Haifang Li

Prevotella copri, a predominant commensal bacterium in the human gut, exhibits positive or negative correlations with multiple metabolic disorders through its abundance dynamics. Although its association with rheumatoid arthritis pathogenesis is established, the effect of P. copri on bone metabolism remains elusive. This study demonstrates that P. copri exposure induces systemic bone metabolic imbalance in both normal physiological murine models and in vitro-cultured bone marrow-derived adherent cells (BMDCs), which is characterized by exacerbated osteoclastogenesis. Notably, succinate acts as a critical bioactive metabolite, with its specific receptor SUCNR1 being involved in its regulation on bone metabolism. P. copri or succinate intervention triggers bone inflammatory responses, prominently elevating IL-6 expression. Intriguingly, the osteoclastic activation is abolished in Il-6-knockout mice upon P. copri or succinate challenge. These findings delineate a succinate-SUCNR1-IL-6 signaling axis through which P. copri disrupts bone homeostasis, proposing novel therapeutic strategies for bone disorders such as osteoporosis via modulating gut microbiota composition (e.g., diet-mediated Prevotella suppression), reducing succinate bioavailability, and pharmacological antagonism of SUCNR1.

Obesity, diabetes mellitus (DM), metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular diseases (CVDs) share pathogenic mechanisms like oxidative stress and inflammation. Resveratrol (RSV) offers therapeutic potential by activating the sirtuin (SIRT) signaling network. This review synthesizes RSV’s pharmacological impacts on adipose, pancreatic, hepatic, and cardiovascular tissues, focusing on the AMPK/SIRT1/PGC-1α axis, PI3K/AKT pathways, and epigenetic modulations. Despite robust preclinical data, a significant translational gap exists. Clinical evidence is heterogeneous, often contradicting animal studies due to varying dosages, durations, and population characteristics. RSV acts as a pan-SIRT activator, though its precise SIRT1 activation mechanism, direct or via NAD+ modulation, remains debated. In obesity, RSV promotes adipose beiging and thermogenesis, yet clinical weight loss is modest. For DM, it preserves β-cell function and improves insulin sensitivity, primarily benefiting diabetic populations with variable glycemic outcomes. In MASLD, RSV ameliorates steatosis and fibrosis in models, but large-scale human trials confirming histological benefits are lacking. Regarding CVDs, RSV protects against endothelial dysfunction and inflammation, showing minor improvements in biomarkers like blood pressure, though hard endpoints need validation. Major limitations hinder clinical efficacy, such as poor oral bioavailability, rapid metabolism, and significant interindividual pharmacokinetic variability. The lack of standardized formulations further complicates systemic exposure. Nevertheless, the RSV-SIRT axis remains a unified metabolic and epigenetic modulator, stabilizing cellular microenvironments across organ systems. It represents a promising target for complex metabolic syndromes. Future research should prioritize overcoming bioavailability challenges through novel delivery systems and investigating synergistic combinatorial therapies to bridge the gap between preclinical promise and clinical reality.

Prevotella is a poorly understood symbiont within the gut microbiota, and its role in host health remains unclear. Here, we report a case-control analysis of a Chinese cohort, in which patients with obesity showed significantly lower fecal Prevotella copri abundance. The administration of P. copri can alleviate fat deposition and promote browning in inguinal white adipose tissue (iWAT) of mice with high-fat diet (HFD)-induced adiposity. We identify succinate as a key metabolite that activates succinate receptor 1 (SUCNR1) to mimic the effects of P. copri. Mice treated with either P. copri or succinate have increased iWAT-resident macrophage populations and IL-6-STAT3 pathway activation. Forkhead box M1 (FOXM1) directly upregulates IL-6 to activate IL-6-STAT3 signaling in P. copri- or succinate-induced iWAT browning. In human WAT, we identify that P. copri and succinate levels are positively correlated with TBX1 and UCP1 transcription. This study reveals the function of P. copri in promoting iWAT browning and suggests potential strategies for alleviating adiposity and associated disorders.

Purpose: With the evolution of dietary habits, obesity has emerged as a significant global health issue. Numerous studies have demonstrated a close association between obesity and gut microbiota; however, the specific contribution of gut microbiota to varying degrees of obesity remains inadequately understood. Consequently, this study aims to characterize the gut microbiota of individuals across different obesity severity levels. Methods: We conducted a comprehensive characterization of the gut microbiome in Chinese obese patients and a healthy control group through the application of 16S rRNA gene sequencing, supplemented by metagenomic sequencing. The study cohort was stratified into five distinct categories based on body mass index (BMI): healthy, overweight, and obesity grades I, II, and III. Results: In obese populations, the gut microbiome structure shifted significantly, with beneficial genera like Faecalibacterium, Roseburia , and Ruminococcus decreasing, and potentially harmful genera such as Blautia, Collinsella , and Streptococcus increasing. These changes impacted host metabolic pathways, including ribosome synthesis, RNA polymerase activity, and DNA repair. Clinical analyses also revealed strong links between specific genera and metabolic markers like lipid metabolism and insulin resistance. Conclusion: Populations with different obesity traits show unique changes in gut flora. The level of dysbiosis, or imbalance in intestinal microbiota, rises with obesity. These microbial changes are linked to host metabolism, indicating that targeting harmful bacteria and supplementing with beneficial ones from normal-weight populations could effectively reduce obesity.

