Gas6 ameliorates intestinal mucosal immunosenescence to prevent the translocation of a gut pathobiont,Klebsiella pneumoniae, to the liver

Abstract

AbstractImmunosenescence refers to the development of weakened and/or dysfunctional immune responses associated with aging. Several commensal bacteria can be pathogenic in immunosuppressed individuals. AlthoughKlebsiella pneumoniaeis a commensal bacterium that colonizes human mucosal surfaces, the gastrointestinal tract, and the oropharynx, it can cause serious infectious diseases, such as pneumonia, urinary tract infections, and liver abscesses, primarily in elderly patients. However, the reason whyK. pneumoniaetargets elderly population remains unclear. This study aimed to determine how the intestinal immune response of the host toK. pneumoniaevaries with age. To this end, the study analyzed anin vivo K. pneumoniaeinfection model using aged mice, as well as anin vitro K. pneumoniaeinfection model using a Transwell insert co-culture system comprised of epithelial cells and macrophages. In this study, we demonstrate that growth arrest-specific 6 (Gas6), released by intestinal macrophages that recognizeK. pneumoniae, inhibits bacterial translocation from the gastrointestinal tract by enhancing tight-junction barriers in the intestinal epithelium. However, in aging mice, Gas6 was hardly secreted underK. pneumoniaeinfection due to decreasing intestinal mucosal macrophages; therefore,K. pneumoniaecan easily invade the intestinal epithelium and subsequently translocate to the liver. Moreover, the administration of Gas6 recombinant protein to elderly mice prevented the translocation of orally infectedK. pneumoniaefrom the gastrointestinal tract and significantly prolonged their survival. From these findings, we conclude that the age-related decrease in Gas6 secretion in the intestinal mucosa is the reason whyK. pneumoniaecan be pathogenic in the elderly, thereby indicating that Gas6 could be effective in protecting the elderly against infectious diseases caused by gut pathogens.Author SummaryAging causes a weakened/dysfunctional human immune system, reducing the ability to combat pathogens. Understanding the molecular mechanisms underlying age-related immunosenescence is critical for the development of preventive therapies against bacterial infectious diseases in elderly individuals.Klebsiella pneumoniaeis a representative “pathobiont” that causes serious systemic infections such as pneumonia, urinary tract infections, and liver abscesses, mainly in the elderly. However, it remains unclear howK. pneumoniaetargets the elderly population. Here, we show that growth arrest-specific 6 (Gas6), released by intestinal macrophages that recognizeK. pneumoniae, inhibits bacterial invasion into the intestinal epithelium and subsequent translocation to the liver. However, in elderly mice, Gas6 is hardly secreted due to decreased intestinal mucosal macrophages; therefore,K. pneumoniaecan easily translocate to the liver from the gastrointestinal tract. We concluded that the reasonK. pneumoniaecan be pathogenic to the elderly is the age-related decrease in Gas6 secretion in the intestinal mucosa. Moreover, we revealed that the administration of Gas6 to elderly mice significantly prevented systemic translocation of orally infectedK. pneumoniae. Our findings provide new insights into the prevention of infectious diseases in the elderly.