The gut microbiome appears to be increasingly responsible for at least some of the decline of the immune system during aging, and a new mouse study shows that it is reversible.
The gut microbiome
The microbiome describes a varied community of bacteria, archaea, eukarya, and viruses that inhabit our guts. The four bacterial phyla of Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria comprise 98% of the intestinal microbiome.
The microbiome community is a complex ecosystem whose activity regulates a number of functions in the gut and interacts with the immune system and energy metabolism. The beneficial bacteria in our guts also help to prevent the growth of harmful bacteria, protect us from invasive microorganisms, and help to maintain the integrity of the intestinal barrier.
There is a strong association between the age-related changes to the gut microbiome and the age-related decline and dysfunction of the immune system known as immunosenescence. Indeed, there is considerable crosstalk between the populations of bacteria that inhabit the microbiome and the various cells of the immune system.
However, which comes first: changes to the gut microbiome that disrupt the immune system or changes to the immune system that change the gut microbiome?
To date, the evidence is increasingly supporting the idea that changes to the gut microbiome, particularly a decline of bacterial diversity and numbers, are the cause and that immunosenescence is the consequence.
Transplanting microbes from young to old
The new study builds on previous evidence and adds support to the notion that changes in the microbiome drive immune decline and dysfunction . Perhaps more interesting is the demonstration that these changes can be reversed using a relatively simple, albeit crude, approach to adjusting the balance of the microbiome.
Peyer’s patches are small masses of lymphatic tissue (lymph nodes) encountered in the ileum region of the small intestine. They are an important part of the immune system, as they monitor intestinal bacteria populations and prevent the growth of pathogenic bacteria in the intestines. In essence, Peyer’s patches are a system that keeps the microbiome in check, particularly ensuring that harmful bacteria are kept in check via the activation of lymphocytes.
Peyer’s patches contain germinal centers, which are sites within all secondary lymphoid organs where mature B cells proliferate, differentiate, change their antibody genes, and switch the class of their antibodies during the course of a normal immune response to an infection. Aging causes the germinal center reaction to become dysfunctional and the immune response to be less effective.
The researchers report that the defective germinal center reaction in the Peyer’s patches of aged mice can be rescued via the use of fecal transfers from young mice into aged mice or by immunizations with cholera toxin without affecting germinal center reactions in peripheral lymph nodes.
One of the organs that is significantly affected by age is the gastrointestinal tract and the gut-associated microbiome. The gut microbiota comprises hundreds of different commensal bacterial species, as well as fungi, protozoa and viruses. These commensal microorganisms are essential for health, affecting the functions of multiple bodily systems, such as host metabolism, brain functions and the immune response. Older individuals have age-related alterations in gut microbial composition, which have been associated with increased frailty, reduced cognitive performance, immune inflammaging and an increased susceptibility to intestinal disorders.
What drives these age-associated changes in the gut microbiota remains unknown. The microbiome is shaped by many factors including host genetics, early life events, diet, and the gut immune system. While some of these factors remain relatively constant throughout life, the function of the immune system is known to deteriorate with age. This prompts the hypothesis that dysbiosis of the intestinal microbiome in older individuals may be driven by altered cross-talk between the host immune system and the microbiota. The gut immune system can regulate the composition of the microbiome by the production of immunoglobulin A (IgA) antibodies that coat commensal bacteria. In the gastrointestinal tract, IgA antibodies are either produced by short-lived plasma cells in the lamina propria or from plasma cells that arise from germinal centre (GC) reactions in Peyer’s patches (PPs). In the lamina propria, plasma cells can be generated with or without T cell help, and typically secrete IgA antibodies that are encoded by germline immunoglobulin genes. In GCs, B cells proliferate and undergo somatic mutation of their immunoglobulin genes. GC B cells which are able to bind antigen with improved affinity after somatic mutation receive positive selection signals from T follicular helper (Tfh) cells and follicular dendritic cells that facilitate their differentiation into long-lived antibody secreting plasma cells that secrete high-affinity IgA. Negative regulation of the GC reaction is mediated by suppressive T follicular regulatory (Tfr) cells that limit the output of the GC. Loss of Tfh or Tfr cells or the absence of somatic hypermutation in GC B cells results in changes in the gut IgA repertoire which alter the composition of the gut microbiome. This suggests that GC-derived IgA antibodies can regulate the commensal microbiome.
The studies described above have established the existence of a relationship between GC reactions and the microbiome. Some of these studies indicate clearly that the microbiome is causally influenced by the GC reaction. In the case of the gut-associated defects seen with advancing age in the GC reaction and gut microbiota, however, the direction of causation is unclear. Here, we report that the defective GC reaction in aged mice could be boosted by co-housing with younger animals, by direct faecal transplantation from adult donors and by oral administration of cholera toxin. This demonstrates that the age-dependent defect in the gut GC reaction is not irreversible, but can be corrected by changing the microbiota or by delivery of a bacterial derived toxin.
The gut microbiome is becoming better known for its contributions to multiple aspects of aging, especially for its key role in inflammaging, the chronic smoldering background of inflammation that accompanies aging, drives the loss of tissue repair and regeneration, and facilitates the progression of various age-related diseases.
The transplanting of beneficial microbes via fecal transplant or other methods offers a relatively low-tech approach to the problem and could potentially find utility in humans to help better manage microbiome diversity and immune function during aging.
 Stebegg, M., Silva-Cayetano, A., Innocentin, S., Jenkins, T. P., Cantacessi, C., Gilbert, C., & Linterman, M. A. (2019). Heterochronic faecal transplantation boosts gut germinal centres in aged mice. Nature Communications, 10(1), 2443.