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Given that human Campylobacter jejuni infections are rising globally and antibiotic treatment is not recommended, infected patients would substantially benefit from alternative therapeutic strategies. Short-chain fatty acids such as butyrate are known for their health benefits, including anti-microbial and anti-inflammatory effects. This prompted us to investigate potential disease-alleviating properties of butyrate treatment during acute murine C. jejuni -induced enterocolitis. Therefore, following gut microbiota depletion IL-10 -/- mice were challenged with 10 9 viable C. jejuni cells by oral gavage and treated with butyrate via the drinking water (22 g/L) starting on day 2 post-infection. As early as day 3 post-infection, butyrate reduced diarrheal severity and frequency in treated mice, whereas on day 6 post-infection, gastrointestinal C. jejuni burdens and the overall clinical outcomes were comparable in butyrate- and placebo-treated cohorts. Most importantly, butyrate treatment dampened intestinal pro-inflammatory immune responses given lower colonic numbers of apoptotic cells and neutrophils, less distinct TNF-α secretion in mesenteric lymph nodes and lower IL-6 and MCP-1 concentrations in the ileum. In conclusion, results of our preclinical intervention study provide evidence that butyrate represents a promising candidate molecule for the treatment of acute campylobacteriosis., Competing Interests: All authors declare no conflicts of interest. The funders had no role in study design, data collection and analysis, publication decision, or manuscript preparation.

Foodborne Campylobacter jejuni infections are on the rise and responsible for worldwide serious health issues. Increasing resistance of C. jejuni strains against antimicrobial treatments, necessitates antibiotics-independent treatment options for acute campylobacteriosis. Activated charcoal (AC) constitutes a long-known and safe compound for the treatment of bacterial enteritis. In this preclinical intervention study, we addressed potential anti-pathogenic and immune-modulatory effects of AC during acute experimental campylobacteriosis. Therefore, microbiota-depleted IL-10 -/- mice were infected with C. jejuni by gavage and challenged with either AC or placebo via the drinking water starting on day 2 post-infection. On day 6 post-infection, AC as compared to placebo-treated mice did not only harbor lower intestinal pathogen loads but also presented with alleviated C. jejuni -induced clinical signs such as diarrhea and wasting symptoms. The improved clinical outcome of AC-treated mice was accompanied by less colonic epithelial cell apoptosis and reduced pro-inflammatory immune responses in the intestinal tract. Notably, AC treatment did not only alleviate intestinal, but also extra-intestinal and systemic immune responses as indicated by dampened pro-inflammatory mediator secretion. Given the anti-pathogenic and immune-modulatory properties of AC in this study, a short-term application of this non-toxic drug constitutes a promising antibiotics-independent option for the treatment of human campylobacteriosis.

Human campylobacteriosis, commonly caused by Campylobacter jejuni, is a food-borne infection with rising prevalence causing significant health and socioeconomic burdens worldwide. Given the threat from emerging antimicrobial resistances, the treatment of infectious diseases with antibiotics-independent natural compounds is utmost appreciated. Since the health-beneficial effects of cumin-essential-oil (EO) have been known for centuries, its potential anti-pathogenic and immune-modulatory effects during acute experimental campylobacteriosis were addressed in the present study. Therefore, C. jejuni -challenged secondary abiotic IL-10 -/- mice were treated perorally with either cumin-EO or placebo starting on day 2 post-infection. On day 6 post-infection, cumin-EO treated mice harbored lower ileal pathogen numbers and exhibited a better clinical outcome when compared to placebo controls. Furthermore, cumin-EO treatment alleviated enteropathogen-induced apoptotic cell responses in colonic epithelia. Whereas, on day 6 post-infection, a dampened secretion of pro-inflammatory mediators, including nitric oxide and IFN-γ to basal levels, could be assessed in mesenteric lymph nodes of cumin-EO treated mice, systemic MCP-1 concentrations were elevated in placebo counterparts only. In conclusion, our preclinical intervention study provides first evidence for promising immune-modulatory effects of cumin-EO in the combat of human campylobacteriosis. Future studies should address antimicrobial and immune-modulatory effects of natural compounds as adjunct antibiotics-independent treatment option for infectious diseases.

