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

Immunosenescence refers to the development of weakened and/or dysfunctional immune responses associated with aging. Several commensal bacteria can be pathogenic in immunosuppressed individuals. Although Klebsiella pneumoniae is 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 why K. pneumoniae is a more prevalent cause of infection in the elderly population remains unclear. This study aimed to determine how the host's intestinal immune response to K. pneumoniae varies with age. To this end, the study analyzed an in vivo K. pneumoniae infection model using aged mice, as well as an in vitro K. pneumoniae infection model using a Transwell insert co-culture system comprising epithelial cells and macrophages. In this study, we demonstrate that growth arrest-specific 6 (Gas6), released by intestinal macrophages that recognize K. 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 under K. pneumoniae infection due to decreasing intestinal mucosal macrophages; therefore, K. pneumoniae can 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 K. pneumoniae from 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 why K. pneumoniae can 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 pneumoniae is 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 how K. pneumoniae is a more prevalent cause of infection in the elderly population. Here, we show that growth arrest-specific 6 (Gas6), released by intestinal macrophages that recognize K. 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. pneumoniae can easily translocate to the liver from the gastrointestinal tract. We concluded that the reason K. pneumoniae can 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 infected K. pneumoniae. Our findings provide new insights into the prevention of infectious diseases in the elderly.