Type 2 diabetes (T2D) is a well-known risk factor for tuberculosis (TB), but little is known about the impact of pre-diabetes on the susceptibility to TB and the relative contribution of hyperglycemia vs. obesity.
To address this knowledge gap we performed M. tuberculosis (Mtb) infection studies in a murine model of pre-diabetes. Mice were fed a high-fat diet (HFD) or a normal chow diet (NCD) for 12 weeks, at which point HFD fed mice had increased body fat, impaired glucose tolerance and hyperinsulinemia, but comparable HbA1c to NCD fed mice. After aerosol infection with Mtb H37Rv, HFD fed mice had more severe TB disease including more necrotic lung lesions and reduced production of pro-inflammatory cytokines and chemokines (TNF-α, IFN-γ, IL-1b, CCL2) at the site of disease.
To determine whether the increased susceptibility of the HFD fed mice is associated with hyperglycemia or obesity, we performed diet reversal experiments. Mice fed a HFD for 12 weeks were switched to a NCD for an additional 10 weeks (HFD/NCD), while control mice were fed a NCD for a total of 22 weeks (NCD/NCD). At the end of this period, HFD/NCD mice had lost body weight and had normal glucose tolerance, but continued to have an increased body fat percentage compared to NCD/NCD mice. Importantly, when these mice were infected with Mtb the HFD/NCD fed mice had significantly lower lung mycobacterial burden at eight weeks post-infection compared to NCD/NCD fed mice.
Together, these results demonstrate that pre-diabetes increases susceptibility to TB and that re-establishment of glucose tolerance through rapid weight loss while maintaining sufficient adipose tissue is associated with significantly reduced TB disease severity. Our findings are consistent with observations in humans that high BMI without hyperglycemia is protective against TB and our novel murine model offers the opportunity to further study the underlying immunological and endocrine mechanisms of this association.