Liver diseases including hepatic injury, hepatitis, metabolic-associated fatty liver disease, and hepatocellular carcinoma have emerged as critical public health challenges globally. The fibrinogen (FG) superfamily proteins, primarily comprising FG, FG-like protein (FGL) 1, and FGL2, have been demonstrated to exert regulatory effects on hepatic tissue regeneration, lipid metabolism homeostasis, and oncogenic processes in hepatocytes. This review systematically examines the pathophysiological correlations between FG superfamily members and major hepatic disorders. Physiologically, FG superfamily proteins function as hepatoprotective mediators through their intrinsic capacity to enhance hepatic parenchymal regeneration and extracellular matrix remodeling. However, emerging evidence reveals their dual regulatory properties, whereby overactivation of these hepatokines paradoxically induces a pathological shift characterized by pro-inflammatory cascades, metabolic derangement potentiation, and tumor invasion and metastasis promotion. Specifically, we elucidate the molecular mechanisms underlying their involvement in hepatitis progression, metabolic-associated fatty liver disease pathogenesis, and hepatocellular carcinoma tumorigenesis. Furthermore, we highlight their therapeutic potential in hepatic disease management, particularly emphasizing that targeting the FGL1/lymphocyte activation gene 3 immune checkpoint axis represents a novel paradigm in precision cancer immunotherapy.

Clostridium butyricum (CB), a commensal gut bacterium with established probiotic properties, has demonstrated therapeutic potential in diverse human and animal pathologies. Despite its recognized benefits, the precise mechanisms underlying its influence on bone metabolism remain poorly understood. This study investigates the effects of CB on bone metabolism in murine models and elucidates the involved molecular pathways. Intragastric administration of CB to juvenile female mice significantly elevated osteogenic and osteoclastogenic gene expression profiles, correlating with increased bone mineral content (BMC) and bone mineral density (BMD). GC-MS metabolomic profiling identified butyric acid and acetic acid as primary bacterial metabolites. Subsequent in vitro analyses revealed that sodium butyrate (SB), sodium acetate (SA), and their combination (SB + SA) potently upregulated osteogenic/osteoclastogenic markers in total bone marrow adherent cells (BMCs). Concordant results were observed in vivo, where dietary supplementation with these metabolites enhanced bone remodeling. Notably, flow cytometry demonstrated significant expansion of CD45⁺/CD11b⁺ myeloid populations in bone marrow following CB or metabolite treatments, coinciding with upregulated pro-inflammatory gene such as Il-6 expression. Crucially, the bone remodeling effects of both CB and its metabolites were substantially diminished in Il-6-knockout (Il-6-KO) mice. These findings establish that CB enhances bone remodeling through butyrate- and acetate-dependent activation of inflammatory signaling pathways, particularly IL-6-mediated mechanisms. This study provides novel insights into microbiota-bone axis interactions and proposes probiotic interventions as potential therapeutic strategies for metabolic bone disorders.

As the most prevalent hepatic disorder worldwide, metabolic dysfunction-associated steatotic liver disease (MASLD) afflicts over one-third of the global population, representing a significant public health challenge. The multifactorial pathogenesis of this condition is principally rooted in metabolic dysregulation. It is notable that emerging evidence highlights a critical role for gut microbiota (GM) in disease initiation and progression. This comprehensive review elaborates some representative GM species that influence hepatic lipid metabolism and elucidates the mechanisms through which GM dysbiosis exacerbates MASLD pathogenesis. Importantly, the positive or negative effects of intestinal bacterial communities on MASLD are largely dependent on their special metabolites, such as short chain fatty acids, ethanol, and trimethylamine N-oxide. Current therapeutic strategies targeting GM modulation, including prebiotics, probiotics, fecal microbiota transplantation, specific medicines, and bacteriphages, demonstrate promising efficacy that partially restores microbial equilibrium and mitigates hepatic steatosis. Although limitations still persist in achieving sustained clinical remission, the expanding frontier of microbiome research continues to refine our understanding of host-microbiota crosstalk in MASLD. Future investigations integrating multiple approaches and longitudinal clinical data hold potential to unravel complex microbial networks, paving the way for innovative therapeutic breakthroughs in metabolic liver disease management.