摘要
Tuberculosis(TB)is one of the deadliest infectious diseases in the world.The meta-bolic disease type 2 diabetes(T2D)significantly increases the risk of developing ac-tive TB.Effective new TB vaccine candidates and novel therapeutic interventions are required to meet the challenges of global TB eradication.Recent evidence suggests that the microbiota plays a significant role in how the host responds to infection,in-jury and neoplastic changes.Animal models that closely reflect human physiology are crucial in assessing new treatments and to decipher the underlying immunological defects responsible for increased TB susceptibility in comorbid patients.In this study,using a diet-induced murine T2D model that reflects the etiopathogenesis of clinical T2D and increased TB susceptibility,we investigated how the intestinal microbiota may impact the development of T2D,and how the gut microbial composition changes following a very low-dose aerosol infection with Mycobacterium tuberculosis(Mtb).Our data revealed a substantial intestinal microbiota dysbiosis in T2D mice compared to non-diabetic animals.The observed differences were comparable to previous clini-cal reports in TB patients,in which it was shown that Mtb infection causes rapid loss of microbial diversity.Furthermore,diversity index and principle component analyses demonstrated distinct clustering of Mtb-infected non-diabetic mice vs.Mtb-infected T2D mice.Our findings support a broad applicability of T2D mice as a tractable small animal model for studying distinct immune parameters,microbiota and the immune-metabolome of TB/T2D comorbidity.This model may also enable answers to be found to critical outstanding questions about targeted interventions of the gut mi-crobiota and the gut-lung axis.
基金
the National Health and Medical Research Council(NHMRC)through a CJ Martin Biomedical Early Career Fellowship(grant number APP1052764)
a Career Development Fellowship(grant number APP1140709)
a New Investigator Project Grant(grant num-ber APP1120808)
an Australian Institute of Tropical Health and Medicine(AITHM)Capacity Building Grant(grant number 15031)to A.K&NK
HDS was supported by an AITHM scholarship.