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. 2021 Mar 23;4(2):181-188.
doi: 10.1002/ame2.12159. eCollection 2021 Jun.

A murine model of tuberculosis/type 2 diabetes comorbidity for investigating the microbiome, metabolome and associated immune parameters

Harindra D Sathkumara  1 , Janet L Eaton  2 , Matt A Field  1   3   4 , Brenda L Govan  1   2 , Natkunam Ketheesan  5 , Andreas Kupz  1
Affiliations

A murine model of tuberculosis/type 2 diabetes comorbidity for investigating the microbiome, metabolome and associated immune parameters

Harindra D Sathkumara et al. Animal Model Exp Med. .

Abstract

Tuberculosis (TB) is one of the deadliest infectious diseases in the world. The metabolic disease type 2 diabetes (T2D) significantly increases the risk of developing active 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, injury 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 clinical 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 microbiota and the gut-lung axis.

Keywords: gut microbiota; host microbe interaction; infectious diseases; tuberculosis; type 2 diabetes.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Diet‐induced model of murine type 2 diabetes. A, 4‐ to 6‐wk‐old C57BL/6 male mice were fed with either EDD or SD for 30 weeks to induce murine T2D. B, Body weight was measured throughout the diet intervention period. Following dietary intervention, levels of fasting blood glucose (C), serum HbA1c (D) and glucose tolerance (E) were determined as cardinal features of human T2D. The effect of diets on gut microbiota was monitored by observing the changes in phylum Bacteroidetes (F) and Actinobacteria (G). H, Relationship of T2D‐assocaited metabolic parameters and the abundance of Bacteroidetes and Actinobacteria. Results are presented as pooled data means ± SEM (B), individual data points (C‐E), min to max in box plots (F, G) and a heat map (H) from 30‐40 mice (B), 10‐20 mice (C‐E, H), and 20‐25 mice (F, G) per group. Positive and negative correlation coefficient (r) values indicate a positive or negative linear relationship, respectively (H). *P < .05; **P < .01; ***P < .001; ****P < .0001; ns: not significant by unpaired two‐tailed Student's t test (B‐G) and Pearson correlation coefficient test (H). AUC, area under the curve; Carbo., carbohydrate; EDD, energy dense diet; FBG, fasting blood glucose; GTT, glucose tolerance test; SD, standard diet
FIGURE 2
FIGURE 2
Type 2 diabetes and aerosol Mtb infection markedly alter the intestinal microbial composition in mice. A, T2D and ND mice were infected with a very low dose of aerosol Mtb (10‐20 CFUs) and lung bacterial loads and gut microbiota changes were assessed. B, Mtb numbers in the lung at 14, 28 and 45 d p.i. in T2D and ND mice. C, Gut microbiota composition at the phylum level was characterized. D, Abundance of Firmicutes and Bacteroidetes in naïve and Mtb‐infected T2D and ND mice at 45 d p.i. E, Firmicutes to Bacteroidetes (F/B) ratio in naïve and Mtb‐infected T2D and ND mice at 45 d p.i. F, Gut microbiota composition at the family level was also characterized. G, PCA plot and Shannon diversity index in naïve and Mtb‐infected ND and T2D mice at 45 d p.i. The arrows indicate the shift of the ND and T2D clusters following Mtb infection. Results are presented as pooled data means ± SEM (B), relative proportions (C, F) and individual data points (D, E, G) from 4‐5 mice per group (B‐G). *P < .05; **P < .01; ***P < .001; ****P < .0001; ns: not significant by unpaired two‐tailed Student's t test (B‐F) and one‐way ANOVA followed by Tukey's test (G). Data are mean ± SEM (B, D, E), and quartiles in violin plots (G). ΝD, non‐diabetic; T2D, type 2 diabetes
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