Preventive Role of Salsalate in Diabetes Is Associated With Reducing Intestinal Inflammation Through Improvement of Gut Dysbiosis in ZDF Rats

Abstract

A safe and effective approach is needed to prevent and reduce the incidence of diabetes worldwide. The hypoglycemic efficacy of salicylic acid (salsalate, SAL), which has antiinflammatory properties, has been empirically demonstrated in studies conducted at the Joslin Diabetes Center and elsewhere. Here, we investigated the potential role of SAL in preventing the onset of diabetes in Zucker diabetic fatty (ZDF) rats and attempted to elucidate its underlying mechanisms. ZDF and Zucker lean (ZL) rats were administered a high-fat diet with or without SAL intervention, and their relative rates of diabetes were compared. Our results showed that all rats in the placebo group developed diabetes, whereas only 10% of the SAL-treated rats presented with impaired glucose tolerance (IGT). None of the latter progressed to diabetes. Relative to the untreated rats, SAL lowered plasma glucagon and insulin while improving insulin sensitivity and b-cell function. SAL may protect against hyperglycemia by increasing the microbial diversity, ameliorating gut dysbiosis, restoring intestinal epithelial cell connections, inhibiting endotoxin influx into the blood, and attenuating inflammation. Together, these findings suggest that SAL may be a candidate prophylactic therapy against diabetes. The protective role of SAL may be attributed to its ability to reduce intestinal inflammation and improve gut dysbiosis.

Altered Fecal Microbiome and Correlations of the Metabolome with Plasma Metabolites in Dairy Cows with Left Displaced Abomasum

“…In addition, we found that the abundance of salicylic acid, which is derived from the catabolism of gut microbiota, decreased during LDA events. Zhang et al ( 44 ) reported that salicylic acid negatively modulates the abundance of Prevotella , further suppressing the inflammation response. Of note, 4-pyridoxic acid, cytidine, and salicylic acid were regarded as prediction factors of LDA in this study.…”

Acai berry extract as a regulator of intestinal inflammation pathways in a Caco‐2 and RAW 264.7 co‐culture model

“…Dysbiosis, described as a disorder of or alteration in the density and/or composition of intestinal microbiota, may promote gut permeability, actuate innate immunity, regulate the metabolism of lipid and glucose, provoke light inflammatory responses, and lead to symptoms related to diabetes mellitus (Buford, 2017; Zhang et al., 2020). The intestinal barrier strictly maintains gut permeability via TJ complexes and a mucus layer, which prevents abnormal leakage and invasion of pathogen‐associated molecular patterns (PAMPs) into the circulation and separates gut microbiota and host molecules (Kim & Kim, 2019).…”

Hypolipidemic and insulin sensitizing effects of salsalate beyond suppressing inflammation in a prediabetic rat model

“…Smith et al suggested that the mechanism by which salsalate improves glucose homeostasis and NAFLD is via salicylate-driven mitochondrial uncoupling ( Smith, et al, 2016 ). Antidiabetic effect of salsalate may be also related to reducing intestinal inflammation and improved gut dysbiosis that was observed in ZDF rats ( Zhang, et al, 2020 ). Although several studies have found increased adiponectin levels after salsalate administration ( Wang, et al, 2014 ; Salastekar, et al, 2017 ), which could contribute to improvement of insulin sensitivity, in the present study salsalate did not affect adiponectin levels.…”