A novel enterotype enriched with respiratory super-dominant pathobionts is associated with immunosuppression in...

Perturbations of the gut microbiota in pulmonary tuberculosis (PTB) patients, often antibiotic-induced, are frequently observed; however, the defining features of this dysbiosis and its relationship with clinical phenotypes remain insufficiently characterized.

In this cross-sectional study, we collected fecal samples from 66 PTB patients and performed 16S rRNA gene (V3-V4) sequencing. Species-level taxonomic profiling was conducted using the Human Gut Microbiome Analysis Database (HGMAD). Enterotypes were constructed, and their associations with PTB were investigated. The predictive capacity of enterotype-specific microbial signatures (enterosignatures) for clinical phenotypes was assessed.

Taxonomic analysis revealed significantly reduced prevalence of high-abundance bacteria group in PTB patients (43.84%) compared to healthy controls (HC, 98.01%), indicating increased microbiota heterogeneity. Known pathogenic species, predominantly common respiratory opportunistic pathogens (e.g., Haemophilus parainfluenzae, Acinetobacter baumannii, Veillonella parvula), were more prevalent in the PTB cohort (21.37% vs. 11.49% in HC). Enterotype analysis revealed a distinct cluster, designated ETE (Enterobacterales-dominated enterotype), which was predominantly observed in PTB patients and differed from the conventional Prevotella-dominated enterotype (ETP) and Bacteroides-dominated enterotype (ETB), identified in HC. ETE was significantly enriched in taxa including Acinetobacter baumannii, Enterococcus, Veillonella, Pseudomonas, and Streptococcus, exhibited lower alpha diversity, and functional inference using PICRUSt2 suggested relative lower immune-related pathways. Clinically, ETE was associated with lower cellular immunity and a trend toward higher C-reactive protein (CRP) levels. A model based on ten super-dominant respiratory pathobionts enterosignatures effectively predicted key clinical phenotypes, with area under the curves (AUCs) of 0.83 for CD4⁺ T-cell count, 0.74 for CD8⁺ T-cell count, 0.74 for CD4⁺/CD8⁺ ratio, 0.93 for CRP, 0.78 for CA125, and 0.70 for Mtb positivity. SHapley Additive exPlanation (SHAP) analysis identified Enterobacterales and Veillonella as key negative predictors for T-cell counts, while Streptococcus and Enterobacteriaceae were positive predictors for CRP. In the CA125 model, Veillonella acted as a positive predictor and Enterobacterales as a negative predictor.

This cross-sectional study identifies a distinct, PTB-associated enterotype (ETE) characterized by enrichment of respiratory pathobionts and associated with altered immune parameters in PTB patients. Enterosignatures derive from ETE represent exploratory biomarkers with promising predictive capacity for clinical outcomes, though their generalizability warrants validation in independent, prospective cohorts.