Gut microbiota characteristics and its immunoregulatory role in inflammatory depression: joint clinical and animal data

Abstract Previous studies have reported that inflammatory depression is a treatment-resistant depression subtype and that disturbed gut microbiota may be the source of low-grade inflammation. But the gut microbiota’s features and its role of immunoregulation in this subtype of depression remains uncertain. We propose that Toll-like receptor 4 (TLR-4)/nuclear factor kappa-B (NF-κB) and the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling pathway activated by disordered gut microbiota could contribute to intestinal and central inflammation in inflammatory depression. To test this hypothesis, we performed studies in both humans and mice. Gut microbiota composition in stool, inflammation factor and short chain fatty acid (SCFAs) in plasma, inflammatory and permeability marker in intestinal mucosa were analyzed in inflammatory depression patients. Then we performed fecal microbiota transplantation (FMT) and probiotic supplement to determine whether the behavioral phenotypes were linked with disturbed gut microbiota in inflammatory depression. Compared with non-inflammatory depression and HCs, the relative abundance of Bacteroides was significantly higher, and Clostridium was lower in inflammatory depression patients. Further, we found that SCFA-producing species increased with abnormal butanoate metabolism in the inflammatory depression patients following shotgun metagenomic sequencing. After FMT, gut microbiota in inflammatory depression increased inflammatory factors, those including as hs-CRP, TLR-4, NF-κB, NLRP3, Caspase-1, Interleukin-1β (IL-1β), and iba-1. We also found that intestinal mucosal permeability increased in recipient mice with depressive and anxiety-like behaviors. Clostridium butyricum treatment can normalize the gut microbiota, repair “gut leak,” decrease peripheral and central inflammatory factors, and have an antidepressant-like effect in the mouse model inflammatory depression. Together, our study findings indicate that inflammatory depression patients have increased pro-inflammatory genera and decreased SCFA-producing genera. Gut microbiota-derived inflammatory processes mediated by TLR-4/NF-κB–NLRP3 inflammasome signaling pathway are involved in neuroinflammation in inflammatory depression.