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Obeticholic Acid Inhibits Anxiety via Alleviating Gut Microbiota-Mediated Microglia Accumulation in the Brain of High-Fat High-Sugar Diet Mice.

ABSTRACT: Anxiety is one of the complications of metabolic disorders (MDs). Obeticholic acid (OCA), the bile acids (BAs) derivative, is a promising agent for improving MDs in association with gut dysbiosis. Yet, its protective effect on MDs-driven anxiety remains unknown. Here, we assessed the serum biochemical parameters and behavioral performance by open field and Morris water maze tests in HFHS diet-induced MDs mice after OCA intervention for nine and 18 weeks. Moreover, antibiotics intervention for microbial depletion was conducted simultaneously. We found that OCA treatment inhibited the initiation and progression of anxiety in HFHS diet-MDs mice via a microbiota-BAs-brain axis: OCA decreased the neuroinflammatory microglia and IL-1β expression in the hippocampus, reversed intestinal barrier dysfunction and serum proinflammatory LPS to a normal level, modified the microbial community, including the known anxiety-related Rikenellaceae and Alistipes, and improved the microbial metabolites especially the increased BAs in feces and circulation. Moreover, the OCA-reversed bile acid taurocholate linked disordered serum lipid metabolites and indole derivatives to anxiety as assessed by network analysis. Additionally, microbial depletion with antibiotics also improved the anxiety, microgliosis and BAs enrichment in the experimental MDs mice. Together, these findings provide microbiota-BAs-brain axis as a novel therapeutic target for MDs-associated neuropsychiatric disorders.

SUBMITTER: Wu L

PROVIDER: S-EPMC7999854 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Multiple lines of evidence suggest that the gut microbiota plays vital roles in metabolic diseases such as hyperlipidemia. Previous studies have confirmed that krill oil can alleviate hyperlipidemia, but the underlying mechanism remains unclear. To discern whether krill oil changes the structure of the gut microbiota during the hyperlipidemia treatment, 72 mice were acclimatized with a standard chow diet for 2 weeks and then randomly allocated to receive a standard chow diet (control group, n = 12) or a high-sugar-high-fat (HSHF) diet supplemented with a low (100 μg/g·d, HSHF+LD group, n = 12), moderate (200 μg/g·d, HSHF+MD group, n = 12) or high dosage of krill oil (600 μg/g·d, HSHF+HD group, n = 12), simvastatin (HSHF+S group, n = 12) or saline (HSHF group, n = 12) continuously for 12 weeks. The resulting weight gains were attenuated, the liver index and the low-density lipoprotein, total cholesterol and triglyceride concentrations showed a stepwise reduction in the treated groups compared with those of the control group. A dose-dependent modulation of the gut microbiota was observed after treatment with krill oil. Low- and moderate- doses of krill oil increased the similarity between the composition of the HSHF diet-induced gut microbiota and that of the control, whereas the mice fed the high-dose exhibited a unique gut microbiota structure that was different from that of the control and HSHF groups. Sixty-five key operational taxonomic units (OTUs) that responded to the krill oil treatment were identified using redundancy analysis, of which 26 OTUs were increased and 39 OTUs were decreased compared with those of the HSHF group. In conclusion, the results obtained in this study suggest that the structural alterations in the gut microbiota induced by krill oil treatment were dose-dependent and associated with the alleviation of hyperlipidemia. Additionally, the high-dose krill oil treatment showed combined effects on the alleviation of hyperlipidemia and obesity.

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Obeticholic Acid Inhibits Anxiety via Alleviating Gut Microbiota-Mediated Microglia Accumulation in the Brain of High-Fat High-Sugar Diet Mice.

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