Therapeutic Oral Application of Carvacrol Alleviates Acute Campylobacteriosis in Mice Harboring a Human Gut Microbiota

Abstract

Human Campylobacter jejuni infections are rising globally. Since antibiotics are usually not indicated in acute campylobacteriosis, antibiotic-independent intervention measures are desirable. The phenolic compound carvacrol constitutes a promising candidate molecule given its antimicrobial and immune-modulatory features. To test the disease-alleviating effects of oral carvacrol treatment in acute murine campylobacteriosis, IL-10−/− mice harboring a human gut microbiota were perorally infected with C. jejuni and treated with carvacrol via the drinking water. Whereas C. jejuni stably established in the gastrointestinal tract of mice from the placebo cohort, carvacrol treatment resulted in lower pathogen loads in the small intestines on day 6 post infection. When compared to placebo, carvacrol ameliorated pathogen-induced symptoms including bloody diarrhea that was accompanied by less distinct histopathological and apoptotic cell responses in the colon. Furthermore, innate and adaptive immune cell numbers were lower in the colon of carvacrol- versus placebo-treated mice. Notably, carvacrol application dampened C. jejuni-induced secretion of pro-inflammatory mediators in intestinal, extra-intestinal and systemic organs to naive levels and furthermore, resulted in distinct shifts in the fecal microbiota composition. In conclusion, our preclinical placebo-controlled intervention study provides evidence that therapeutic carvacrol application constitutes a promising option to alleviate campylobacteriosis in the infected vertebrate host.

Prophylactic Oral Application of Activated Charcoal Mitigates Acute Campylobacteriosis in Human Gut Microbiota-Associated IL-10−/− Mice

“…At the end of the experiment, C. jejuni infected mice exhibited higher enterobacterial numbers, but lower loads of obligate anaerobic species including bifidobacteria, Bacteroides/Prevotella species, C. coccoides and C. leptum groups when compared to naive control animals that were, however, independent of the prophylactic oral AC application. The here observed C. jejuni induced fecal microbiota shifts could be confirmed by our previous studies showing increased colonic enterobacterial counts but decreased obligate anaerobic bacterial numbers during acute campylobacteriosis in hma IL-10 −/− mice [32,37]. Given that direct antibiotic effects of AC have not been described to date, the risk of dysbiosis and of the development of antibacterial resistance upon AC treatment can be considered as negligible.…”

“…Within less than a week following oral C. jejuni infection, hma IL-10 −/− mice were shown to develop key symptoms of severe campylobacteriosis, such as acute enterocolitis with bloody diarrhea and wasting and pro-inflammatory immune responses that do not only affect the intestinal tract, but also extra-intestinal organs including the livers, kidneys, lung, and the systemic circulation [32]. Our recent study underscored the suitability of the hma IL-10 −/− mouse model to test the disease-alleviating effects of defined molecules such as carvacrol, for instance, during acute campylobacteriosis [37]. This prompted us to unravel the disease-mitigating effects of AC when applied prophylactically to hma IL-10 −/− in our pre-clinical placebo-controlled trial.…”

Carvacrol prophylaxis improves clinical outcome and dampens apoptotic and pro-inflammatory immune responses upon Campylobacter jejuni infection of human microbiota-associated IL-10−/− mice

“…In addition, oral carvacrol pretreatment resulted in diminished intestinal secretion of pro-inflammatory mediators ( Fig. 7 ), which was also the case when carvacrol treatment was initiated after C. jejuni infection [ 43 ]. In support, carvacrol application could decrease pro-inflammatory mediator secretion from stimulated macrophages and T lymphocytes in vitro [ 62 , 63 ], whereas the expression of pro-inflammatory cytokines was down-regulated in LPS-challenged broiler chicken following oral carvacrol challenge [ 64 ].…”

“…Overall, the hma IL-10 À/À mouse model constitutes a reliable experimental tool to dissect the triangular relationship between C. jejuni, vertebrate host immunity, and the human gut microbiota and mimics key features of severe campylobacteriosis in humans [42]. In addition, it enables us to test novel interventive measures, such as therapeutic and/ or prophylactic regimens with defined molecules alone or in combination within a preclinical setting [41] as validated by our recent placebo-controlled intervention studies [43][44][45][46].…”

Investigating bacteriophages as a novel multiple-hurdle measure against Campylobacter: field trials in commercial broiler plants

“…Campylobacteriosis is the most commonly reported foodborne bacterial zoonosis, requiring effective mitigation measures throughout the food chain for public health 39 . Since single measures did not result in reliable reduction in practical settings, a multiple-hurdle approach for Campylobacter mitigation was investigated.…”