Since human infections with Campylobacter jejuni including antibiotic-resistant strains are rising worldwide, natural compounds might constitute promising antibiotics-independent treatment options for campylobacteriosis. Since the health-beneficial properties of garlic have been known for centuries, we here surveyed the antimicrobial and immune-modulatory effects of garlic essential oil (EO) in acute experimental campylobacteriosis. Therefore, secondary abiotic IL-10 -/- mice were orally infected with C. jejuni strain 81-176 and garlic-EO treatment via the drinking water was initiated on day 2 post-infection. Mice from the garlic-EO group displayed less severe clinical signs of acute campylobacteriosis as compared to placebo counterparts that were associated with lower ileal C. jejuni burdens on day 6 post-infection. Furthermore, when compared to placebo application, garlic-EO treatment resulted in alleviated colonic epithelia cell apoptosis, in less pronounced C. jejuni induced immune cell responses in the large intestines, in dampened pro-inflammatory mediator secretion in intestinal and extra-intestinal compartments, and, finally, in less frequent translocation of viable pathogens from the intestines to distinct organs. Given its potent immune-modulatory and disease-alleviating effects as shown in our actual preclinical placebo-controlled intervention study, we conclude that garlic-EO may be considered as promising adjunct treatment option for acute campylobacteriosis in humans.

The prevalence of infections with the zoonotic enteritis pathogen Campylobacter coli is increasing. Probiotic formulations constitute promising antibiotic-independent approaches to reduce intestinal pathogen loads and modulate pathogen-induced immune responses in the infected human host, resulting in acute campylobacteriosis and post-infectious sequelae. Here, we address potential antipathogenic and immuno-modulatory effects of the commercial product Aviguard ® during experimental campylobacteriosis. Secondary abiotic IL-10 -/- mice were infected with a C. coli patient isolate on days 0 and 1, followed by oral Aviguard ® treatment on days 2, 3 and 4. Until day 6 post-infection, Aviguard ® treatment could lower the pathogen burdens within the proximal but not the distal intestinal tract. In contrast, the probiotic bacteria had sufficiently established in the intestines with lower fecal loads of obligate anaerobic species in C. coli -infected as compared to uninfected mice following Aviguard ® treatment. Aviguard ® application did not result in alleviated clinical signs, histopathological or apoptotic changes in the colon of infected IL-10 -/- mice, whereas, however, Aviguard ® treatment could dampen pathogen-induced innate and adaptive immune responses in the colon, accompanied by less distinct intestinal proinflammatory cytokine secretion. In conclusion, Aviguard ® constitutes a promising probiotic compound to alleviate enteropathogen-induced proinflammatory immune responses during human campylobacteriosis.

Campylobacter ( C. ) jejuni infections pose progressively emerging threats to human health worldwide. Given the rise in antibiotic resistance, antibiotics-independent options are required to fight campylobacteriosis. Since the health-beneficial effects of clove have been known for long, we here analyzed the antimicrobial and immune-modulatory effects of clove essential oil (EO) during acute experimental campylobacteriosis. Therefore, microbiota-depleted interleukin-10 deficient (IL-10 -/- ) mice were perorally infected with C. jejuni and treated with clove EO via drinking water starting on day 2 post-infection. On day 6 post-infection, lower small- and large-intestinal pathogen loads could be assessed in clove EO as compared to placebo treated mice. Although placebo mice suffered from severe campylobacteriosis as indicated by wasting and bloody diarrhea, clove EO treatment resulted in a better clinical outcome and in less severe colonic histopathological and apoptotic cell responses in C. jejuni infected mice. Furthermore, lower colonic numbers of macrophages, monocytes, and T lymphocytes were detected in mice from the verum versus the placebo cohort that were accompanied by lower intestinal, extra-intestinal, and even systemic proinflammatory cytokine concentrations. In conclusion, our preclinical intervention study provides first evidence that the natural compound clove EO constitutes a promising antibiotics-independent treatment option of acute campylobacteriosis in humans.

Human infections with enteropathogenic Campylobacter jejuni ( C. jejuni ) including multi-drug resistant isolates are emerging worldwide. Antibiotics-independent approaches in the combat of campylobacteriosis are therefore highly desirable. Since the health-beneficial including anti-inflammatory and anti-infectious properties of cardamom have been acknowledged for long, we here addressed potential anti-pathogenic and immune-modulatory effects of this natural compound during acute campylobacteriosis. For this purpose, microbiota-depleted IL-10 -/- mice were orally infected with C. jejuni strain 81-176 and subjected to cardamom essential oil (EO) via the drinking water starting on day 2 post-infection. Cardamom EO treatment resulted in lower intestinal pathogen loads and improved clinical outcome of mice as early as day 3 post-infection. Furthermore, when compared to mock controls, cardamom EO treated mice displayed less distinct macroscopic and microscopic inflammatory sequelae on day 6 post-infection that were paralleled by lower colonic numbers of macrophages, monocytes, and T cells and diminished pro-inflammatory mediator secretion not only in the intestinal tract, but also in extra-intestinal and, remarkably, systemic organs. In conclusion, our preclinical intervention study provides the first evidence that cardamom EO comprises a promising compound for the combat of acute campylobacteriosis and presumably prevention of post-infectious morbidities.

