in the murine model of 2,4,6‐trinitrobenzenesulfonic acid (TNBS)‐induced colitis. Resveratrol treatment in mice with colitis led to an increase in CD4+FOXP3+ and CD4+IL‐10+ T cells, and a decrease in CD4+IFN‐γ+ and CD4+IL‐17+ T cells. 16S rRNA gene sequencing to investigate alterations in the gut microbiota revealed that TNBS caused significant dysbiosis, which was reversed following resveratrol treatment. Analysis of cecal flush revealed that TNBS administration led to an increase in species such as Bacteroides acidifaciens, but decrease in species such as Ruminococcus gnavus and Akkermansia mucinphilia, as well as a decrease in SCFA i‐butyric acid. However, resveratrol treatment restored the gut bacteria back to homeostatic levels, and increased production of i‐butyric acid. Fecal transfer experiments confirmed the protective role of resveratrol‐induced microbiota against colitis inasmuch as such recipient mice were more resistant to TNBS‐colitis and exhibited polarization toward CD4+FOXP3+ T cells and decreases in CD4+IFN‐γ+ and CD4+IL‐17+ T cells. Collectively, these data demonstrate that resveratrol‐mediated attenuation of colitis results from reversal of microbial dysbiosis induced during colitis and such microbiota protect the host from colonic inflammation by inducing Tregs while suppressing inflammatory Th1/Th17 cells.
Gut microbiome composition and SCFA production are altered by resveratrol to prevent development of colitis and induce Tregs, as validated by fecal transfer experiments.