Pre-Diabetes Increases Tuberculosis Disease Severity, While High Body Fat Without Impaired Glucose Tolerance Is Protective.

Roma Sinha,Antje Blumenthal,Sahar Keshvari,Chen Chen,Meg L Donovan,Helle Bielefeldt-Ohmann,Stacey Bartlett,Katharina Ronacher,Jessica C Kling,Minh Dao Ngo,Sumaira Z Hasnain,Kirsty R Short

doi:10.3389/fcimb.2021.691823

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 and 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.

Highlights

Tuberculosis (TB) remains one of the top 10 causes of death worldwide killing more than 1.4 million people in 2019 (WHO, 2020)
Blood glucose concentrations after glucose challenge were higher at 15, 30, 60 and 120 min in high fat diet (HFD)-fed mice (Figure 1E) with significantly higher area under the curve (AUC) in oral glucose tolerance tests (OGTT) (Figure 1F), while fasting blood glucose and glycated hemoglobin (HbA1c) were similar between normal chow diet (NCD) and HFD-fed mice (Figure S1). This phenotype of obesity combined with dysglycemia mimics human pre-diabetes, which is characterized by insulin resistance and impaired glucose tolerance, but HbA1c levels below those of diabetes patients
To address this current knowledge gap, we developed a pre-diabetes model of M. tuberculosis (Mtb) infection and demonstrated more severe TB disease and altered immune responses to Mtb in the lung and blood of mice with impaired glucose tolerance

Summary

Introduction

Tuberculosis (TB) remains one of the top 10 causes of death worldwide killing more than 1.4 million people in 2019 (WHO, 2020). Type 2 diabetes (T2D) increases the risk of developing TB as well as the risk of adverse TB treatment outcomes (Critchley et al, 2017). People with TB and T2D co-morbidity have a 88% higher risk of death during treatment, a 64% higher risk of relapse and are twice as likely to develop drug-resistant TB (Huangfu et al, 2019). Obesity in absence of dysglycemia protects against TB (Lonnroth et al, 2010; Aibana et al, 2016; Lin et al, 2018) and individuals with high BMI are less likely to die during TB treatment (Yen et al, 2016).

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