The gut microbiome alters immunophenotype and survival from sepsis

Abstract

The microbiome is increasingly implicated in immune regulation and mortality from sepsis. Mice with identical genetic backgrounds but distinct microbiomes were obtained from different vendors and analyzed following cecal ligation and puncture (CLP), β diversity of the microbiome measured from feces demonstrated significant differences between The Jackson Laboratory (Jax; Bar Harbor, ME, USA) and Charles River Laboratories (CR; Wilmington, MA, USA) C57/B6 mice. Jax mice had 7‐d mortality of 90% following CLP, whereas CR mice had a mortality of 53%. Differences in vendor were associated with altered immunophenotype with increased splenic IFN‐γ+CD4+ T cells, effector memory CD4+ T cells, and central memory CD4+ T cells and increased Peyer's patch effector memory CD4+ T cells in septic CR mice. To determine whether differences in the microbiome were responsible for these differences, Jax and CR mice were cohoused for 3 wk, after which they assumed a similar microbiota composition. Cohoused mice had improved survival following CLP compared to Jax mice and had similar survival regardless of their vendor of origin. All differences in immunophenotype between septic Jax and CR mice disappeared following cohousing. These findings suggest that the microbiome plays a crucial role in survival and the host immune response from sepsis and represents a potential target for therapeutic intervention.—Fay, K. T., Klingensmith, N. J., Chen, C.‐W., Zhang, W., Sun, Y., Morrow, K. N., Liang, Z., Burd, E. M., Ford, M. L., Coopersmith, C. M. The gut microbiome alters immunophenotype and survival from sepsis. FASEB J. 33, 11258–11269 (2019). http://www.fasebj.org

Therapeutic Potential of the Gut Microbiota in the Management of Sepsis

“…In animal models, the effect of the gut microbiome on sepsis outcome has been clearly demonstrated by different studies. In a well-designed recent study, sepsis evolution was analyzed in genetically identical, age-and sex-matched mice obtained from different vendors and subjected to cecal ligation and puncture (CLP), the most frequently used model of sepsis [17]. Beta diversity of the microbiome measured from feces of mice coming from two different laboratories demonstrated significant differences and, more importantly, mice from the first lab had significantly higher mortality following CLP, as compared to mice from the second lab (90% vs. 53%).…”

Fecal microbiota transplantation reconstructs the gut microbiota of septic mice and protects the intestinal mucosal barrier

“…Organization has recognized sepsis as a global health priority 5 . Despite significant advancement in our understanding of the pathophysiology of sepsis, treatment of sepsis is limited to antibiotics, aggressive fluid resuscitation, vasopressor administration, and supportive care, and no targeted therapeutics for sepsis are approved for usage in patients 6 .…”

“…Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [5][6][7] . The syndrome can be induced by a wide variety of microbes and, by definition, involves a maladaptive response to a pathogen 5 .…”

“…Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [5][6][7] . The syndrome can be induced by a wide variety of microbes and, by definition, involves a maladaptive response to a pathogen 5 . The gastrointestinal (GI) tract has long been hypothesized to play an integral role in the pathophysiology of sepsis, by both driving and perpetuating multiple organ dysfunction 8,9 .…”

“…The gastrointestinal (GI) tract has long been hypothesized to play an integral role in the pathophysiology of sepsis, by both driving and perpetuating multiple organ dysfunction 8,9 . The original concept of gut-derived sepsis proposed that the altered inflammatory milieu induced by overwhelming infection leads to intestinal hyperpermeability, allowing luminal contents, including intact microbes, and microbial products, to escape their natural environment where they can cause either local or distant injury 1,5,6,10 .…”