Systemic Infection of Gut Pathobiont <i>Klebsiella pneumoniae</i> Is Prevented by Gas6/Axl Signals in the Intestinal Epithelium

Some commensal bacteria can be pathogenic to immunosenescenced individuals. Klebsiella pneumoniae is a gut pathobiont that causes serious systemic infections in elderly; however, why K. pneumoniae can target the elderly population is uncertain. Here, we show that growth arrest-specific 6 (Gas6), released by macrophages that recognized K. pneumoniae, inhibited the bacterial invasion into the intestinal epithelial cells by enhancing tight-junction barriers via Gas6/Axl signaling. But, in aging mice, Gas6 was hardly secreted, thereby the bacteria were easier to invade into the intestinal epithelial cells and subsequent translocate to the liver. Administration of Gas6 to elderly mice significantly prevented the systemic infection with K. pneumoniae. Our findings show that weakening of the tight-junction barrier of intestinal mucosa due to age-related decrease in Gas6 is closely associated with the development of K. pneumoniae pathogenicity, demonstrating that Gas6 could be effective in protecting the elderly against infectious disease.Funding Information: This work was supported by the Kao Research Council for the Study of Healthcare Science (C93102) (to H.T.). The infection models in this work were partly supported by a 2021 Tokai University School of Medicine Research Aid grant (to H.T.), by Ohyama Health Foundation Inc. (to H.T.), and by the Japan Agency for Medical Research and Development (21ck0106701h0001) (to J.M.).Declaration of Interests: The authors have no potential conflicts of interest to disclose.Ethics Approval Statement: All animal experiments were approved by the Keio University Animal Research Committee (no. 19048) and the Tokai University Animal Research Committee (no. 222002), and were conducted in accordance with the "Act on Welfare and Management of Animals of Japan", "Standards relating to the Care and Keeping and Reducing Pain of Laboratory Animals", "Standards relating to the Methods of Destruction of Animals", "Guidelines for Proper Conduct of Animal Experiments", and the "Fundamental Guidelines for Proper Conduct of Animal Experiment".