Microbiome-mediated neutrophil recruitment via CXCR2 and protection from amebic colitis

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Abstract
The disease severity of Entamoeba histolytica infection ranges from asymptomatic to life-threatening. Recent human and animal data implicate the gut microbiome as a modifier of E. histolytica virulence. Here we have explored the association of the microbiome with susceptibility to amebiasis in infants and in the mouse model of amebic colitis. Dysbiosis occurred symptomatic E. histolytica infection in children, as evidenced by a lower Shannon diversity index of the gut microbiota. To test if dysbiosis was a cause of susceptibility, wild type C57BL/6 mice (which are innately resistant to E. histiolytica infection) were treated with antibiotics prior to cecal challenge with E. histolytica. Compared with untreated mice, antibiotic pre-treated mice had more severe colitis and delayed clearance of E. histolytica. Gut IL-25 and mucus protein Muc2, both shown to provide innate immunity in the mouse model of amebic colitis, were lower in antibiotic pre-treated mice. Moreover, dysbiotic mice had fewer cecal neutrophils and myeloperoxidase activity. Paradoxically, the neutrophil chemoattractant chemokines CXCL1 and CXCL2, as well as IL-1β, were higher in the colon of mice with antibiotic-induced dysbiosis. Neutrophils from antibiotic pre-treated mice had diminished surface expression of the chemokine receptor CXCR2, potentially explaining their inability to migrate to the site of infection. Blockade of CXCR2 increased susceptibility of control non-antibiotic treated mice to amebiasis. In conclusion, dysbiosis increased the severity of amebic colitis due to decreased neutrophil recruitment to the gut, which was due in part to decreased surface expression on neutrophils of CXCR2. Amebiasis, caused by intestinal infection of Entamoeba histolytica, is one of the leading causes of parasite infection-related mortality and morbidity around the world. However, pathogenesis, such as determinant factors of infection outcome, is still unclear although recent data indicate that the gut microbiome plays an important role. In the present study, we firstly found that dysbiosis, which was represented by a lower Shannon diversity index of the gut microbiota, occurred symptomatic E. histolytica infection in children living in endemic area. In mouse model, we demonstrated that dysbiosis induced by antibiotic pre-treatment increased the severity of amebic colitis due to decreased neutrophil activity as well as decreased IL-25 associated mucosal defense in the gut. Moreover, we demonstrated surface expression on neutrophils of CXCR2 was diminished in mice with dysbiosis, which resulted in decreased neutrophil recruitment to the gut. This study is of fundamental importance in amebiasis research for the discovery of a mechanism of microbiome-mediated resistance to amebiasis via neutrophil trafficking to the gut. The work is importantly of broad interest in infectious diseases and immunology for the discovery that neutrophil mediated protection can be disturbed by dysbiosis.
Funding Information
  • National Institutes of Health (R01 AI026649)

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