Pre-diabetes increases tuberculosis disease severity, while high body fat without impaired glucose tolerance is protective

Abstract

Type 2 diabetes (T2D) is a well-known risk factor for tuberculosis (TB), but little is known about pre-diabetes and the relative contribution of impaired glucose tolerance vs. obesity towards susceptibility to TB. Here, we developed a preclinical model of pre-diabetes and TB. Mice fed a high fat diet (HFD) for 12 weeks presented with impaired glucose tolerance and hyperinsulinemia compared to mice fed normal chow diet (NCD). Infection with M. tuberculosis (Mtb) H37Rv after the onset of dysglycemia was associated with significantly increased lung pathology, lower concentrations of TNF-α, IFN-γ, IFN-β, IL-10 and a trend towards higher bacterial burden at 3 weeks post infection. To determine whether the increased susceptibility of pre-diabetic mice to TB is reversible and is associated with dysglycemia or increased body fat mass, we performed a diet reversal experiment. Pre-diabetic mice were fed a NCD for 10 additional weeks (HFD/NCD) at which point glucose tolerance was restored, but body fat mass remained higher compared to control mice that consumed NCD throughout the entire experiment (NCD/NCD). Upon Mtb infection HFD/NCD mice had significantly lower bacterial burden compared to NCD/NCD mice and this was accompanied by restored IFN-γ responses. Our findings demonstrate that pre-diabetes increases susceptibility to TB, but a high body mass index without dysglycemia is protective. This murine model offers the opportunity to further study the underlying immunological, metabolic and endocrine mechanisms of this association.

Diabetes-associated Susceptibility to Tuberculosis: Contribution of Hyperglycemia vs. Dyslipidemia

“…Consistent with this observation several other studies reported that obesity in the absence of hyperglycemia protects against TB [35][36][37] and individuals with high BMI are less likely to die during TB treatment. Similar observations were made in a murine model [38].…”

“…These studies used a streptozotocin-induced model of diabetes. A 12-week high-fat diet based murine model of pre-diabetes showed a trend towards higher Mtb burden in animals with impaired glucose tolerance, significantly higher lung pathology scores and impaired cytokine responses both in the lung and in blood [38]. Interestingly, restoration of glucose tolerance while maintaining high body fat conferred resistance to TB in the murine model described above.…”

A blunted GPR183/oxysterol axis during dysglycemia results in delayed recruitment of macrophages to the lung during M. tuberculosis infection

“…Since diabetes is a well known risk factor for TB and we previously showed that mice with HFD-induced dysglycemia have more severe TB [2], we next investigated whether this is linked to changes in oxysterol production in the lung. We observed that Mtb-infection in dysglycemic animals induced Ch25h expression similar to in normoglycemic animals (Figure 1B red vs. black bars), and the concentrations of 25-OHC were similarly comparable between the animals (Figure 1E red vs. black bar).…”

“…TB patients with T2D co-morbidity are at higher risk of adverse TB treatment outcomes and increased mortality [1]. Several different animal models of diabetes show increased susceptibility to TB [2][3][4][5][6][7][8]. We previously reported that dysglycemic M. tuberculosis (Mtb) -infected mice had more severe TB with a trend towards higher lung bacterial burden, significantly lower pulmonary concentrations of tumor necrosis factor (TNF)-α and interferon (IFN)-γ during early infection (3 weeks post infection (p.i.))…”

“…accompanied by significantly worse lung pathology at 8 weeks p.i. compared to normoglycemic control animals [2]. While various mechanisms likely contribute to an impaired host defense in subjects with hyperglycemia, chronic low-grade inflammation leading to defects in the innate immune responses against Mtb and the subsequent delay in activating adaptive immune responses have been suggested as cellular mechanisms of TB susceptibility [6].…”