The Use of Mesalazine and Prebiotics on Metabolic Inflammation in Thirteen Lined Ground Squirrels and Outbred Mice

Abstract

Metabolic inflammation is a systemic inflammation event that occurs during fattening characterized by an accumulation of macrophages and pro-inflammatory cytokines. Mesalazine is a gut localized nonsteroidal anti-inflammatory drug (NSAID), and prebiotics help boost anti-inflammatory gut microbiota which work to reduce gut inflammation. The objective of this study is to determine if a diet containing mesalazine, prebiotics (inulin and pectin), or a mesalazine /prebiotic mixture will alter metabolic inflammation in 13-lined ground squirrels (Jctidomys tridecemlineatus) and diversity outbred (DO) mice. We chose ground squirrels, a hibernator, as our model because they rapidly gain adipose mass during their active season. Further, DO mice were chosen for their diverse genetics, more similar to ground squirrels and humans than inbred mice. For this study, DO mice were given a gut microbiota transfer from ground squirrels 48 hours after emerging from hibernation before the beginning of treatment. We hypothesized that the diet containing the mixture of mesalazine, and prebiotics would have the greatest effect on metabolic inflammation because both compounds work to reduce inflammation in the gut. Squirrels and mice stayed on their assigned treatment for 8 weeks and tissues were collected from a subset of animals after 4 and 8 weeks of treatment. We examined levels of the proinflammatory cytokines tumor necrosis factor (TNF)-a, and interleukin (IL)-6 as well as the anti-inflammatory cytokine interleukin (IL)-10 in the ileum, colon, and omental white adipose tissue (oWAT) using sandwich ELISA. Ileum tissue showed the most significance compared to colon and oWAT tissues. In the ileum, IL-10 increased over 8 weeks, whereas TNF-a decreased over 8 weeks in mesalazine-treated animals. IL-6, however, increased significantly over 8 weeks within the prebiotic treatment in the ileum ofTLGS. IL-10 was highest at the 8- week time point in the ileum ofTLGS, whereas TNF- a was highest at the 4-week time point for TLGS. Mice IL-10 was the most significant at 4 weeks but remained high over the course of 8 weeks in the ileum. In the colon, IL-6, TNF-a, and IL-10 decreased over 8 weeks in TLGS. In mice, IL-6 and TNF-a decreased over 8 weeks, where IL-10 increased, in prebiotics only. oWAT did not show any change in any of the animals treated. Glucose tolerance fluctuated over time and varied among treatment groups in TLGS and mice. Body weight increased across all treatments for all treated animals, whereas energy intake remained the same for mice and increased for TLGS. This could suggest that including more prebiotics via fruits and vegetables within a diet is beneficial for reducing metabolic inflammation, and including an anti-inflammatory drug will aid in reducing gut inflammation, which could serve as a potential new treatment for metabolic disease.