TY - JOUR
T1 - Berberine improves colitis by triggering AhR activation by microbial tryptophan catabolites
AU - Jing, Wanghui
AU - Dong, Sijing
AU - Luo, Xialin
AU - Liu, Jingjing
AU - Wei, Bin
AU - Du, Wei
AU - Yang, Lin
AU - Luo, Hua
AU - WANG, Yitao
AU - Wang, Sicen
AU - Lu, Haitao
N1 - Funding information:
This work was supported by the National Natural Science Foundation of China Grants (Grant 81603370 and 81503034), China Postdoctoral Science Foundation Grant (Grant 2019M653671), the Macao Science and Technology Development Fund [SKL-QRCM (UM) -2020-2022], the Natural Science Foundation of Shaanxi Province (Grant 2017JQ8006), the project of Shaanxi Administration of Traditional Chinese Medicine (Grant 2019-ZZ-ZY007), the National Key R&D Program of China (Nos. 2017YFC1308600 and 2017YFC1308605) and Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University (KLSB2019KF-01).
PY - 2021/2
Y1 - 2021/2
N2 - Inflammatory bowel diseases (IBD) are kind of recurrent inflammatory issues that occur in the gastrointestinal tract, and currently clinical treatment is still unideal due to the complex pathogenesis of IBD. Basically, gut barrier dysfunction is triggered by gut microbiota dysbiosis that is closely associated with the development of IBD, we thus investigated the therapeutic capacity of berberine (BBR) to improve the dysregulated gut microbiota, against IBD in rats, using a combinational strategy of targeted metabolomics and 16 s rDNA amplicon sequencing technology. Expectedly, our data revealed that BBR administration could greatly improve the pathological phenotype, gut barrier disruption, and the colon inflammation in rats with dextran sulfate sodium (DSS)-induced colitis. In addition, 16S rDNA-based microbiota analysis demonstrated that BBR could alleviate gut dysbiosis in rats. Furthermore, our targeted metabolomics analysis illustrated that the levels of microbial tryptophan catabolites in the gastrointestinal tract were significantly changed during the development of the colitis in rats, and BBR treatment can significantly restore such changes of the tryptophan catabolites accordingly. At last, our in vitro mechanism exploration was implemented with a Caco-2 cell monolayer model, which verified that the modulation of the dysregulated gut microbiota to change microbial metabolites coordinated the improvement effect of BBR on gut barrier disruption in the colitis, and we also confirmed that the activation of AhR induced by microbial metabolites is indispensable to the improvement of gut barrier disruption by BBR. Collectively, BBR has the capacity to treat DSS-induced colitis in rats through the regulation of gut microbiota associated tryptophan metabolite to activate AhR, which can greatly improve the disrupted gut barrier function. Importantly, our finding elucidated a novel mechanism of BBR to improve gut barrier function, which holds the expected capacity to promote the BBR derived drug discovery and development against the colitis in clinic setting.
AB - Inflammatory bowel diseases (IBD) are kind of recurrent inflammatory issues that occur in the gastrointestinal tract, and currently clinical treatment is still unideal due to the complex pathogenesis of IBD. Basically, gut barrier dysfunction is triggered by gut microbiota dysbiosis that is closely associated with the development of IBD, we thus investigated the therapeutic capacity of berberine (BBR) to improve the dysregulated gut microbiota, against IBD in rats, using a combinational strategy of targeted metabolomics and 16 s rDNA amplicon sequencing technology. Expectedly, our data revealed that BBR administration could greatly improve the pathological phenotype, gut barrier disruption, and the colon inflammation in rats with dextran sulfate sodium (DSS)-induced colitis. In addition, 16S rDNA-based microbiota analysis demonstrated that BBR could alleviate gut dysbiosis in rats. Furthermore, our targeted metabolomics analysis illustrated that the levels of microbial tryptophan catabolites in the gastrointestinal tract were significantly changed during the development of the colitis in rats, and BBR treatment can significantly restore such changes of the tryptophan catabolites accordingly. At last, our in vitro mechanism exploration was implemented with a Caco-2 cell monolayer model, which verified that the modulation of the dysregulated gut microbiota to change microbial metabolites coordinated the improvement effect of BBR on gut barrier disruption in the colitis, and we also confirmed that the activation of AhR induced by microbial metabolites is indispensable to the improvement of gut barrier disruption by BBR. Collectively, BBR has the capacity to treat DSS-induced colitis in rats through the regulation of gut microbiota associated tryptophan metabolite to activate AhR, which can greatly improve the disrupted gut barrier function. Importantly, our finding elucidated a novel mechanism of BBR to improve gut barrier function, which holds the expected capacity to promote the BBR derived drug discovery and development against the colitis in clinic setting.
KW - AhR activation
KW - Berberine
KW - gut barrier function
KW - inflammatory bowel disease
KW - microbial tryptophan catabolites
UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85097867642&origin=inward
U2 - 10.1016/j.phrs.2020.105358
DO - 10.1016/j.phrs.2020.105358
M3 - Journal article
C2 - 33285228
SN - 1043-6618
VL - 164
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 105358
ER -