Regulatory T Cell Specificity Directs Tolerance versus Allergy against Aeroantigens in Humans.

FOXP3+ regulatory T cells (Tregs) maintain tolerance against self-antigens and innocuous environmental antigens. However, it is still unknown whether Treg-mediated tolerance is antigen specific and how Treg specificity contributes to the selective loss of tolerance, as observed in human immunopathologies such as allergies. Here, we used antigen-reactive T cell enrichment to identify antigen-specific human Tregs. We demonstrate dominant Treg-mediated tolerance against particulate aeroallergens, such as pollen, house dust mites, and fungal spores. Surprisingly, we found no evidence of functional impairment of Treg responses in allergic donors. Rather, major allergenic proteins, known to rapidly dissociate from inhaled allergenic particles, have a generally reduced capability to generate Treg responses. Most strikingly, in individual allergic donors, Th2 cells and Tregs always target disparate proteins. Thus, our data highlight the importance of Treg antigen-specificity for tolerance in humans and identify antigen-specific escape from Treg control as an important mechanism enabling antigen-specific loss of tolerance in human allergy.

Oral microbiota signatures in post-traumatic stress disorder (PTSD) veterans.

Post-traumatic stress disorder (PTSD) represents a global public health concern, affecting about 1 in 20 individuals. The symptoms of PTSD include intrusiveness (involuntary nightmares or flashbacks), avoidance of traumatic memories, negative alterations in cognition and mood (such as negative beliefs about oneself or social detachment), increased arousal and reactivity with irritable reckless behavior, concentration problems, and sleep disturbances. PTSD is also highly comorbid with anxiety, depression, and substance abuse. To advance the field from subjective, self-reported psychological measurements to objective molecular biomarkers while considering environmental influences, we examined a unique cohort of Israeli veterans who participated in the 1982 Lebanon war. Non-invasive oral 16S RNA sequencing was correlated with psychological phenotyping. Thus, a microbiota signature (i.e., decreased levels of the bacteria sp_HMT_914, 332 and 871 and Noxia) was correlated with PTSD severity, as exemplified by intrusiveness, arousal, and reactivity, as well as additional psychopathological symptoms, including anxiety, hostility, memory difficulties, and idiopathic pain. In contrast, education duration correlated with significantly increased levels of sp_HMT_871 and decreased levels of Bacteroidetes and Firmicutes, and presented an inverted correlation with adverse psychopathological measures. Air pollution was positively correlated with PTSD symptoms, psychopathological symptoms, and microbiota composition. Arousal and reactivity symptoms were correlated with reductions in transaldolase, an enzyme controlling a major cellular energy pathway, that potentially accelerates aging. In conclusion, the newly discovered bacterial signature, whether an outcome or a consequence of PTSD, could allow for objective soldier deployment and stratification according to decreases in sp_HMT_914, 332, 871, and Noxia levels, coupled with increases in Bacteroidetes levels. These findings also raise the possibility of microbiota pathway-related non-intrusive treatments for PTSD.

Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism.

AIMS: Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. METHODS AND RESULTS: Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. CONCLUSION: Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.

Murine Models for the Investigation of Colonization Resistance and Innate Immune Responses in Campylobacter Jejuni Infections.

