Abstract
Human campylobacteriosis represents an infectious enteritis syndrome caused by Campylobacter species, mostly Campylobacter jejuni. Given that C. jejuni infections are rising worldwide and antibiotic treatment is usually not indicated, novel treatment options for campylobacteriosis are needed. Urolithin-A constitutes a metabolite produced by the human gut microbiota from ellagitannins and ellagic acids in berries and nuts which have been known for their health-beneficial including anti-inflammatory effects since centuries. Therefore, we investigated potential pathogen-lowering and immunomodulatory effects following oral application of synthetic urolithin-A during acute campylobacteriosis applying perorally C. jejuni infected, microbiota-depleted IL-10−/− mice as preclinical inflammation model. On day 6 post infection, urolithin-A treated mice harbored slightly lower pathogen loads in their ileum, but not colon as compared to placebo counterparts. Importantly, urolithin-A treatment resulted in an improved clinical outcome and less pronounced macroscopic and microscopic inflammatory sequelae of infection that were paralleled by less pronounced intestinal pro-inflammatory immune responses which could even be observed systemically. In conclusion, this preclinical murine intervention study provides first evidence that oral urolithin-A application is a promising treatment option for acute C. jejuni infection and paves the way for future clinical studies in human campylobacteriosis.
Highlights
Campylobacteriosis is clinically characterized by acute enteritis upon infection with thermo-tolerant Campylobacter species, in most cases Campylobacter jejuni [1,2,3,4,5,6]
Microbiota depleted IL-10−/− mice were perorally infected with 109 colony forming units (CFU) C. jejuni strain 81-176 on days 0 and 1 and subjected to either urolithin-A or placebo treatment via the drinking water as initiated on day 2 p.i
Our cultural analyses revealed that on days 2, 3 and 4 post infection (p.i.), fecal C. jejuni numbers were lower in the urolithin-A as compared to the placebo cohort (p < 0.01–0.001), whereas later-on, comparably high median pathogen loads of approximately 109 CFU per g fecal sample could be determined (not significant (n.s.); Supplementary Figure S1)
Summary
Campylobacteriosis is clinically characterized by acute enteritis upon infection with thermo-tolerant Campylobacter species, in most cases Campylobacter jejuni [1,2,3,4,5,6]. The absence of clinical signs in the Campylobacter colonized avian host has been attributed to a non-responsiveness of the birds’ innate immune system to the bacteria. This is in support of the resistance of birds to lipopolysaccharide (LPS) within the cell walls of Gram-negative bacteria including pathogens of the Campylobacter clade which produce a truncated variant of LPS termed lipooligosaccharide (LOS) [7]. Results from previous studies suggest that these differences in pathogen recognition might be caused by species-specific variations in the recognition of Campylobacter LOS by the specific innate receptor Toll-like-receptor (TLR)-4 [8]
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