Multi-omics analyses with stool-type stratification in patient cohorts and Blautia identification as a potential bacterial modulator in T2DM

Heterogeneity in host and gut microbiota hampers microbial precision intervention of type 2 diabetes mellitus (T2DM). Here, we investigate novel features for patient-stratification and bacterial modulators for intervention, using cross-sectional patient cohorts and animal experiments. We collected stool/blood/urine samples from 103 recent-onset T2DM patients and 25 healthy controls (HCs), performed gut microbial composition/metabolite profiling, and combined it with host-transcriptome/metabolome/cytokines and clinical data. Stool-type (dry/loose-stool), a feature of stool-microenvironment recently explored in microbiome studies, was used for T2DM patientstratification as it explained most of the variation in multi-omics dataset among all clinical parameters in our covariate analysis. T2DM with dry-stool (DM-DS) and loose-stool (DM-LS) were clearly differentiated from HC and each other by LightGBM-models, optimal among multiple machine-learning models. Compared to DM-DS, DM-LS exhibited discordant gut microbial taxonomic and functional profiles, severe host metabolic disorder, and excessive insulin secretion. Further cross-measurement-association-analysis linked the differential microbial profiles, in particular Blautia abundances, to T2DM phenotypes in our stratified multi-omics dataset. Notably, oral supplementation of Blautia to T2DM mice induced inhibitory effects on lipid accumulation, weight gain, and blood-glucose elevation with simultaneous modulation of gut bacterial composition, revealing the therapeutic potential of Blautia. Our study highlights the clinical implications of stool-microenvironment stratification and Blautia supplementation in T2DM, offering promising prospects for microbial precision treatment of metabolic diseases.