A compartment-resolved framework for microbial sulfur-reactive sulfur signaling in diabetic cardiomyopathy: from gut metabolism to cardiac sulfur responses

Diabetic cardiomyopathy (DCM) is an important substrate of diabetes-related heart failure and is increasingly considered within a gut-heart systems framework. Here, we propose a compartment-resolved microbial sulfur-cardiac signaling model rather than a linear pathway in which free gut-derived sulfide species are assumed to reach the myocardium intact. Gut microbes generate sulfide through dissimilatory sulfate reduction, anaerobic sulfite reduction, assimilatory sulfur pathways, and sulfur-amino-acid catabolism, whereas intestinal epithelial cells and liver strongly constrain systemic exposure through mitochondrial sulfide oxidation. Recent work reports that microbial sulfide-associated metabolism can influence enteroendocrine GLP-1 signaling, hepatic PPARα-dependent metabolism, and systemic sulfur handling through intestinal SQOR-dependent pathways; however, none of these studies demonstrates direct sulfur transfer from microbial metabolism to the diabetic heart or establishes a sulfur-specific causal pathway leading to myocardial persulfidation. In parallel, diabetic-heart studies report sulfide-donor-responsive persulfidation candidates including MuRF1 Cys44, SYVN1/Hrd1 Cys115, and SENP1 Cys683, but the evidence is concentrated in an overlapping research program and is methodologically dependent. We therefore separate better-supported local processes, cross-organ supporting evidence, and unresolved DCM-specific links, and outline source-resolved isotope tracing, microbial genetics, host sulfur-enzyme models, and orthogonal site-resolved persulfidation assays needed to test causality.