Connecting the Aging of the Gut Microbiome to Thymic Involution and Immune System Dysfunction
The composition of the gut microbiome, the specific microbial species that are present and their numbers relative to one another, varies from individual to individual and appears to influence health significantly, perhaps to a similar degree as lifestyle choices regarding diet and exercise. Further, the composition of the gut microbiome shifts with age in harmful ways, reducing the number of microbes that produce beneficial metabolites such as butyrate, while increasing the number of microbes that act to provoke an ever greater inflammatory reaction from the immune system. The chronic inflammation of aging is disruptive to tissue structure and function throughout the body, and in this way a poor gut microbiome can accelerate the onset and progression of age-related conditions and mortality.
The relationship between the gut microbiome and immune system is bidirectional. The immune system gardens the gut microbiome, so the aging of the immune system allows problematic microbes to grow in number. But equally, the aged gut microbiome can negatively affect the immune system. Today's open access paper looks at one of the ways in which this can happen, by accelerating the atrophy of active tissue in the thymus, a process known as thymic involution. The thymus is a small organ near the heart. Its primary function is to host the maturation of thymocytes produced in the bone marrow; these cells migrate to the thymus and undergo a process of selection to become T cells of the adaptive immune system. As the thymus atrophies with age, the supply of new T cells declines. With reinforcements, the adaptive immune system becomes ever more dysfunctional over time, populated by senescent, exhausted, and malfunctioning T cells.
The epithelium of the gastrointestinal tract represents the largest mucosal lining in the body that effectively limits the permeation of luminal microorganisms, antigens, and toxins through its paracellular space, a process that is regulated by intercellular tight junctions. Advancing age is accompanied by physiological changes to the intestine, including mucus layer thinning and remodelling of intestinal epithelial tight junction proteins, which contribute towards the breakdown of intestinal barrier function. This permits commensal bacteria and their products, such as lipopolysaccharide, from the gut lumen into the bloodstream (referred to as a leaky gut). Age-related intestinal barrier dysfunction is closely linked to the progressive deterioration of systemic health and the gradual appearance of metabolic defects. Moreover, recent evidence from animal studies indicates that it is a major contributor to low-grade systemic inflammation, termed inflammaging. Human intestinal barrier dysfunction, determined by elevated circulating lipopolysaccharide-binding protein (LBP) levels, is also associated with impaired physical function and inflammaging in healthy aged adults; highlighting the importance of investigating the role of intestinal barrier dysfunction in ageing.
Concurrently with changes to intestinal homeostasis, ageing is accompanied by remodelling of the immune system that attenuates the host's ability to mount robust immune responses, resulting in an immunocompromised state, termed immunesenescence. One of the most striking features of immune ageing is the progressive shrinkage (involution) of the thymus that is characterised by the loss of thymic epithelial cells (TECs), expansion of perivascular spaces, increased thymic adiposity and the accumulation of senescent cells; together resulting in a loss of functional spaces for the development of thymocytes. Collectively this compromises the process of thymopoiesis and result in a reduced thymic output of naïve T cells and the homeostatic expansion of peripheral memory T cell subsets. Further, chronic lifelong antigenic stimulation leads to the accumulation of senescent T cells in the periphery, which impair tissue immunosurveillance and drive a state of prolonged basal inflammation in aged individuals, termed inflammageing.
Despite these interesting findings, the relationship between intestinal barrier dysfunction and immune ageing is poorly understood. Herein we report that intestinal membrane permeability increases with age in humans and is accompanied by enhanced systemic microbial translocation that contributes to the lifelong antigenic burden, driving a reduction in naïve T cell thymic output and an accumulation of terminally differentiated, senescent T cells in the periphery. The emergence of these hallmarks of T cell ageing hinders the ability of these cells to fight invading pathogens and enhances their ability to produce pro-inflammatory cytokines, which ultimately contribute to the inflammatory state of the aged host. Further, we demonstrate that aged germ-free mice, which do not exhibit age-related intestinal barrier dysfunction, are protected from the accumulation of microbial products in the thymus and maintain their thymic architecture. Together, these findings provide novel evidence of a causal relationship between intestinal barrier dysfunction and T cell ageing.