Lithium Carbonate Treatment Alleviates Gut Inflammation Through Activating Treg Cell Responses in a Microbiota-Dependent Manner

Background: Recent evidence suggests that antidepressant and anti-anxiety treatments may also have a place in resolving inflammation through the gut-brain axis. Lithium carbonate (LC) is one of the most commonly used drugs for bipolar disorder. However, little is known about the effects of LC on gut inflammation. In this study, we explore the protective effect of LC on colitis, and clarify its underlying mechanism of intestinal microbial dependence. Methods: Colitis mice were established by oral administration of 2.5% dextran sulfate sodium (DSS). Colon inflammation severity in mouse model was measured by body weight change, mortality, colon length, disease activity index (DAI) score and H&E staining. Gut microbiota alteration were analyzed through high-throughput 16S rRNA gene sequencing. Enzyme-linked immunosorbent assay (ELISA) were conducted to measure the colon cytokines profile. The frequency of immune cells in lamina propria (LP) were phenotyped by flow cytometry. Findings: LC treatment significantly alleviated colon inflammation in DSS-induced colitis models. It is worth noting that when antibiotics (ABX) are used to deplete the intestinal microbiota, the protective effect of LC on colon inflammation is not significant. LC treatment downregulated the levels of pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and IL-17A in colon tissue, and upregulated the levels of immunosuppressive cytokine IL-10. The 16S rRNA sequencing results showed that LC administration significantly increased gut microbial diversity and altered flora composition, especially accumulated the abundance of potential probiotics Akkermansia muciniphila (A. muciniphila). Moreover, LC treatment selectively activated the anti-inflammatory responses of colonic regulatory T (Treg) cells and maintained intestinal homeostasis. Fecal microbiota transplantation (FMT), and Akkermansia muciniphila (A. muciniphila) single bacteria gavage experiments confirmed this intestinal flora-dependent mechanism. Interpretation: Accordingly, our results demonstrate the role of LC as a potential regulator of intestinal flora in the prevention and treatment of gut inflammation. Therefore, LC treatment or targeting specific microbiota, such as A. muciniphila, provides a new strategy for the treatment of ulcerative colitis or IBD. Funding Statement: This work was supported by the National Natural Science Foundation of China (Grant NO.82030020). Declaration of Interests: None declared. Ethics Approval Statement: All animal experimental protocols were performed following the guidelines of the National Institutes of Health guide for the care and use of Laboratory Animals, approved by the Third Military Medical University Institutional Animal Care and Use Committee.