Intestinal microbiota disruption limits the isoniazid mediated clearance of Mycobacterium tuberculosis in mice

• Published in: European journal of immunology 2020-12, Vol.50 (12), p.1976-1987
• Main Authors: Negi, Shikha, Pahari, Susanta, Bashir, Hilal, Agrewala, Javed N.
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Digestive system; Disease Models, Animal; Dysbacteriosis; Dysbiosis - immunology; Dysbiosis - microbiology; Female; Gastrointestinal Microbiome - immunology; Gastrointestinal tract; Immune clearance; Immune response; Immunity, Innate - immunology; Immunosuppressive agents; Immunotherapy; Innate immunity; intestinal microbiota; Intestinal microflora; Intestine; Intestines - immunology; Intestines - microbiology; Isoniazid; Isoniazid - immunology; Lung - immunology; Lung - microbiology; Mice; Mice, Inbred C57BL; Microbiota; Microbiota - immunology; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; T cells; Toxicity; Tuberculosis; Tuberculosis - immunology; Tuberculosis - microbiology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.202048556

Tuberculosis (TB) continues to remain a global threat due to the emergence of drug‐resistant Mycobacterium tuberculosis (Mtb) strains and toxicity associated with TB drugs. Intestinal microbiota has been reported to affect the host response to immunotherapy and drugs. However, how it affects the potency of first‐line TB drug isoniazid (INH) is largely unknown. Here, we examined the impact of gut microbial dysbiosis on INH efficiency to kill Mtb. In this study, we employed in vivo mouse model, pretreated with broad‐spectrum antibiotics (Abx) cocktail to disrupt their intestinal microbial population prior to Mtb infection and subsequent INH therapy. We demonstrated that microbiota disruption results in the impairment of INH‐mediated Mtb clearance, and aggravated TB‐associated tissue pathology. Further, it suppressed the innate immunity and reduced CD4 T‐cell response against Mtb. Interestingly, a distinct shift of gut microbial profile was noted with abundance of Enterococcus and reduction of Lactobacillus and Bifidobacterium population. Our results show that the intestinal microbiota is crucial determinant in efficacy of INH to kill Mtb and impacts the host immune response against infection. This work provides an intriguing insight into the potential links between host gut microbiota and potency of INH. Broad‐spectrum antibiotics deplete the healthy intestinal microbes. This interferes with the action of antituberculosis drug isoniazid to kill pathogenic Mtb in mice. Thus, beneficial microbes are crucial for effectiveness of anti‐TB therapy and protective innate and T‐cell response in host.