Investigating the role of age-related intestinal barrier dysfunction and microbial translocation in driving immunesenescence

Conway, Jessica ORCID: 0000-0002-1108-7952 (2024). Investigating the role of age-related intestinal barrier dysfunction and microbial translocation in driving immunesenescence. University of Birmingham. Ph.D.

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Abstract

The human gut is populated by millions of microorganisms and the intestinal epithelium functions as a dynamic barrier against microbes and the environment. The gut microbiota and its metabolites play a vital role in host functional homeostasis, including immune responses. Advancing age is accompanied by alterations in the gut microbiome composition and metabolite profile. Concurrently, ageing is accompanied by remodelling of the immune system, termed immunesenescence, which exerts negative effects on aged host health. However, the precise impact of microbiome changes on immunity are poorly understudied. This thesis aims to improve our understanding of the intricate relationship between the ageing gut microbiome, intestinal barrier dysfunction and immunesenescence.

In this thesis, we identified associations between intestinal barrier dysfunction and features of thymic involution and accelerated T cell ageing in older adults and confirmed a causal relationship between microbial translocation and thymic ageing using an aged germ-free mice model. Next, we linked the age-related loss of core commensals (Lactobacillus and Bifidobacterium) and reduced bioavailability of immunomodulatory microbial metabolites (short-chain fatty acids and secondary bile acids) with an unhealthy immune system and low influenza vaccine immunogenicity in old age. Lastly, we explored the potential for dietary patterns, such as the Mediterranean diet and multi-vitamin supplementation, as a strategy to promote healthy immune ageing. These novel findings extend our understanding of the consequences of age-related changes in the microbial-immune-metabolic axis and provide evidence for designing future microbiome-targeted interventions that restore immune homeostasis and promote healthy ageing in older adults.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):