Mechanosensation of the heart and gut elicits hypometabolism and vigilance in mice
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Sodium oligomannate disrupts the adherence of Ribhigh bacteria to gut epithelia to block SAA-triggered Th1 inflammation in 5XFAD transgenic mice
Sodium oligomannate (GV-971), an oligosaccharide drug approved in China for treating mild-to-moderate Alzheimer’s disease (AD), was previously found to recondition the gut microbiota and limit altered peripheral Th1 immunity in AD transgenic mice. As a follow-up study, we here made advances by pinpointing a Lactobacillus murinus (L.m.) strain that highly expressed a gene encoding a putative adhesin containing Rib repeats (Ribhigh–L.m.) particularly enriched in 5XFAD transgenic mice. Mechanistically, Ribhigh–L.m. adherence to the gut epithelia upregulated fecal metabolites, among which lactate ranked as the top candidate. Excess lactate stimulated the epithelial production of serum amyloid A (SAA) in the gut via the GPR81-NFκB axis, contributing to peripheral Th1 activation. Moreover, GV-971 disrupted the adherence of Ribhigh–L.m. to gut epithelia via direct binding to Rib, which corrected the excess lactate, reduced SAA, and alleviated Th1-skewed inflammation. Together, we gained further insights into the molecular link between gut bacteria and AD progression and the mechanism of GV-971 in treating AD.
Microbiome-based interventions to modulate gut ecology and the immune system
The gut microbiome lies at the intersection between the environment and the host, with the ability to modify host responses to disease-relevant exposures and stimuli. This is evident in how enteric microbes interact with the immune system, e.g., supporting immune maturation in early life, affecting drug efficacy via modulation of immune responses, or influencing development of immune cell populations and their mediators. Many factors modulate gut ecosystem dynamics during daily life and we are just beginning to realise the therapeutic and prophylactic potential of microbiome-based interventions. These approaches vary in application, goal, and mechanisms of action. Some modify the entire community, such as nutritional approaches or faecal microbiota transplantation, while others, such as phage therapy, probiotics, and prebiotics, target specific taxa or strains. In this review, we assessed the experimental evidence for microbiome-based interventions, with a particular focus on their clinical relevance, ecological effects, and modulation of the immune system.
Bifidobacterium animalis subsp. lactis A6 ameliorates bone and muscle loss via modulating gut microbiota composition and enhancing butyrate production
Systematic bone and muscle loss is a complex metabolic disease, which is frequently linked to gut dysfunction, yet its etiology and treatment remain elusive. While probiotics show promise in managing diseases through microbiome modulation, their therapeutic impact on gut dysfunction-induced bone and muscle loss remains to be elucidated. Employing dextran sulfate sodium (DSS)-induced gut dysfunction model and wide-spectrum antibiotics (ABX)-treated mice model, our study revealed that gut dysfunction instigates muscle and bone loss, accompanied by microbial imbalances. Importantly, Bifidobacterium animalis subsp. lactis A6 (B. lactis A6) administration significantly ameliorated muscle and bone loss by modulating gut microbiota composition and enhancing butyrate-producing bacteria. This intervention effectively restored depleted butyrate levels in serum, muscle, and bone tissues caused by gut dysfunction. Furthermore, butyrate supplementation mitigated musculoskeletal loss by repairing the damaged intestinal barrier and enriching beneficial butyrate-producing bacteria. Importantly, butyrate inhibited the NF-κB pathway activation, and reduced the secretion of corresponding inflammatory factors in T cells. Our study highlights the critical role of dysbiosis in gut dysfunction-induced musculoskeletal loss and underscores the therapeutic potential of B. lactis A6. These discoveries offer new microbiome directions for translational and clinical research, providing promising strategies for preventing and managing musculoskeletal diseases.
Cannabinoid-2 receptor depletion promotes non-alcoholic fatty liver disease in mice via disturbing gut microbiota and tryptophan metabolism
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a spectrum of liver damage starting with liver steatosis and lipid disorders presented as the hallmark. Cannabinoid-2 receptor (CB2R) is the receptor of endocannabinoids mainly expressed in immune cells. Our preliminary study revealed the preventative role of CB2R in liver injury related to lipid metabolism. In this study, we aimed to explore the role of CB2R in NAFLD and the underlying mechanism related to microbial community. High-fat diet-induced NAFLD model was established in mice. We found that hepatic CB2R expression was significantly reduced in NAFLD mice and CB2R–/– mice fed with normal chow. Interestingly, cohousing with or transplanted with microbiota from WT mice, or treatment with an antibiotic cocktail ameliorated the NAFLD phenotype of CB2R–/– mice. The gut dysbiosis in CB2R–/– mice including increased Actinobacteriota and decreased Bacteroidota was similar to that of NAFLD patients and NAFLD mice. Microbial functional analysis and metabolomics profiling revealed obviously disturbed tryptophan metabolism in NAFLD patients and NAFLD mice, which were also seen in CB2R–/– mice. Correlation network showed that the disordered tryptophan metabolites such as indolelactic acid (ILA) and xanthurenic acid in CB2R-/- mice were mediated by gut dysbiosis and related to NAFLD severity indicators. In vitro and in vivo validation experiments showed that the enriched tryptophan metabolites ILA aggravated NAFLD phenotypes. These results demonstrate the involvement of CB2R in NAFLD, which is related to gut microbiota-mediated tryptophan metabolites. Our findings highlight CB2R and the associated microbes and tryptophan metabolites as promising targets for the treatment of NAFLD.
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