Conserved neuropeptidergic regulation of intestinal integrity in invertebrate models of aging

Abstract

Age-related decline in intestinal barrier function impacts survival across species, but the underlying cell intrinsic and extrinsic factors remain unclear. Here, we demonstrate a role for neuropeptides in regulating aging-associated increases in intestinal leakiness. Adult-specific knockdown of insulin-like peptides daf-28 or ins-7 in C. elegans neurons or dilp3 in D. melanogaster neurons improves intestinal integrity and lifespan of these animals, respectively. Neuropeptide knockdowns activate intestinal DAF-16/FOXO transcription factor that likely increases expression of epithelial barrier components. Furthermore, age-associated changes in neuronal DAF-28 peptide secretion mirrors C. elegans reproductive span and overexpression of this peptide suppresses the improved intestinal health in long-lived germline-less animals. Collectively, we show that intestinal integrity is subject to neuronal regulation, and this neuropeptidergic axis may be modulated by the animal’s germline.

Understanding the factors regulating host–microbiome interactions using Caenorhabditis elegans

“…In fact, the standard C. elegans diet bacteria, OP50, are efficiently destroyed in the grinder of healthy, young animals, but can colonize the intestinal lumen in aged animals [ 100 ]. In addition, age-related depletion of the mucus-like layer and decline in gut barrier function is known to enhance intestinal leakiness and gut dysbiosis, which negatively impacts overall health and lifespan ([ 101 , 102 ]; figure 1 d ). Different members of the microbiota are known to impact the gut epithelium, with some pathogens disrupting it and a number of commensals fortifying it [ 103 ].…”

“…However, how C. elegans commensals modify gut mucin layer and the underlying epithelium is not well explored. In C. elegans , the impact of microbes on the gut barrier function can be readily accessed by implementing the Smurf assays, where a blue or florescent dye is fed to animals to measure the extent of gut leakiness, as the dye leaks from the damaged gut lumen into the body cavity [ 102 , 104 ].…”