Aging of the Intestinal Barrier as a Driving Cause of Chronic Inflammation

Chronic inflammation is a feature of aging, and causes disruption of cell and tissue function throughout the body. Short term inflammation is a necessary feature of regeneration from injury and defense against pathogens, but when inflammatory signaling is maintained for the long term it becomes very harmful. The risk of suffering all of the common diseases of aging is strongly connected to raised inflammation. Given this, we might ask what causes age-related systemic inflammation, and thus where should the research community seek to intervene, in order to reverse this undesirable aspect of degenerative aging.

A growing burden of senescent cells is one noteworthy cause, actively encouraging inflammation via the senescence-associated secretory phenotype. The metabolic activity of excess visceral fat tissue is another. Disruption of the intestinal barrier is also an area of focus for the research community, and the subject of today's open access review paper.

The intestinal barrier is made up of mucus, epithelial cells connected by tight junctions that prevent the passage of unwanted pathogens and molecules, and patrolling immune cells, intended to maintain a separation between the gut and tissues surrounding the gut. Unfortunately, like all structures and systems in the body, the barrier becomes dysfunctional with age. The result is greater inflammation, as unwanted materials leak into tissue.

The Intestinal Barrier Dysfunction as Driving Factor of Inflammaging

In recent years, the function of the intestinal barrier has received increasing scientific attention as more and more intra- and extra-intestinal diseases, such as irritable bowel syndrome, inflammatory bowel diseases such as Crohn's disease, type 1 diabetes, colorectal cancer, acute inflammation-related diseases such as sepsis, and allergic diseases, were found to be associated with a dysfunctional intestinal barrier. The results of various animal studies demonstrated a link between intestinal barrier dysfunction and aging. For instance, aged monkeys had poorer intestinal barrier function, increased systemic inflammation, and higher microbial translocation compared to young animals. In Drosophila models, intestinal barrier dysfunction has been shown to predict the approaching death of flies.

In this review, we want to explore whether intestinal barrier dysfunction and the accompanying alterations to the intestinal microbiota composition are driving factors for the increasing proinflammatory status during aging known as inflammaging. Inflammaging was first described as a combination of a reduced ability to deal with stressors and the resulting increase in proinflammatory milieu. More recently, inflammaging was defined as a "chronic, sterile, low-grade inflammation" that occurs during aging. A similar concept is metaflammation, describing a metabolically driven inflammation caused by nutrient excess.

Due to the major role of the intestinal barrier in preventing bacterial toxins and pathogens from the intestinal lumen entering into circulation, an impaired barrier function or even minor changes in the regulation of the epithelial, microbial, biochemical, or immunological barrier might contribute to aging-associated decline as well as disease development.

The alterations found at the level of intestinal microbiota composition and intestinal barrier function in aging have been proposed to be interlinked with aging-associated decline in other organs, such as the liver. Due to its anatomical location receiving a more or less 'unfiltered' blood from the gut, the liver is confronted not only with nutrients, but also many xenobiotics, as well as bacterial toxins and metabolites stemming from the intestinal microbiota, along with endocrine mediators. This allows for a rather direct communication between the gut and the liver.

In summary, the gastrointestinal epithelial barrier, with its multiple layers and its various function, is affected by the physiological aging process. However, as its role in healthy aging or disease development becomes increasingly evident, attempts to restore the barrier function, e.g., through modulation via microbiota modifications, supplementing strains such as Lactobacillus plantarum or their metabolites, are of special interest. Besides microbiota modulation through probiotic strains or postbiotics, the current and future treatment of epithelial barrier dysfunction could include nutritional interventions and also bioactive pharmaceutical molecules, biologicals, or mucoprotectants.