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"Leaky Gut" with Age Improved through Dietary Restriction

 Flies eating a Spartan diet are protected from leaky gut and the systemic inflammation associated with it as they age. Conversely, flies on a rich Atkins-like diet are more prone to developing intestinal permeability, a condition linked to a variety of human conditions including inflammatory bowel disease.

At present, as the pathogenesis of inflammatory and immunological diseases is unclear, there are few effective therapeutic drugs available in clinical practice. In such a context, the appropriate preclinical research techniques and models are required to help companies and researchers further develop and evaluate new drugs. Our Preclinical Pharmacodynamics Department has been deeply involved in this field for years, developing reliable animal-based efficacy evaluation models aimed at different targets and pathways, thus facilitating the clinical transformation of new drugs.

Publishing in PLOS Genetics through an article titled “Dietary restriction improves intestinal cellular fitness to enhance gut barrier function and lifespan in D. melanogaster,” researchers from the Kapahi lab at the Buck Institute show that gaps in the intestinal barrier are caused by an age-related increase in the death of intestinal epithelial cells, also known as enterocytes.

 

“The integrity of our gut declines with age and problems with intestinal permeability are now suspect in chronic inflammation, metabolic diseases, and even neurological diseases like Alzheimer’s,” explained senior study investigator Pankaj Kapahi, Ph.D., a professor at the Buck Institute. “The possibility that dietary restriction, or the use of dietary restriction mimetics, could help prevent this decline in humans opens a new area of research that could influence health span and longevity.”

 

Interestingly, the Buck researchers observed that levels of dMyc act as a barometer of cellular fitness in enterocytes, post-mitotic intestinal cells. They found that cells that have too little dMyc get eliminated by neighboring cells through a process termed “cell competition” in an attempt to maintain gut health.

 

“We demonstrated that dietary restriction (DR) slows the age-related decline in intestinal integrity by enhancing enterocyte cellular fitness through up-regulation of dMyc in the intestinal epithelium,” the authors wrote. “Reduction of dMyc in enterocytes induced cell death, which leads 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.”

 

“Levels of dMyc naturally decline with age in enterocytes, leading to excessive cell loss and thus a leaky gut,” added lead study investigator Kazutaka Akagi, Ph.D., a former postdoc in Dr. Kapahis laboratory and who now runs his own lab at the National Center for Geriatrics and Gerontology in Aichi, Japan. “In our study, this decline in dMyc was enhanced by the rich diet, while dietary restriction maintained dMyc level in the flies, preventing leaky gut and extending the lifespan of the animals.”

 

Finally, the research team looked at the role of dysbiosis, an imbalance in the intestinal bacteria or microbiome of the flies, as a potential contributor to leaky gut. Even though dysbiosis has been proposed as a leading cause of leaky gut, researchers found that removing intestinal bacteria with antibiotics conferred only minimal protection to the animals and did not prevent age-related damage to enterocytes.

 

“The intestinal epithelium is affected by everything that moves through the gut. It would make sense that diet would have a major impact on the health of those cells, especially over a lifetime of eating,” Dr. Kapahi concluded. “While we understand the interest in the role of the microbiome, we think that diet may ultimately be the primary driver in cellular changes leading to leaky gut.”

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