Targeting the Intestinal Mucosa and Microbiome to Prevent Neonatal Late-onset Sepsis

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PROJECT SUMMARY Targeting the Intestinal Mucosa and Microbiome to Prevent Neonatal Late-onset Sepsis. Late-onset sepsis (LOS) is a leading cause of morbidity and mortality in premature infants and is thought to be caused by the systemic spread of commensal microbes. Perturbation in the developing intestinal microbiome (dysbiosis) is far more common in premature infants than in full-term infants and is thought to underlie their heightened susceptibility to LOS, although the mechanisms that predispose to this are not well understood. We recently developed a new murine model of neonatal LOS, which has confirmed the long-held clinical suspicion of a direct link between dysbiosis and LOS. We discovered that, by altering the developing microbiome to prevent dysbiosis, we were able to prevent LOS. This protection correlated with the abundance of endogenous Ligilactobacillus (formerly Lactobacuillus) murinus, some isolates of which proved to be effective in preventing LOS when administered as probiotics. Remarkably, however, even closely-related L. murinus isolates differed considerably in their probiotic efficacy, as did other strains of Lactobacilli—including a number of strains that are components of commercial probiotics. Moreover, we have found that probiotic strains of L. murinus that prevented dysbiosis and LOS altered the oxygen status of the intestinal epithelium, suggesting that these strains may modulate intestinal redox status to prevent the outgrowth of facultative anaerobes that can respire oxygen or other respiratory terminal electron acceptors. Although a major mechanism driving dysbiosis in adults is increased availability of substrates of bacterial respiration that allows facultative anaerobes to outcompete the obligate anaerobes that predominate in a healthy microbiome, our preliminary studies indicate that mechanisms that predispose the adult intestine to dysbiosis under conditions of inflammation or infection are at least partially disparate with those in the immature neonatal intestine. We therefore posit that the neonatal intestine is susceptible to dysbiosis via mechanisms distinct from those previously characterized in adults, reflecting developmental immaturity of the intestines and early instability of the developing intestinal microbiome. Here, we will take a team science approach to elucidate both host and microbial determinants of neonatal dysbiosis that predispose to LOS, marrying the efforts of two labs with complementary expertise in intestinal biology and immunity (Weaver), and microbial genetics and bacterial respiration (Gray) with collaborators who are leaders in microbial genomics (Julie Segre), inflammation-associated gut dysbiosis (Sebastian Winter) and neonatology (Namasivayan Ambalavanan). Through the identification of mechanisms of dysbiosis unique to the developing intestines and microbiome we will provide a foundation for more rational design of probiotics and prebiotics for therapeutic interventions that prevent LOS in premature infants.