Gut microbiota dysbiosis observed in tuberculosis patients resolves partially with anti-tuberculosis therapy

ABSTRACT Objective Mycobacterium tuberculosis (Mtb) primarily affects the lungs with involvement of other organs causing tuberculosis (TB) in humans. Since the lung-gut axis is bidirectional, and the gut microbiota contributes to metabolic and immune homeostasis, we looked at the gut microbiota and metabolites of TB patients and controls, and whether the perturbations, if any, resolve with anti-tuberculosis treatment. Methods In this multicentric case-control study, a total of 107 fecal samples belonging to drug naïve active tuberculosis (ATB) patients and controls (non-tuberculosis: NTB and healthy), were collected from two clinical sites in India. A group of drug-naïve ATB patients (n=10) from one site was followed-up and monitored at 2, 4, 6, and 8 months of their anti-tuberculosis treatment. The fecal microbiome and metabolome of these study participants were characterized by 300 bp pair end sequencing of the V3-V4 region of 16S rRNA gene and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS) respectively to identify disease and treatment-specific variations, if any. Results Drug naïve ATB and NTB patients showed a significant reduction of gut microbial diversity with respect to age matched healthy controls in both the clinical sites. ATB patient’s had underrepresentation of gut commensals such as Faecalibacterium prausnitzii, Prevotella copri DSM 18205, Coprococcus catus, and overrepresentation of Clostridium difficile ATCC 9689 = DSM 1296. Longitudinally followed-up ATB patients showed elimination of Alkalihalobacillus with treatment initiation, whereas harmful taxa such as Stenotrophomonas and Klebsiella pneumoniae appeared in treatment-completed subjects. Interestingly, the fecal metabolites also showed group-specific differences, clustering ATB patients away from the controls irrespective of the study sites. Consistently, fecal 2-piperidinone abundance was higher in ATB patients compared to healthy controls. The fecal metabolome of longitudinally followed-up ATB patients showed a gradual shift towards healthy during the course of treatment completion. Conclusion Gut microbial dysbiosis observed in tuberculosis patients at case presentation is partially resolved with 6 months of treatment completion and also reflected in their metabolite level. The observed microbial and metabolite imbalance in these ATB patients could explain disease pathology which needs further exploration to exploit their translational potential for therapeutics development.