Abstract
The role of oxidative and nitrosative stress has been implied in both physiology and pathophysiology of metabolic disorders. Inducible nitric oxide synthase (iNOS) has emerged as a crucial regulator of host metabolism and gut microbiota activity. The present study examines the role of the gut microbiome in determining host metabolic functions in the absence of iNOS. Insulin-resistant and dyslipidemic iNOS−/− mice displayed reduced microbial diversity, with a higher relative abundance of Allobaculum and Bifidobacterium, gram-positive bacteria, and altered serum metabolites along with metabolic dysregulation. Vancomycin, which largely depletes gram-positive bacteria, reversed the insulin resistance (IR), dyslipidemia, and related metabolic anomalies in iNOS−/− mice. Such improvements in metabolic markers were accompanied by alterations in the expression of genes involved in fatty acid synthesis in the liver and adipose tissue, lipid uptake in adipose tissue, and lipid efflux in the liver and intestine tissue. The rescue of IR in vancomycin-treated iNOS−/− mice was accompanied with the changes in select serum metabolites such as 10-hydroxydecanoate, indole-3-ethanol, allantoin, hippurate, sebacic acid, aminoadipate, and ophthalmate, along with improvement in phosphatidylethanolamine to phosphatidylcholine (PE/PC) ratio. In the present study, we demonstrate that vancomycin-mediated depletion of gram-positive bacteria in iNOS−/− mice reversed the metabolic perturbations, dyslipidemia, and insulin resistance.
Highlights
Type 2 diabetes is a multitudinous metabolic disorder that arises from a complex interaction among genetic and environmental elements including dysregulated microbiota composition and function (Ahlqvist et al, 2018)
Multidimensional scaling analysis through principal coordinate plot represents that the bacterial communities between the WT and Inducible nitric oxide synthase (iNOS)−/− mice varied significantly (Figure 1E)
N-acetyl neuraminate, isocitrate, and citramalate were positively correlated, while glyceraldehyde was negatively correlated with taxa associated with glucose intolerance. 4Pyridoxate, melatonin, bile acids, and pigments were positively correlated with taxa associated with glucose intolerance (Figure S12D). These results suggest that metabolites involved in lipids, amino acids, bile acids, nucleic acids, carbohydrate, and bacterial-derived/ dependent metabolism exhibited significant correlation with gram-positive bacterial taxa linked to Insulin resistance (IR) and dyslipidemia in iNOS−/− mice. Involvement of both gram-positive and gram-negative bacteria has been reported in diabetes and metabolic syndrome; most of the studies on gram-negative bacteria linked LPSmediated inflammation with metabolic dysregulation (Rawat et al, 2012; Pushpanathan et al, 2016; Radilla-Vázquez et al, 2016; Liu et al, 2019). iNOS−/− mice are, protected against LPS-induced inflammation and the associated metabolic perturbations (Chauhan et al, 2003; Carvalho-Filho et al, 2006; House et al, 2012). iNOS−/− mice were insulin resistant and dyslipidemic on chow, low-fat diet (LFD), and high-fat diet (HFD) diets, which was improved substantially by nitrite supplementation (Kanuri et al, 2017; Aggarwal et al, 2019; Pathak et al, 2019; Aggarwal et al, 2020)
Summary
Type 2 diabetes is a multitudinous metabolic disorder that arises from a complex interaction among genetic and environmental elements including dysregulated microbiota composition and function (Ahlqvist et al, 2018). Antibiotic-induced depletion of the short-chain fatty acid (SCFA)-producing gut microbes reduced the levels of microbialderived colonic SCFA in children and enhanced the likelihood to develop obesity and metabolic syndrome later in life (Korpela et al, 2017; Li et al, 2017a; Wilkins and Reimer, 2021). Studies in humans have implied both gram-positive and gram-negative bacteria in the metabolic perturbations and obesity (Rawat et al, 2012; Pushpanathan et al, 2016; Radilla-Vázquez et al, 2016; Liu et al, 2019). These studies indicate the strong association of gut microbiota with obesity and related metabolic disorders (Cox and Blaser, 2013)
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