Resveratrol Alleviates Acute Campylobacter jejuni Induced Enterocolitis in a Preclinical Murine Intervention Study

Abstract

The polyphenolic compound resveratrol has been shown to exert health-beneficial properties. Given globally emerging Campylobacter infections in humans, we addressed potential anti-pathogenic, immuno-modulatory and intestinal epithelial barrier preserving properties of synthetic resveratrol in the present preclinical intervention study applying a murine acute campylobacteriosis model. Two days following peroral C. jejuni infection, secondary abiotic IL-10−/− mice were either subjected to resveratrol or placebo via the drinking water. Whereas placebo mice suffered from acute enterocolitis at day 6 post-infection, resveratrol treatment did not only lead to improved clinical conditions, but also to less pronounced colonic epithelial apoptosis as compared to placebo application. Furthermore, C. jejuni induced innate and adaptive immune cell responses were dampened in the large intestines upon resveratrol challenge and accompanied by less colonic nitric oxide secretion in the resveratrol versus the placebo cohort. Functional analyses revealed that resveratrol treatment could effectively rescue colonic epithelial barrier function in C. jejuni infected mice. Strikingly, the disease-alleviating effects of resveratrol could additionally be found in extra-intestinal and also systemic compartments at day 6 post-infection. For the first time, our current preclinical intervention study provides evidence that peroral resveratrol treatment exerts potent disease-alleviating effects during acute experimental campylobacteriosis.

Resveratrol Prevents Campylobacter jejuni-Induced Leaky gut by Restoring Occludin and Claudin-5 in the Paracellular Leak Pathway

“…In our in vitro assays, the concentration of resveratrol required to block C. jejuniinduced barrier defects was 100 µM (23 μg/ml), which was lower than the MIC required to act directly against C. jejuni. Likewise, the resveratrol concentration used for the in vivo experiments was close to, but lower than, the MIC of C. jejuni 81-176 with 456.5 μg/ml (Heimesaat et al, 2020). Thus, the protective effects of resveratrol appear to be targeted to the host response rather than to a direct anti-bacterial effect in the infected animals (Heimesaat et al, 2020).…”

“…Anti-apoptotic effects of resveratrol have been reported in H 2 O 2 -stimulated Caco-2 cells (Wang et al, 2016), and were confirmed in the present study. Campylobacter jejuni-infected IL-10 −/− mice treated with resveratrol showed lower apoptotic cell numbers in the colon when compared with placebo-treated C. jejuni-infected mice (Heimesaat et al, 2020). Nevertheless, several studies and clinical trials showed that resveratrol also induced apoptosis in cancer cells (Berman et al, 2017;Singh et al, 2017;El-Kott et al, 2019).…”

“…Thus, in keeping with our in vitro results, the anti-Campylobacter effect of resveratrol seems to be based more on improving barrier function at the epithelial level than by attenuating cytokine release. To comply with the guidelines of the 3R principles to reduce the number of animal experiments, we used animal biopsies and experimental in vivo data from an ongoing study in collaboration (Heimesaat et al, 2020).…”

“…Concerning C. jejuni infections, we have shown recently that resveratrol treatment alleviates intestinal inflammation and macroscopic sequelae of campylobacteriosis in a standardized murine preclinical disease model (Heimesaat et al, 2020). To determine mechanisms underlying the beneficial effects of resveratrol in the treatment of campylobacteriosis, we performed experiments in different models.…”

Anti-Pathogenic and Immune-Modulatory Effects of Peroral Treatment with Cardamom Essential Oil in Acute Murine Campylobacteriosis

“…In fact, within six days following peroral C. jejuni infection, microbiota-depleted IL-10 −/− mice did not only display high pathogen loads in their intestinal tract, but also suffered from wasting and bloody diarrhea indicative for acute enterocolitis and succumbed to infection [ 15 ]. This acute C. jejuni infection and inflammation model has been proven suitable to test distinct pathogenic virulence factors such as proteases [ 16 , 17 , 18 ], flagellins, and adhesins [ 19 ], which also holds true for the evaluation of defined molecules and compounds, regarding their anti-pathogenic and immune-modulatory properties in preclinical intervention studies [ 20 , 21 , 22 , 23 , 24 , 25 ].…”