Microbial product translocation and mortality in adults hospitalised with HIV-associated tuberculosis: a prospective observational cohort study

Background: HIV-associated tuberculosis (HIV-TB) results in unacceptably high mortality rates despite appropriate treatment. Patients hospitalized with HIV-TB often have disseminated tuberculosis and sepsis syndrome which may result in gastro-intestinal barrier dysfunction and facilitate microbial product translocation. Microbial product translocation may contribute to HIV-TB deaths by driving systemic inflammation. Objectives: To assess microbial product translocation and gastrointestinal epithelial damage in patients hospitalized with HIV-TB and the association with 12-week mortality and biomarkers of tuberculosis dissemination. To describe the bacterial blood microbiome (abundance and diversity) in patients with HIV-TB, its association with mortality and tuberculosis dissemination and compare to outpatient controls. Methods: Patients hospitalized with a new diagnosis of HIV-TB were enrolled and prospectively followed for 12 weeks. Markers of microbial product translocation and gastrointestinal damage were measured in a subset (n=373) and bacterial 16s rDNA was quantitated and metagenomic sequencing performed in 235 patients. Microbial product translocation and gastrointestinal epithelial damage marker concentrations were compared between hospitalized patients who died and survivors and inpatients compared to HIVpositive outpatient controls. Logistic regression analysis was performed to determine associations with mortality. Bacterial abundance, diversity and immune perturbation was measured and analysed across patient outcome groups and in patients with tuberculosis dissemination. Results: Patients hospitalized with HIV-TB had significantly higher concentrations of bacterial 16s rDNA, soluble CD14 (sCD14), lipopolysaccharide binding protein (LBP), trefoil factor 3 (TFF3) and lower endotoxin core antibody IgM (EndoCAB), compared to outpatient controls. Soluble CD14 and TFF3 were significantly higher and EndoCAB lower in inpatients who died versus survivors. TFF3 was independently associated with mortality. LPS, sCD14, LBP, EndoCAB and TFF3 showed significant trends in patients with positive biomarkers of tuberculosis dissemination. Metagenomic sequencing showed higher diversity in hospitalised HIV-TB patients compared to controls, but diversity was not different between outcome groups. Mycobacterium genus proportions were increased in hospitalised patients who died compared to survivors. Conclusion: We found evidence of increased gastrointestinal epithelial damage and microbial product translocation in patients hospitalized with HIV-TB and in patients with positive biomarkers for tuberculosis dissemination, however, only TTF3 (a marker of gastrointestinal epithelial damage), was independently associated with mortality.