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Intestinal dysbiosis compromises alveolar macrophage immunity to Mycobacterium tuberculosis

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Abstract

Current treatments for tuberculosis (TB) are effective in controlling Mycobacterium tuberculosis (Mtb) growth, yet have significant side effects and do not prevent reinfection. Therefore, it is critical to understand why our host defense system is unable to generate permanent immunity to Mtb despite prolonged anti-tuberculosis therapy (ATT). Here, we demonstrate that treatment of mice with the most widely used anti-TB drugs, rifampicin (RIF) or isoniazid (INH) and pyrazinamide (PYZ), significantly altered the composition of the gut microbiota. Unexpectedly, treatment of mice with the pro-Mtb drugs INH and PYZ, but not RIF, prior to Mtb infection resulted in an increased bacterial burden, an effect that was reversible by fecal transplantation from untreated animals. Mechanistically, susceptibility of INH/PYZ-treated mice was associated with impaired metabolism of alveolar macrophages and defective bactericidal activity. Collectively, these data indicate that dysbiosis induced by ATT administered to millions of individuals worldwide may have adverse effects on the anti-Mtb response of alveolar macrophages.

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Acknowledgements

We thank the Surette laboratory at McMaster University for 16S rDNA sequencing and helpful discussions related to the project. This work was supported by a CIHR operating grant (MOP-130579) to I.L.K., a CIHR Foundation Grant (FDN-143273) to M.D., the generous support of J.T. Costello Memorial Research Fund, the Richard and Edith Strauss Canada Foundation, the LIoyd Carr-Harris Foundation, and Microbiome and Disease Tolerance Centre at McGill University. N.K. is a recipient of a Fonds de recherche du Québec—Santé (FRQS) Postdoctoral Fellowship. J.X. is a Canada Research Chair in Bioinformatics and Big Data Analytics, I.L.K. is a Canada Research Chair in Barrier Immunity and M.D. holds an FRQS Award and the Strauss Chair in Respiratory Diseases.

Author information

N.K. performed experiments, analyzed data, and wrote the manuscript; L.M. and G.F. performed experiments and provided technical input; A.D. performed microbiome analyses and generated figures; J.X. provided technical input and data interpretation regarding the microbiome analyses; D.M. provided financial support and conceptual input; M.D. and I.L.K. conceived the original idea, supervised the project, and wrote the manuscript.

Competing interests:

The authors declare no conflicts of interest.

Correspondence to Maziar Divangahi or Irah L. King.

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