The Combination of Intestinal Alkaline Phosphatase Treatment with Moderate Physical Activity Alleviates the Severity of Experimental Colitis in Obese Mice via Modulation of Gut Microbiota, Attenuation of Proinflammatory Cytokines, Oxidative Stress Biomarkers and DNA Oxidative Damage in Colonic Mucosa.

Dagmara Wojcik-Grzybek,Marcin Surmiak,Slawomir Kwiecien,Agata Mlodzinska,Adrianna Wojcik,Marcin Magierowski,Tomasz Brzozowski,Magdalena Hubalewska-Mazgaj,Jan Bilski,Agnieszka Mazur-Bialy,Zbigniew Sliwowski,Anna Dobrut

doi:10.3390/ijms23062964

Dagmara Wojcik-Grzybek, Marcin Surmiak + Show 10 more

Open Access

https://doi.org/10.3390/ijms23062964

Copy DOI

Abstract

Inflammatory bowel diseases (IBD) are commonly considered as Crohn’s disease and ulcerative colitis, but the possibility that the alterations in gut microbiota and oxidative stress may affect the course of experimental colitis in obese physically exercising mice treated with the intestinal alkaline phosphatase (IAP) has been little elucidated. Mice fed a high-fat-diet (HFD) or normal diet (ND) for 14 weeks were randomly assigned to exercise on spinning wheels (SW) for 7 weeks and treated with IAP followed by intrarectal administration of TNBS. The disease activity index (DAI), grip muscle strength test, oxidative stress biomarkers (MDA, SOD, GSH), DNA damage (8-OHdG), the plasma levels of cytokines IL-2, IL-6, IL-10, IL-12p70, IL-17a, TNF-α, MCP-1 and leptin were assessed, and the stool composition of the intestinal microbiota was determined by next generation sequencing (NGS). The TNBS-induced colitis was worsened in obese sedentary mice as manifested by severe colonic damage, an increase in DAI, oxidative stress biomarkers, DNA damage and decreased muscle strength. The longer running distance and weight loss was observed in mice given IAP or subjected to IAP + SW compared to sedentary ones. Less heterogeneous microbial composition was noticed in sedentary obese colitis mice and this effect disappeared in IAP + SW mice. Absence of Alistipes, lower proportion of Turicibacter, Proteobacteria and Faecalibacterium, an increase in Firmicutes and Clostridium, a decrease in oxidative stress biomarkers, 8-OHdG content and proinflammatory cytokines were observed in IAP + SW mice. IAP supplementation in combination with moderate physical activity attenuates the severity of murine colitis complicated by obesity through a mechanism involving the downregulation of the intestinal cytokine/chemokine network and oxidative stress, the modulation of the gut microbiota and an improvement of muscle strength.

Highlights

Inflammatory bowel diseases (IBD) are a heterogeneous group of disorders of the digestive tract, encompassing two major phenotypic forms: Crohn’s disease (CD) and ulcerative colitis (UC) [1]
A significant increase in weight was observed in HFD fed mice with colitis treated with intestinal alkaline phosphatase (IAP) as compared to the respective values of weight recorded in trinitrobenzenesulfonic acid (TNBS) colitis mice fed a HFD or those with TNBS colitis exercising on spinning wheels (SW) (p < 0.05, Table 1)
Our present study demonstrates that experimental colitis in obese mice was ameliorated by the combined application of moderate physical activity on spinning wheels with IAP and that this effect was accompanied with changes in intestinal microbiota, a profound reduction of plasma levels of proinflammatory biomarkers and the attenuation of oxidative stress markers in the colonic mucosa

Summary

Introduction

Inflammatory bowel diseases (IBD) are a heterogeneous group of disorders of the digestive tract, encompassing two major phenotypic forms: Crohn’s disease (CD) and ulcerative colitis (UC) [1]. IAP act as a major regulator of gut intestinal permeability, having impact on the intestinal tight junction [25] This enzyme is considered one of the most important factors in the protection of the intestinal mucosa, being responsible for the maintenance of intestinal homeostasis [26]. We have reported that voluntary exercise and IAP exerted a beneficial protective effect against inflammatory intestinal changes [36]; the alterations in microbiota at the phylum and genus levels, oxidative stress biomarkers, protein expression of proinflammatory factors as well as skeletal muscle strength changes in obesity-induced exacerbation of colitis have not been studied before. We have examined the changes in the macroscopic and microscopic appearance of colonic mucosa, oxidative stress, proinflammatory cytokines and muscle tension assessed have been associated with the development of intestinal inflammation in experimental murine models of colitis [37]. Scie. 2s0p22e, c23i,a2l9l6y4 in obese mice subjected to moderate exercise with or without IAP treatment3.of 29

Methods

Results

Conclusion