Gut Microbiome Dynamics Associated with Rifamycin Therapy for Latent Tuberculosis Infection: Findings from a Prospective Cohort Study

Abstract

Abstract Background: Latent tuberculosis infection (LTBI) treatment is an effective strategy to eliminate TB in low-incidence settings. Shorter LTBI regimens incorporating the antimicrobial class of rifamycins are designed to improve treatment completion rates. Recent evidence suggests that the rifamycins could induce irreversible gut microbiota changes that impact future anti-TB immunity. Methods: To document the immediate effect of the rifamycins on the gut microbiota, we followed six patients with LTBI initiating four months of monotherapy with rifampin (4R; n=4) or three months of rifapentine in combination with isoniazid (3HP; n=2) and tracked recovery to baseline two months posttreatment completion. We collected stool samples parallel to the LTBI group from healthy volunteers (N=6) unexposed to the rifamycins. We used a questionnaire to collect diet, antibiotics, and lifestyle changes during follow-up. We profiled the gut microbiota using 16S rRNA amplicon sequencing (V1-V2 region). Results: Rifamycin exposure resulted in a 4.24% decrease in alpha diversity, compared to a 3.27% decrease in the controls. While the change in alpha diversity was small and not statistically different from changes observed in controls, significant bacterial community dissimilarity correlated with treatment duration (R2 = 0.269, P=0.041) and dose (R2 =0.201, P = 0.001) were observed. This rifamycin-associated dysbiosis was characterized by a depletion of butyrate-producing taxa (Clostridium-XIVa and Roseburia) and expansion of potentially pathogenic taxa within the Firmicutes and Proteobacteria phyla. Recovery of the gut microbial composition was incomplete two months after treatment ended. Conclusion: TB prophylaxis with the rifamycins induced minimal changes in the overall gut microbiota diversity but a significant shift in gut microbial composition. A larger clinical study with a longer follow-up time is necessary to confirm the extent to which the gut microbiota can recover from this rifamycin-induced dysbiosis to inform strategies to mitigate potential LTBI treatment sequelae.