Pulmonary <i>Mycobacterium tuberculosis</i> infection alters the hepatic immunometabolic landscape and compromises insulin responsiveness early after infection

Abstract Immunity against Mycobacterium tuberculosis (Mtb) is associated with both regional and systemic inflammation as well as with metabolic disruption in tuberculosis (TB) patients. The metabolic and immunological responses are intertwined but the specific impact of localized disease on systemic metabolism is not well defined. We investigated the impact of low dose aerosol infection of the lung with Mtb on the systemic metabolic regulatory organ – the liver. Using an unbiased approach we defined the mRNA and protein dysregulation occurring in the early stage of infection. We found that infection leads to immune pathway activation and reduced metabolic activity in liver. Comparison of the gene expression patterns between of the lung, liver and blood revealed organ specific metabolic gene dysregulation in the context of non-organ specific activation of interferon response pathways. We have also found that infection leads to suppression of carbohydrate and lipid metabolism, without alteration of fasting or random blood glucose levels. Infected mice show reduced sensitivity to exogenous insulin but the glucose tolerance remains intact indicating insulin resistance. Analysis of metabolomics data from public repository reveals a metabolic signature of insulin resistance correlates with TB progression. Taken together, our finding shows that aerosol Mtb infection influences hepatic metabolism very soon after infection and may contribute to early metabolic disease. Defining the early interplay between localised infection, inflammation and metabolic regulation is key to understanding the impact of latent and subclinical TB on the large proportion of the World’s population who do not exhibit TB symptoms but who are infected with Mtb. Supported by Grants from Royal Society Wolfson Merit Award (AMC) Newton Fellowship (MKD), Wellcome Trust Institutional Support Fund Fellowship (MKD), MRC award MR/P011136/1 (AMC).