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.

Human Campylobacter infections are emerging worldwide and constitute significant health burdens. We recently showed that the immunopathological sequelae in Campylobacter jejuni -infected mice were due to Toll-like receptor (TLR)-4 dependent immune responses induced by bacterial lipooligosaccharide (LOS). Information regarding the molecular mechanisms underlying Campylobacter coli -host interactions are scarce, however. Therefore, we analyzed C. coli -induced campylobacteriosis in secondary abiotic IL-10 -/- mice with and without TLR4. Mice were infected perorally with a human C. coli isolate or with a murine commensal Escherichia coli as apathogenic, non-invasive control. Independent from TLR4, C. coli and E. coli stably colonized the gastrointestinal tract, but only C. coli induced clinical signs of campylobacteriosis. TLR4 -/- IL-10 -/- mice, however, displayed less frequently fecal blood and less distinct histopathological and apoptotic sequelae in the colon versus IL-10 -/- counterparts on day 28 following C. coli infection. Furthermore, C. coli -induced colonic immune cell responses were less pronounced in TLR4 -/- IL-10 -/- as compared to IL-10 -/- mice and accompanied by lower pro-inflammatory mediator concentrations in the intestines and the liver of the former versus the latter. In conclusion, our study provides evidence that TLR4 is involved in mediating C. coli -LOS-induced immune responses in intestinal and extra-intestinal compartments during murine campylobacteriosis.

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.

Human Campylobacter jejuni infections are emerging, and constitute a significant health burden worldwide. The ubiquitously expressed pituitary adenylate cyclase-activating polypeptide (PACAP) is well-known for its cell-protective and immunomodulatory effects. In our actual intervention study, we used an acute campylobacteriosis model and assessed the potential disease-alleviating effects of exogenous PACAP. Therefore, secondary abiotic IL-10 -/- mice were perorally infected with C. jejuni and treated with synthetic PACAP38 intraperitoneally from day 2 until day 5 post-infection. Whereas PACAP did not interfere with the gastrointestinal colonization of the pathogen, mice from the PACAP group exhibited less severe clinical signs of C. jejuni -induced disease, as compared to mock controls, which were paralleled by alleviated apoptotic, but enhanced cell proliferative responses in colonic epithelia on day 6 post-infection. Furthermore, PACAP dampened the accumulation of macrophages and monocytes, but enhanced regulatory T cell responses in the colon, which were accompanied by less IFN-γ secretion in intestinal compartments in PACAP versus mock-treated mice. Remarkably, the inflammation-dampening properties of PACAP could also be observed in extra-intestinal organs, and strikingly, even the systemic circulation on day 6 post-infection. For the first time, we provide evidence that synthetic PACAP might be a promising candidate to combat acute campylobacteriosis and post-infectious sequelae.

Human Campylobacter -infections are progressively rising globally. However, the molecular mechanisms underlying C. coli -host interactions are incompletely understood. In this study, we surveyed the impact of the host-specific intestinal microbiota composition during peroral C. coli infection applying an established murine campylobacteriosis model. Therefore, microbiota-depleted IL-10 -/- mice were subjected to peroral fecal microbiota transplantation from murine versus human donors and infected with C. coli one week later by gavage. Irrespective of the microbiota, C. coli stably colonized the murine gastrointestinal tract until day 21 post-infection. Throughout the survey, C. coli -infected mice with a human intestinal microbiota displayed more frequently fecal blood as their murine counterparts. Intestinal inflammatory sequelae of C. coli -infection could exclusively be observed in mice with a human intestinal microbiota, as indicated by increased colonic numbers of apoptotic epithelial cells and innate as well as adaptive immune cell subsets, which were accompanied by more pronounced pro-inflammatory cytokine secretion in the colon and mesenteric lymph nodes versus mock controls. However, in extra-intestinal, including systemic compartments, pro-inflammatory responses upon pathogen challenge could be assessed in mice with either microbiota. In conclusion, the host-specific intestinal microbiota composition has a profound effect on intestinal and systemic pro-inflammatory immune responses during C. coli infection.

