Indole 3-Propionic Acid Derived From Gut Microbiota Partially Activates Aryl Hydrocarbon Receptor To Promote Macrophage Phagocytosis And Attenuate Septic Injury

1.BackgroundSepsis is a common and complex clinical syndrome,which is characterized by an unbalanced response of the host to excessive immunity and immunosuppression of infection,and is associated with acute organ dysfunction and a high risk of death.In view of the high morbidity and mortality of sepsis,it is of great clinical significance to further understand the mechanism of occurrence and development and explore effective treatment in sepsis.Gut microbiota is closely associated with sepsis.Indole 3-propionic acid(IPA)is a tryptophan deamination product derived from gut microbiota and has an intracellular signaling activity.IPA can maintain intestinal integrity,improve intestinal barrier function,regulate immunity and attenuate inflammatory response.In the process of occurrence and development of sepsis,the abundance of gut microbiota,which produce IPA,may decrease.In addition,aryl hydrocarbon receptor(AhR)is a kind of cytoplasmic receptor.The activation of AhR by metabolites of gut microbiota including IPA plays a key role in the regulation of immune function.However,the effect of IPA on sepsis and whether AhR is involved are still not clear.2.ObjectivesTo determine whether IPA activates AhR to promote macrophage phagocytosis and play a protective role in sepsis.In addition,to explore the relationship between IPA and sepsis in patients.3.Methods1)In the mouse model of sepsis induced by cecal ligation and puncture,the effects of IPA on survival rate,clinical score,bacterial load and organ damage were assessed by exogenous supplement.2)In vivo and vitro,phagocytosis of FITC-Escherichia coli by macrophages was detected by flow cytometry to reflect the phagocytic function of macrophage.3)The level of IPA in feces of patients with sepsis was detected by ELISA,and the correlation between the level of IPA and the severity of sepsis was analyzed.In addition,the ROC curve of IPA in the diagnosis and prediction mortality of sepsis was drawn.4.Results1)IPA derived from gut microbiota was related to the survival of septic mice.2)IPA improved the survival of septic mice,reduced the bacterial load,and attenuates liver and lung injury caused by sepsis.3)AhR inhibitors reversed the effects of IPA on improving survival,reducing bacterial load,and attenuating liver and lung injury in septic mice.4)In vivo and in vitro,IPA enhanced the phagocytosis of macrophages through activating AhR.The depletion of macrophages reversed the protective effect of IPA on sepsis.5)On the day of admission of ICU(day 0),the level of IPA in feces of patients with sepsis was significantly lower than that of the control group.Fecal IPA levels in septic patients with bacteremia were significantly lower than those without bacteremia.In addition,in patients with sepsis,a decrease in IPA was associated with poor clinical outcomes and had the potential to diagnose and predict mortality in sepsis.5.ConclusionsIndole 3-propionic acid derived from gut microbiota partially activates aryl hydrocarbon receptor to promote macrophage phagocytosis,attenuates septic injury and may be a new strategy for sepsis treatment.