Abstract
Loss of gut integrity is linked to various human diseases including inflammatory bowel disease. However, the mechanisms which lead to loss of barrier function remain poorly understood. Using D. melanogaster, we demonstrate that dietary restriction (DR) slows the age-related decline in intestinal integrity by enhancing enterocyte cellular fitness through upregulation of dMyc in the intestinal epithelium. Reduction of dMyc in enterocytes induces cell death through JNK signaling leading to increased gut permeability and reduced lifespan upon DR. Genetic mosaic and epistasis analyses suggest that cell competition, whereby neighboring cells eliminate unfit cells by apoptosis, mediates cell death in enterocytes with reduced levels of dMyc. Reducing enterocyte apoptosis partially rescued the increased gut permeability and shortened lifespan upon loss of dMyc. We propose that dMyc acts as a barometer of enterocyte cell fitness impacting intestinal homeostasis in response to changes in diet and age.
Highlights
The intestinal epithelium forms a permeable barrier that segregates the internal and external environments, allowing for the absorption of nutrients, but at the same time keeping toxic substances and pathogens from entering the body
Age-related disruption of gut integrity has been observed in both mammals and fruit flies and is a determinant of lifespan
Commensal dysbiosis has been proposed as a leading cause of gut barrier dysfunction, antibiotic treatment does not prevent the age-related increase in gut permeability
Summary
The intestinal epithelium forms a permeable barrier that segregates the internal and external environments, allowing for the absorption of nutrients, but at the same time keeping toxic substances and pathogens from entering the body. Increasing gut permeability is one of the risk factors for developing inflammatory bowel disease (IBD, including ulcerative colitis and Crohn’s disease) [1] and contributes to systemic immune activation, which promotes the progression of chronic inflammation [2], a known risk factor for aging and some age-related diseases [3,4]. Several mechanisms have been postulated to influence intestinal permeability. These include changes in the microbiota, luminal secretion of mucins and anti-microbial peptides (AMPs), and tight junction proteins [2,5]. Increased intestinal apoptosis and gut barrier dysfunction have been linked to multiple diseases, including necrotizing enterocolitis (NEC), IBD, intestinal cancer, and HIV infection [6,7,8]. The causal link between intestinal apoptosis and gut barrier function remains to be established
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