Dataset Information

Upregulation of Intestinal Barrier Function in Mice with DSS-Induced Colitis by a Defined Bacterial Consortium Is Associated with Expansion of IL-17A Producing Gamma Delta T Cells.

ABSTRACT: Bacterial consortium transplantation (BCT) is a promising alternative to fecal microbiota transplantation in treating inflammatory bowel disease (IBD). Here, we showed that a defined bacterial consortium derived from healthy mice was able to enhance the intestinal barrier function of mice with dextran sulfate sodium (DSS)-induced colitis. Interestingly, we found that the bacterial consortium significantly promoted the expansion of IL-17A-producing ??T (??T17) cells in colonic lamina propria, which was closely associated with changing of intestinal microbial composition. The increased IL-17A secretion upon treatment with microbial products derived from the bacterial consortium was accompanied with upregulation of TLR2 expression by ??T cells, and it might be responsible for the upregulation of mucosal barrier function through IL-17R-ACT1-mediated recovery of the disrupted occludin subcellular location. Changing of some specific microbial groups such as Bifidobacterium and Bacillus spp. was closely correlated with the promotion of TLR2⁺ ??T cells. Our results support that BCT can restore the alliance between commensal microbiota and intestinal ??T cells, which contributes to the improvement of intestinal barrier function. This study provides new insight into the development of bacteria transplantation therapy for the treatment of IBD.

SUBMITTER: Li M

PROVIDER: S-EPMC5506203 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Upregulation of Intestinal Barrier Function in Mice with DSS-Induced Colitis by a Defined Bacterial Consortium Is Associated with Expansion of IL-17A Producing Gamma Delta T Cells.

Li Ming M Wang Bing B Sun Xiaotong X Tang Yan Y Wei Xiaoqing X Ge Biying B Tang Yawei Y Deng Ying Y He Chunyang C Yuan Jieli J Li Xia X

Frontiers in immunology 20170712

Bacterial consortium transplantation (BCT) is a promising alternative to fecal microbiota transplantation in treating inflammatory bowel disease (IBD). Here, we showed that a defined bacterial consortium derived from healthy mice was able to enhance the intestinal barrier function of mice with dextran sulfate sodium (DSS)-induced colitis. Interestingly, we found that the bacterial consortium significantly promoted the expansion of IL-17A-producing γδT (γδT17) cells in colonic lamina propria, whi ...[more]

PMID: 28747917

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Project description:Ulcerative colitis (UC) is a chronic inflammatory disease, characterized by recurrent flares of mucosal inflammation, which is limited in the colon and rectum. Compromised epithelial barrier functions have been indicated in the initiation of UC. Carnosol (CA), a natural active ortho-diphenol diterpene compound, is one of the active ingredients in plants such as rosemary and sage. The anti-inflammatory and anti-oxidative effects of CA have been reported in several animal models, but its effect on mucosal inflammation remains elusive. We established a mouse experimental colitis model characterized by epithelial barrier destruction using dextran sulfate sodium (DSS). CA was intraperitoneally administrated. Flow cytometry was performed to determine phenotypes of intraepithelial lymphocytes and lamina propria cells. qRT-PCR was used for gene expression. ER stress in the colon was determined by immunofluorescence staining and qRT-PCR. Thapsigargin was used to induce ER stress in HCT-116 cells in vitro. We found CA significantly alleviated DSS-induced colitis in mice marked by relieved clinical symptoms and colonic pathological damage. Inflammatory cell infiltration and cytokine expression in the colon were suppressed by CA during colitis. Furthermore, CA restored epithelial barrier functions and intestinal intraepithelial lymphocyte (IEL) homeostasis in mice with DSS insults. Mechanistically, we induced endoplasmic reticulum (ER) stress in HCT-116 cells (an intestinal epithelial cell line) with thapsigargin, and CA reversed this effect. In addition, we collected inflamed mucosal biopsies from 23 patients with UC, and cultured overnight with or without CA, showing CA significantly reduced expression of ER stress signaling molecule and pro-inflammatory agents. Our data demonstrate that CA acts as an effective drug for experimental colitis and maintains proper epithelial barrier functions via suppressing epithelial ER stress, providing new evidence that CA might be a promising therapeutic candidate for UC.

Project description:The Integrative Human Microbiome Project and other cohort studies have indicated that inflammatory bowel disease is accompanied by dysbiosis of gut microbiota, decreased production of secondary bile acids, and increased levels of primary bile acids. Secondary bile acids, such as ursodeoxycholic acid (UDCA) and lithocholic acid (LCA), have been reported to be anti-inflammatory, yet it remains to be studied whether introducing selected bacteria strains to restore bile acid metabolism of the gut microbiome can alleviate intestinal inflammation. In this study, we screened human gut bacterial strains for bile acid metabolism and designed a consortium of three species, including Clostridium AP sp000509125, Bacteroides ovatus, and Eubacterium limosum, and named it BAC (bile acid consortium). We showed that the three-strain gut bacterial consortium BAC is capable of converting conjugated primary bile acids taurochenodeoxycholic acid and glycochenodeoxycholic acid to secondary bile acids UDCA and LCA in vitro. Oral gavage treatment with BAC in mice resulted in protective effects against dextran sulfate sodium (DSS)-induced colitis, including reduced weight loss and increased colon length. Furthermore, BAC treatment increased the fecal level of bile acids, including UDCA and LCA. BAC treatment enhanced intestinal barrier function, which may be attributed to the increased activation of the bile acid receptor TGR5 by secondary bile acids. Finally, we examined the remodeling of gut microbiota by BAC treatment. Taken together, the three-strain gut bacterial consortium BAC restored the dysregulated bile acid metabolism and alleviated DSS-induced colitis. Our study provides a proof-of-concept demonstration that a rationally designed bacterial consortium can reshape the metabolism of the gut microbiome to treat diseases. IMPORTANCE Secondary bile acids have been reported to be anti-inflammatory, yet it remains to be studied whether introducing selected bacteria strains to restore bile acid metabolism of the gut microbiome can alleviate intestinal inflammation. To address this gap, we designed a consortium of human gut bacterial strains based on their metabolic capacity to produce secondary bile acids UDCA and LCA, and we evaluated the efficacy of single bacterial strains and the bacterial consortium in treating the murine colitis model. We found that oral gavage of the bacterial consortium to mice restored secondary bile acid metabolism to increase levels of UDCA and LCA, which induced the activation of TGR5 to improve gut-barrier integrity and reduced the inflammation in murine colitis. Overall, our study demonstrates that rationally designed bacterial consortia can reshape the metabolism of the gut microbiome and provides novel insights into the application of live biotherapeutics for treating IBD.

Dataset Information

Upregulation of Intestinal Barrier Function in Mice with DSS-Induced Colitis by a Defined Bacterial Consortium Is Associated with Expansion of IL-17A Producing Gamma Delta T Cells.

Publications

Upregulation of Intestinal Barrier Function in Mice with DSS-Induced Colitis by a Defined Bacterial Consortium Is Associated with Expansion of IL-17A Producing Gamma Delta T Cells.

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