Intestinal Alkaline Phosphatase Combined with Voluntary Physical Activity Alleviates Experimental Colitis in Obese Mice. Involvement of Oxidative Stress, Myokines, Adipokines and Proinflammatory Biomarkers

Abstract

Intestinal alkaline phosphatase (IAP) is an essential mucosal defense factor involved in the process of maintenance of gut homeostasis. We determined the effect of moderate exercise (voluntary wheel running) with or without treatment with IAP on the course of experimental murine 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis by assessing disease activity index (DAI), colonic blood flow (CBF), plasma myokine irisin levels and the colonic and adipose tissue expression of proinflammatory cytokines, markers of oxidative stress (SOD2, GPx) and adipokines in mice fed a standard diet (SD) or high-fat diet (HFD). Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant decrease in CBF, and a significant increase in the colonic expression of tumor necrosis factor-alpha (TNF-α), IL-6, IL-1β and leptin mRNAs and decrease in the mRNA expression of adiponectin. These effects were aggravated in sedentary HFD mice but reduced in exercising animals, potentiated by concomitant treatment with IAP, especially in obese mice. Exercising HFD mice demonstrated a substantial increase in the mRNA for adiponectin and a decrease in mRNA leptin expression in intestinal mucosa and mesenteric fat as compared to sedentary animals. The expression of SOD2 and GPx mRNAs was significantly decreased in adipose tissue in HFD mice, but these effects were reversed in exercising mice with IAP administration. Our study shows for the first time that the combination of voluntary exercise and oral IAP treatment synergistically favored healing of intestinal inflammation, strengthened the antioxidant defense and ameliorated the course of experimental colitis; thus, IAP may represent a novel adjuvant therapy to alleviate inflammatory bowel disease (IBD) in humans.

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

“…We have confirmed our previous observation [ 36 ] that the combination of voluntary physical activity, along with IAP administration, improved DAI as compared with mice accessing SW only, or those administered with IAP alone against colitis, as reflected by gross macroscopic and microscopic assessments. This marked improvement in colitis was manifested by a reduction in mucosal bleeding and hemorrhagic lesions, less inflammatory reaction, white blood cells’ mucosal infiltration and greater signs of regeneration of damaged colonic mucosa.…”

“…Interestingly, the IAP-KO mice are characterized by dysbiosis but the administration of exogenous IAP reversed this dysbiosis when compared to wild type mice [ 35 ]. Recently, we have reported that voluntary exercise and IAP exerted a beneficial protective effect against inflammatory intestinal changes [ 36 ]; however, 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. Therefore, our present study was designed to evaluate the effect of IAP administration, combined or not with moderate physical activity, on experimental colitis, with a major focus addressed to changes in intestinal microbiota, since microbiota alterations have been associated with the development of intestinal inflammation in experimental murine models of colitis [ 37 ].…”

Leonurine Attenuates Obesity-Related Vascular Dysfunction and Inflammation

“…Obesity and metabolic disorders are accompanied by chronic low-grade inflammation. Inflammatory cytokines in adipose tissue induced by obesity, such as TNF-α, IL-1β, and IL-6, increased [ 29 , 30 , 31 ]. In addition, adipose tissue macrophages in obese mice showed more pro-inflammatory phenotypes.…”

Role of Intestinal Alkaline Phosphatase in Innate Immunity

“…IAP also has an indirect role in maintaining barrier function by inhibiting proinflammatory molecules such as LPS and cytokines including tumor necrosis factor-alpha (TNF-α) and IL-1β, which disrupt barrier function. Danielak et al showed that supplementation of IAP in combination with voluntary exercise caused a reduced expression of proinflammatory cytokines TNF-α, IL-1 β, and IL-6 in a colitis mouse model fed with standard diet (SD) or high-fat diet (HFD) [ 27 ]. In another study, oral IAP reduced TNF-α and IL-6 in brains of mice mode of heart failure [ 22 ].…”