Interplay of the ENS and Microbiota With Murine Gut Epithelium‐Derived Organoids in Aging

The intestine is one of the first organs to show signs of aging, including cellular changes, microbiota shifts, and reduced regenerative capacity. The different components of the gut-such as the epithelium (which is directly exposed to a diverse array of host-microbe interactions), the microbiota itself, and the underlying enteric nervous system-likely contribute to aging in distinct ways. Understanding their individual and interactive roles is key to elucidating the mechanisms of intestinal aging. To better understand the contribution of individual components to intestinal aging, we analyzed gut tissue characteristics and compared these parameters with the composition and gene expression levels of colonic organoids by using two mouse strains: the aging-resistant SAMR1 line and the SAMP8 line, which exhibit an accelerated aging phenotype. Here, we demonstrate that colonic organoids derived from these mice retain the age-related characteristics of the colonic tissue, including changes in morphology and cellular composition. Furthermore, introducing the enteric nervous system into organoid culture revealed that the age of the epithelium exerts a more pronounced influence on the aging phenotype than the age of the innervating tissue. Interestingly, successfully delivering fecal extracts to organoids revealed that gut microbiota metabolites from aged animals resulted in an aging phenotype of the gut epithelium in vitro. In summary, our findings indicate the impact of aging on the gut epithelium and its interplay with the nervous system and microbiota. This may in future provide new strategies for slowing the aging process in the gut by manipulating the gut commensals.