Intraluminal neutrophils limit epithelium damage by reducing pathogen assault on intestinal epithelial cells during Salmonella gut infection

• Published in: PLoS pathogens 2023-06, Vol.19 (6), p.e1011235-e1011235
• Main Authors: Gül, Ersin, Enz, Ursina, Maurer, Luca, Abi Younes, Andrew, Fattinger, Stefan A, Nguyen, Bidong D, Hausmann, Annika, Furter, Markus, Barthel, Manja, Sellin, Mikael E, Hardt, Wolf-Dietrich
• Format: Article
• Language: English
• Subjects: Analysis; Animal models; Animals; Anti-Bacterial Agents; Antibiotics; Antibodies; Biology and Life Sciences; Colitis; Composition; Damage; Defense; Density; Depletion; Digestive system; Digestive tract; Disease; Epithelial Cells; Epithelium; Gastrointestinal tract; Gentamicin; Germfree; Gnotobiotic; Health aspects; Infection; Infections; Inflammation; Intestinal Mucosa; Intestine; Leukocytes (neutrophilic); Measurement; Medicine and Health Sciences; Mice; Microbiota; Microbiota (Symbiotic organisms); Microorganisms; Neutrophils; Pathogens; Prevention; Research and Analysis Methods; Risk factors; Salmonella; Salmonella Infections; Salmonella typhimurium
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011235

Recruitment of neutrophils into and across the gut mucosa is a cardinal feature of intestinal inflammation in response to enteric infections. Previous work using the model pathogen Salmonella enterica serovar Typhimurium (S.Tm) established that invasion of intestinal epithelial cells by S.Tm leads to recruitment of neutrophils into the gut lumen, where they can reduce pathogen loads transiently. Notably, a fraction of the pathogen population can survive this defense, re-grow to high density, and continue triggering enteropathy. However, the functions of intraluminal neutrophils in the defense against enteric pathogens and their effects on preventing or aggravating epithelial damage are still not fully understood. Here, we address this question via neutrophil depletion in different mouse models of Salmonella colitis, which differ in their degree of enteropathy. In an antibiotic pretreated mouse model, neutrophil depletion by an anti-Ly6G antibody exacerbated epithelial damage. This could be linked to compromised neutrophil-mediated elimination and reduced physical blocking of the gut-luminal S.Tm population, such that the pathogen density remained high near the epithelial surface throughout the infection. Control infections with a ssaV mutant and gentamicin-mediated elimination of gut-luminal pathogens further supported that neutrophils are protecting the luminal surface of the gut epithelium. Neutrophil depletion in germ-free and gnotobiotic mice hinted that the microbiota can modulate the infection kinetics and ameliorate epithelium-disruptive enteropathy even in the absence of neutrophil-protection. Together, our data indicate that the well-known protective effect of the microbiota is augmented by intraluminal neutrophils. After antibiotic-mediated microbiota disruption, neutrophils are central for maintaining epithelial barrier integrity during acute Salmonella-induced gut inflammation, by limiting the sustained pathogen assault on the epithelium in a critical window of the infection.