The gut microbiome is made of thousands of microbial species, many of which conduct activities necessary to health. Our tissues have evolved to at least somewhat rely upon the molecules produced by many of these species as they process the food we eat. Unwanted species are also present, generating harmful products that trigger inflammation and tissue dysfunction. With age, the size of harmful microbial populations increase at the expense of the size of helpful microbial populations. Our health suffers as a result. Animal studies have demonstrated that restoring a more youthful composition to the gut microbiome of an old animal, such as via fecal microbiota transplantation from a young donor, can improve health and lengthen life.
The study of communication between cells has moved on from considering only single secreted molecules, one at a time, to incorporate an attempt to understand the role of extracellular vesicles. These vesicles are membrane-wrapped packages containing many different molecules. The scientific community presently categorizes vesicles by size, such as exosomes versus microvesicles. Cataloguing their contents and the factors determining size and contents is a work in progress at the earliest stage; all too little is mapped out. Vesicles are generated and taken by cells constantly. Just as this happens between our own cells, we might expect vesicles to be an important form of communication between the gut microbiome and our cells. Some of that communication will be detrimental to tissue function, as illustrated in today’s open access paper.
Aging is a multifaceted process impacting physiological, genomic, metabolic, and immune functions. This study investigates the role of luminal fecal exosomes (LFEs) in age-associated metabolic dysfunction. We analyzed LFEs from the intestines of young (3-month) and old (24-month) male and female C57BL/6 mice to characterize age-related differences in exosomal proteomic and microRNA cargos. To explore interactions between LFEs and the gut microbiome, naïve young mice were gavage fed with LFEs from old donors, followed by 16S rRNA sequencing. Gut permeability in vitro and in vivo and systemic metabolic effects were assessed.
Bioinformatic analyses identified specific proteins and microRNAs linked to insulin resistance and barrier dysfunction. Heatmaps and principal component analysis revealed distinct differences in LFE profiles between young and old mice. Notably, LFEs from old mice impaired gut barrier integrity and metabolic function in young recipients, with reciprocal effects noted in older mice when receiving LFEs from young mice. Multi-omics profiling, including proteomics and microRNA sequencing, identified age-dependent and gender-related changes in LFE cargo, encompassing host- and microbiome-derived proteins and microRNAs. These age-specific profiles were associated with pathways implicated in cancer, neurobehavioral changes, and metabolic dysfunction.
Our findings highlight that LFEs from old mice are enriched with proteins and microRNAs involved in insulin resistance and gut barrier disruption. Together, these findings identify gut luminal exosomes as age-dependent mediators of microbiome-host communication that contribute to intestinal barrier dysfunction and metabolic decline.
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