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.
Highlights
The glucose tolerance tests (GTT) results showed that the fasting serum glucose and glucose levels at 30, 60 and 120 min after glucose injection were significantly higher in HFHS diet mice than those with normal chow (Figure S2C)
The time spent in the central arena of the Open field (OF) was decreased in HFHS diet mice with the vehicle but unchanged in those with Obeticholic acid (OCA) or ABX when compared with normal chow mice (Figure 1G). These findings indicated that gut microbiota was involved in the pathogenesis of anxiety in HFHS diet-induced metabolic disorders (MDs) mice, which could be inhibited by OCA treatment
While lipids metabolites pointed to the metabolism of polyunsaturated fatty acid (PUFA) ((4Z,7Z,10Z,13Z)-4,7,10,13-hexadecatetraenoic acid), linoleic acids ((+/−) 12(13)-DiHOME) and palmitic acid was decreased in HFHS diet mice compared with normal chow mice and increased in OCA-treated mice (Figure 6D)
Summary
Anxiety is the most prevalent mental health condition affecting 10.4% of the Western world population [1,2] and predicts later neuropsychiatric disorders, including cognitive impairment [1,3]. The available therapeutic drugs for anxiety targeting the central nervous system (CNS) showed many side effects, such as sexual dysfunction, persistent hypertension and metabolic disorders (MDs) [4]. Metabolic disorders (MDs) are recognized as a risk factor for neuropsychiatric diseases, including anxiety recently [5,6]. Preliminary investigations evidenced that intestinal microbiota (IM) and its metabolites were involved in both MDs [7,8] and neuropsychiatric diseases [9,10], indicating a potential role of IM in the development of MDs-associated anxiety.
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