Human infections with the food-borne enteropathogens Campylobacter are progressively rising. Recent evidence revealed that pre-existing intestinal inflammation facilitates enteropathogenic infection subsequently exacerbating the underlying disease. Given that only little is known about C. coli -host interactions and particularly during intestinal inflammation, the aim of the present study was to survey gastrointestinal colonization properties, gut microbiota changes and pro-inflammatory sequelae upon peroral C. coli -infection of IL-10 -/- mice with chronic colitis. C. coli colonized the gastrointestinal tract of mice with varying efficiencies until day 28 post-infection and induced macroscopic and microscopic inflammatory changes as indicated by shorter colonic lengths, more distinct histopathological changes in the colonic mucosa and higher numbers of apoptotic colonic epithelial cells when compared to mock-infected controls. Furthermore, not only colonic innate and adaptive immune cell responses, but also enhanced systemic TNF-α secretion could be observed following C. coli as opposed to mock challenge. Notably, C. coli induced intestinal inflammatory sequelae were accompanied with gut microbiota shifts towards higher commensal enterobacterial loads in the infected gut lumen. Moreover, the pathogen translocated from the intestinal tract to extra-intestinal tissue sites in some cases, but never to systemic compartments. Hence, C. coli accelerates inflammatory immune responses in IL-10 -/- mice with chronic colitis.

Human infections with the food-borne zoonotic pathogen Campylobacter jejuni are progressively rising and constitute serious global public health and socioeconomic burdens. Hence, application of compounds with disease-alleviating properties are required to combat campylobacteriosis and post-infectious sequelae. In our preclinical intervention study applying an acute C. jejuni induced enterocolitis model, we surveyed the anti-pathogenic and immune-modulatory effects of the octapeptide NAP which is well-known for its neuroprotective and anti-inflammatory properties. Therefore, secondary abiotic IL-10 -/- mice were perorally infected with C. jejuni and intraperitoneally treated with synthetic NAP from day 2 until day 5 post-infection. NAP-treatment did not affect gastrointestinal C. jejuni colonization but could alleviate clinical signs of infection that was accompanied by less pronounced apoptosis of colonic epithelial cells and enhancement of cell regenerative measures on day 6 post-infection. Moreover, NAP-treatment resulted in less distinct innate and adaptive pro-inflammatory immune responses that were not restricted to the intestinal tract but could also be observed in extra-intestinal and even systemic compartments. NAP-treatment further resulted in less frequent translocation of viable pathogens from the intestinal tract to extra-intestinal including systemic tissue sites. For the first time, we here provide evidence that NAP application constitutes a promising option to combat acute campylobacteriosis.

Zoonotic Campylobacter , including C. jejuni and C. coli , are among the most prevalent agents of food-borne enteritis worldwide. The immunopathological sequelae of campylobacteriosis are caused by Toll-like Receptor-4 (TLR4)-dependent host immune responses, induced by bacterial lipooligosaccharide (LOS). In order to investigate C. coli -host interactions, including the roles of the human gut microbiota and TLR4, upon infection, we applied a clinical acute campylobacteriosis model, and subjected secondary abiotic, TLR4-deficient IL10 -/- mice and IL10 -/- controls to fecal microbiota transplantation derived from human donors by gavage, before peroral C. coli challenge. Until day 21 post-infection, C. coli could stably colonize the gastrointestinal tract of human microbiota-associated (hma) mice of either genotype. TLR4-deficient IL10 -/- mice, however, displayed less severe clinical signs of infection, that were accompanied by less distinct apoptotic epithelial cell and innate as well as adaptive immune cell responses in the colon, as compared to IL10 -/- counterparts. Furthermore, C. coli infected IL10 -/- , as opposed to TLR4-deficient IL10 -/- , mice displayed increased pro-inflammatory cytokine concentrations in intestinal and, strikingly, systemic compartments. We conclude that pathogenic LOS might play an important role in inducing TLR4-dependent host immune responses upon C. coli infection, which needs to be further addressed in more detail.

: Human Campylobacter jejuni infections inducing campylobacteriosis including post-infectious sequelae such as Guillain-Barré syndrome and reactive arthritis are rising worldwide and progress into a global burden of high socioeconomic impact. Intestinal immunopathology underlying campylobacteriosis is a classical response of the innate immune system characterized by the accumulation of neutrophils and macrophages which cause tissue destruction, barrier defects and malabsorption leading to bloody diarrhea. Clinical studies revealed that enteritis and post-infectious morbidities of human C. jejuni infections are strongly dependent on the structure of pathogenic lipooligosaccharides (LOS) triggering the innate immune system via Toll-like-receptor (TLR)-4 signaling. Compared to humans, mice display an approximately 10,000 times weaker TLR-4 response and a pronounced colonization resistance (CR) against C. jejuni maintained by the murine gut microbiota. In consequence, investigations of campylobacteriosis have been hampered by the lack of experimental animal models. We here summarize recent progress made in the development of murine C. jejuni infection models that are based on the abolishment of CR by modulating the murine gut microbiota and by sensitization of mice to LOS. These advances support the major role of LOS driven innate immunity in pathogenesis of campylobacteriosis including post-infectious autoimmune diseases and promote the preclinical evaluation of novel pharmaceutical strategies for prophylaxis and treatment., Competing Interests: The authors have declared that no competing interests exist.