SUMMARY
Dietary interventions are potentially effective therapies for inflammatory bowel diseases (IBDs). We tested the effect of 4-day fasting-mimicking diet (FMD) cycles on a chronic dextran sodium sulfate (DSS)-induced murine model resulting in symptoms and pathology associated with IBD. These FMD cycles reduced intestinal inflammation, increased stem cell number, stimulated protective gut microbiota, and reversed intestinal pathology caused by DSS, whereas water-only fasting increased regenerative and reduced inflammatory markers without reversing pathology. Transplants of Lactobacillus or fecal microbiota from DSS- and FMD-treated mice reversed DSS-induced colon shortening, reduced inflammation, and increased colonic stem cells. In a clinical trial, three FMD cycles reduced markers associated with systemic inflammation. The effect of FMD cycles on microbiota composition, immune cell profile, intestinal stem cell levels and the reversal of pathology associated with IBD in mice, and the anti-inflammatory effects demonstrated in a clinical trial show promise for FMD cycles to ameliorate IBD-associated inflammation in humans.
The gut microbiota and its metabolites have been shown to play a pivotal role in the regulation of metabolic, endocrine and immune functions. Though the exact mechanism of action remains to be fully elucidated, available knowledge supports the ability of microbiota-fermented short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, to influence epigenetic and metabolic cascades controlling gene expression, chemotaxis, differentiation, proliferation, and apoptosis in several non-immune and immune cell subsets. While used as preferred metabolic substrates and sources of energy by colonic gut epithelial cells, most recent evidence indicates that these metabolites regulate immune functions, and in particular fine-tune T cell effector, regulatory and memory phenotypes, with direct in vivo consequences on the efficacy of chemotherapy, radiotherapy and immunotherapy. Most recent data also support the use of these metabolites over the course of T cell manufacturing, paving the way for refined adoptive T cell therapy engineering. Here, we review the most recent advances in the field, highlighting in vitro and in vivo evidence for the ability of SCFAs to shape T cell phenotypes and functions.
Epidermal growth factor (EGF) receptor (EGFR) is the founding member of the ErbB family of growth factor receptors that control growth, proliferation, differentiation, apoptosis, and cell migration. Selenoprotein W (SEPW1) is a highly conserved, ubiquitously expressed 9 kDa selenocysteine‐containing protein involved in cell cycle control. SEPW1 siRNA inhibited EGFR activation in RWPE‐1, MCF‐10A and MCF‐7 cells, while SEPW1 overexpression increased it. SEPW1 siRNA inhibited EGF‐induced activation of downstream pathways (MAPK, PI3K/Akt, JAK/STAT, and p53), and blocked EGF‐induced cell cycle entry. SEPW1 was associated with peripheral punctuate structures that partially co‐localized with EGFR. Ligand‐bound EGFR failed to traffic towards the nucleus in SEPW1‐depleted cells, indicating that SEPW1 has a role in EGFR trafficking. Consequently, the half‐life, expression, dimerization, and phosphorylation of EGFR were also decreased in SEPW1‐depleted cells. SEPW1 siRNA also inhibited hydrogen peroxide‐induced EGFR phosphorylation. However, SEPW1 siRNA inhibition of EGF‐stimulated EGFR phosphorylation was not decreased by N‐acetylcysteine or sodium orthovanadate, indicating SEPW1 regulation of EGFR does not involve reactive oxygen species or inhibition of protein tyrosine phosphatase. Glutathione peroxidase siRNA partially rescued EGF‐induced cell cycle entry in SEPW1‐depleted cells, showing the effect of SEPW1 depletion is not due to loss of antioxidant protection. Knowledge of the mechanisms underlying SEPW1 regulation of EGFR trafficking may be important to understanding the relationship between dietary selenium and cancer.
Grant Funding Source: Supported by USDA CRIS Project 5306‐51530‐018‐00D
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.