Abstract
The leptin receptor-deficient db/db mouse model is an accepted in vivo model to study obesity, type 2 diabetes, and diabetic kidney disease. Healthy gastrointestinal (GI) microbiota has been linked to weight loss, improved glycemic control, and physiological benefits. We investigated the effect of various drugs on the GI microbiota of db/db mice as compared to control db/m mice. Treatment with long-acting pirfenidone (PFD) increased gut microbial diversity in diabetic db/db mice. Firmicutes, the most abundant phylum in db/m mice, decreased significantly in abundance in db/db mice but showed increased abundance with long-acting PFD treatment. Several bacterial taxa, including Lactobacillus and some Bacteroides, were less abundant in db/db mice and more abundant in long-acting-PFD-treated db/db mice. Long-acting PFD treatment reduced the abundance of Akkermansia muciniphila (5%) as compared to db/db mice (~15%). We conclude that gut microbial dysbiosis observed in db/db mice was partially reversed by long-acting PFD treatment and hypothesize that PFD has beneficial effects, in part, via its influence on the gut microbial metabolite profile. In quantitatively assessing urine metabolites, we observed a high abundance of diabetic ketoacidosis biomarkers, including 3-hydroxybutyric acid and acetoacetic acid in db/db mice, which were less abundant in the long-acting-PFD-treated db/db mice.
Highlights
Type 2 diabetes (T2D) has emerged as a global public health problem
The db/db mice treated with long-acting PFD had slightly lower average HbA1c and glucose levels at 10.8% and 565.2 mg/dL, respectively, with negligible weight changes (Figure 1B)
Microbial diversity decreased in db/db mice with highly abundant Bacteroidetes and lower abundances of Firmicutes, Actinobacteria, and Tenericutes
Summary
Type 2 diabetes (T2D) has emerged as a global public health problem. Epidemiological data show that the prevalence of this disease has increased significantly over the past several decades and continues to increase at alarming rates across the entire world (https://www.cdc.gov/diabetes/data/ statistics). Inflammation in rats with experimental uremia is associated with increased bacterial translocation from the gut into the blood circulation [17]. Microorganisms may ameliorate such outcomes: the administration of Sporosarcina pasteurii in uremic rats prolonged their life span and improved renal function [18]. Human gut microbiota assembled gnotobiotic mice showed an increased abundance of A. muciniphila when fed with a fiber-free diet, which resulted in the absence of fiber-degrading species [22]. T2D patients have a higher abundance of A. muciniphila as compared to non-diabetic controls in the gut microbiota, perhaps due to the intake of metformin [24]
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