Bacteroides methylmalonyl-CoA mutase produces propionate that promotes intestinal goblet cell differentiation and homeostasis.

Propionate is a short-chain fatty acid that is generated upon microbiome-mediated fiber fermentation in the intestine. By modulating immune and metabolic pathways, propionate exerts many health benefits. Key bacterial species, such as Bacteroides thetaiotaomicron, generate propionate, but the biochemical pathways and specific functions remain undetermined. We identified a gene operon-encoding methylmalonyl-CoA mutase (MCM) that contributes to propionate biosynthesis in B. thetaiotaomicron. Colonization of germ-free mice with wild-type or MCM-deficient strains as well as in vitro examination demonstrated that MCM-mediated propionate production promotes goblet cell differentiation and mucus-related gene expression. Intestinal organoids lacking the propionate receptor, GPR41, showed reduced goblet cell differentiation upon MCM-mediated propionate production. Furthermore, although wild-type B. thetaiotaomicron alleviated DSS-induced intestinal inflammation, this effect was abolished in mice receiving the MCM-deficient strain but restored upon propionate supplementation. These data emphasize the critical role of MCM-mediated propionate biosynthesis in goblet cell differentiation, offering potential pathways to ameliorate colitis.

Liver function parameters aspartate aminotransferase and total protein predict functional outcome in stroke patients with non-cardioembolism.

Stroke, classified as cardioembolism and non-cardioembolism (non-CE), entails a large socioeconomic burden on the elderly. The morbidity and mortality of non-CE are high, whereas studies concerning prognostic factors impacting function outcome remain underdeveloped and understudied. Liver function parameters are convenient approaches to predicting prognosis in cardiovascular diseases, but their clinical significance has not been well characterized in stroke, especially in non-CE. In our study, a total of 576 patients with non-CE at 1 year of follow-up were enrolled in a cohort from a consecutive hospital-based stroke registry, with randomly 387 patients as the development cohort and 189 patients as the validation cohort. The univariate and multivariate analyses revealed the following novel findings: (i) The incidence of unfavorable functional outcomes after non-CE was significantly greater (p < 0.01) in patients with higher age, aspartate aminotransferase (AST), the National Institutes of Health Stroke Scale (NIHSS) score, and depressed total protein (TP); (ii) We established a novel model and nomogram to predict stroke prognosis, in addition to the known factors (age and the NIHSS score). The levels of AST and TP were independently correlated with the incidence of unfavorable outcomes [AST: odds ratio (OR) = 1.026, 95% CI (1.002-1.050); TP: OR = 0.944, 95% CI (0.899-0.991)]; (iii) The results persisted in further subgroup analysis stratified by age, gender, the NIHSS score, and other prespecified factors, especially in males 60 years or older. Overall, this study demonstrates that hepatic parameters (AST and TP) after non-CE are considered to be associated with functional outcomes at 1-year follow-up, especially in males aged ≥ 60 years.

γδ T/Interleukin-17A Contributes to the Effect of Maresin Conjugates in Tissue Regeneration 1 on Lipopolysaccharide-Induced Cardiac Injury.

The mechanisms underlying sepsis-induced cardiomyopathy (SIC) remain poorly understood, and there are no specific therapeutics for SIC. We investigated the effects of maresin conjugates in tissue regeneration 1 (MCTR1) on SIC and explored its potential mechanisms. The experiments were conducted using an endotoxemia model induced by lipopolysaccharide (LPS). Mice were given MCTR1 intravenously 6 h after LPS stimulation. Echocardiography was performed to assess cardiac function 12 h after LPS administration. Treatment with MCTR1 significantly enhanced cardiac function and reduced LPS-induced increase of mRNA expression levels of inflammation cytokines. Transcriptomic analysis indicated that MCTR1 inhibited neutrophil chemotaxis via the IL-17 signaling pathway. We confirmed that MCTR1 reduced the expressions of neutrophil chemoattractants and neutrophil infiltration in the LPS-stimulated hearts. MCTR1 also resulted in a considerable reduction in IL-17A production mainly derived from γδ T cells. Moreover, our results provided the first evidence that neutralizing IL-17A or depletion of γδ T cells markedly decreased neutrophil recruitment and enhanced cardiac function in LPS-induced cardiac injury. These results suggest that MCTR1 alleviates neutrophil infiltration thereby improves cardiac function in LPS-induced cardiac injury via the IL-17 signaling pathway. Thus, MCTR1 represented a novel therapeutic strategy for patients with SIC.

Maresin conjugates in tissue regeneration 1 prevents lipopolysaccharide-induced cardiac dysfunction through improvement of mitochondrial biogenesis and function.

Mitochondrial dysfunction is increasingly considered as the center of pathophysiology in sepsis-induced cardiac dysfunction. Maresin conjugates in tissue regeneration 1 (MCTR1) is a newly identified specialized pro-resolving mediator (SPM) and has been shown to accelerate tissue regeneration and exert positive inotropic effects. Our present study aims to investigate the effect of MCTR1 on lipopolysaccharide (LPS)-induced cardiac dysfunction and explore its potential mechanisms. Mice were treated with LPS to generate LPS-induced cardiac dysfunction. H9C2 cells were used to verify the effect of MCTR1 in vitro. LPS injection triggered cardiac dysfunction and increased mRNA expression of inflammation cytokines, which were significantly attenuated by post-treatment of MCTR1. Mechanistically, we found that MCTR1 ameliorated LPS-mediated reduction of protein expression of mitochondrial biogenesis factors and silent information regulator 1 (Sirt1), accompanied by enhancement of mitochondrial biogenesis and function. Besides, Sirt1 inhibitor EX527 inhibited effects of MCTR1 on mitochondrial biogenesis and function, blunted the protective effect of MCTR1 on cardiac function, and prevented enhancement of survival rate. MCTR1 protected against LPS-induced cardiac dysfunction through improvement of mitochondrial biogenesis and function in a Sirt1-dependent manner. Our studies showed that MCTR1 might represent a novel therapeutic strategy for cardiac dysfunction caused by sepsis.