Antibiotic treatment for Tuberculosis induces a profound dysbiosis of the microbiome that persists long after therapy is completed

Abstract

Mycobacterium tuberculosis, the cause of Tuberculosis (TB), infects one third of the world’s population and causes substantial mortality worldwide. In its shortest format, treatment of TB requires six months of multidrug therapy with a mixture of broad spectrum and mycobacterial specific antibiotics, and treatment of multidrug resistant TB is longer. The widespread use of this regimen makes this one of the largest exposures of humans to antimicrobials, yet the effects of TB treatment on intestinal microbiome composition and long-term stability are unknown. We compared the microbiome composition, assessed by both 16S rDNA and metagenomic DNA sequencing, of TB cases during antimycobacterial treatment and following cure by 6 months of antibiotics. TB treatment does not perturb overall diversity, but nonetheless dramatically depletes multiple immunologically significant commensal bacteria. The microbiomic perturbation of TB therapy can persist for at least 1.2 years, indicating that the effects of TB treatment are long lasting. These results demonstrate that TB treatment has dramatic effects on the intestinal microbiome and highlight unexpected durable consequences of treatment for the world’s most common infection on human ecology.

The role of the lung microbiota and the gut-lung axis in respiratory infectious diseases

“…These studies revealed that bacterial diversity in the gut of TB patients is altered and this may correlate with the progress of the disease (Luo et al, 2017;Maji et al, 2018). Anti-TB therapy includes antibiotics, such as rifampicin, that target bacteria other than mycobacteria, and one study showed that prolonged anti-TB treatment broadly alters the gut microbiota of TB patients and that the resulting dysbiotic state persists following cessation of therapy (Wipperman et al, 2017). This suggests that the long anti-TB treatment, which lasts at least 6 months, may render the patients more susceptible to other disorders and infections.…”

Narrow-spectrum antibacterial agents

“…40, 41 Three of the four first-line anti-TB drugs are narrow-spectrum, isoniazid 1 , pyrazinamide 2 , and ethambutol 3 (Figure 1), having little or no activity outside the mycobacterial genus. 42, 43 However, even drug-susceptible TB requires treatment durations of six months with a combination of these mycobacterial specific antibiotics, along with the broad-spectrum antibiotic rifampin. 43 In the case of MDR strains, which are becoming increasingly prevalent, multiple broad-spectrum antibiotics including fluoroquinolones and aminoglycosides are employed, and treatment regimens for multi-drug resistant strains that require these second-line broad-spectrum drugs typically last for two years.…”

“…42, 43 However, even drug-susceptible TB requires treatment durations of six months with a combination of these mycobacterial specific antibiotics, along with the broad-spectrum antibiotic rifampin. 43 In the case of MDR strains, which are becoming increasingly prevalent, multiple broad-spectrum antibiotics including fluoroquinolones and aminoglycosides are employed, and treatment regimens for multi-drug resistant strains that require these second-line broad-spectrum drugs typically last for two years. 40 These lengthy treatment durations represent some of the most extensive exposures of humans to antibiotics, 43 and will undoubtedly have considerable effects upon the commensal microbiota.…”

“…43 In the case of MDR strains, which are becoming increasingly prevalent, multiple broad-spectrum antibiotics including fluoroquinolones and aminoglycosides are employed, and treatment regimens for multi-drug resistant strains that require these second-line broad-spectrum drugs typically last for two years. 40 These lengthy treatment durations represent some of the most extensive exposures of humans to antibiotics, 43 and will undoubtedly have considerable effects upon the commensal microbiota. Given the lengthy treatment regimens required for the treatment of TB, the development of additional narrow-spectrum anti-TB agents that could potentially reduce the dependence on broad-spectrum antibiotics would be particularly valuable.…”

Perspectives for personalized therapy for patients with multidrug‐resistant tuberculosis

“…Importantly, also anti-TB therapy causes changes in microbiota compositions [170,172,178]. Despite maintenance of overall gut microbiota diversity, studies in both, mice and men, revealed standard anti-TB therapy induced long lasting microbiota alterations including reduction of Clostridiales, Bifidobacterium and Lactobacillus amongst others [179,180]. Thus, dysbiosis, either caused by M. tuberculosis infection or antibiotic treatment, could potentially affect immune functions, enhance susceptibility to secondary infections [181][182][183][184][185][186][187] and subsequent exacerbated pathology [188,189].…”