Human infections with the food-borne pathogen Campylobacter jejuni are progressively increasing worldwide and constitute a significant socioeconomic burden to mankind. Intestinal campylobacteriosis in humans is characterized by bloody diarrhea, fever, abdominal pain, and severe malaise. Some individuals develop chronic post-infectious sequelae including neurological and autoimmune diseases such as reactive arthritis and Guillain-Barré syndrome. Studies unraveling the molecular mechanisms underlying campylobacteriosis and post-infectious sequelae have been hampered by the scarcity of appropriate experimental in vivo models. Particularly, conventional laboratory mice are protected from C. jejuni infection due to the physiological colonization resistance exerted by the murine gut microbiota composition. Additionally, as compared to humans, mice are up to 10,000 times more resistant to C. jejuni lipooligosaccharide (LOS) constituting a major pathogenicity factor responsible for the immunopathological host responses during campylobacteriosis. In this chapter, we summarize the recent progress that has been made in overcoming these fundamental obstacles in Campylobacter research in mice. Modification of the murine host-specific gut microbiota composition and sensitization of the mice to C. jejuni LOS by deletion of genes encoding interleukin-10 or a single IL-1 receptor-related molecule as well as by dietary zinc depletion have yielded reliable murine infection models resembling key features of human campylobacteriosis. These substantial improvements pave the way for a better understanding of the molecular mechanisms underlying pathogen-host interactions. The ongoing validation and standardization of these novel murine infection models will provide the basis for the development of innovative treatment and prevention strategies to combat human campylobacteriosis and collateral damages of C. jejuni infections.

Human Campylobacteriosis-A Serious Infectious Threat in a One Health Perspective.

Zoonotic Campylobacter species-mainly C. jejuni and C. coli-are major causes of food-borne bacterial infectious gastroenteritis worldwide. Symptoms of intestinal campylobacteriosis include abdominal pain, diarrhea and fever. The clinical course of enteritis is generally self-limiting, but some infected individuals develop severe post-infectious sequelae including autoimmune disorders affecting the nervous system, the joints and the intestinal tract. Moreover, in immunocompromised individuals, systemic spread of the pathogens may trigger diseases of the circulatory system and septicemia. The socioeconomic costs associated with Campylobacter infections have been calculated to several billion dollars annually. Poultry meat products represent major sources of human infections. Thus, a "One World-One Health" approach with collective efforts of public health authorities, veterinarians, clinicians, researchers and politicians is required to reduce the burden of campylobacteriosis. Innovative intervention regimes for the prevention of Campylobacter contaminations along the food chain include improvements of information distribution to strengthen hygiene measures for agricultural remediation. Given that elimination of Campylobacter from the food production chains is not feasible, novel intervention strategies fortify both the reduction of pathogen contamination in food production and the treatment of the associated diseases in humans. This review summarizes some current trends in the combat of Campylobacter infections including the combination of public health and veterinary preventive approaches with consumer education. The "One World-One Health" perspective is completed by clinical aspects and molecular concepts of human campylobacteriosis offering innovative treatment options supported by novel murine infection models that are based on the essential role of innate immune activation by bacterial endotoxins.

Treatment with the Probiotic Product Aviguard® Alleviates Inflammatory Responses during Campylobacter jejuni-Induced Acute Enterocolitis in Mice.

Prevalences of Campylobacter (C.) jejuni infections are progressively rising globally. Given that probiotic feed additives, such as the commercial product Aviguard®, have been shown to be effective in reducing enteropathogens, such as Salmonella, in vertebrates, including livestock, we assessed potential anti-pathogenic and immune-modulatory properties of Aviguard® during acute C. jejuni-induced murine enterocolitis. Therefore, microbiota-depleted IL-10-/- mice were infected with C. jejuni strain 81-176 by gavage and orally treated with Aviguard® or placebo from day 2 to 4 post-infection. The applied probiotic bacteria could be rescued from the intestinal tract of treated mice, but with lower obligate anaerobic bacterial counts in C. jejuni-infected as compared to non-infected mice. Whereas comparable gastrointestinal pathogen loads could be detected in both groups until day 6 post-infection, Aviguard® treatment resulted in improved clinical outcome and attenuated apoptotic cell responses in infected large intestines during acute campylobacteriosis. Furthermore, less distinct pro-inflammatory immune responses could be observed not only in the intestinal tract, but also in extra-intestinal compartments on day 6 post-infection. In conclusion, we show here for the first time that Aviguard® exerts potent disease-alleviating effects in acute C. jejuni-induced murine enterocolitis and might be a promising probiotic treatment option for severe campylobacteriosis in humans.

Vitamin D Reverses Disruption of Gut Epithelial Barrier Function Caused by Campylobacter jejuni.

Infections by the zoonotic foodborne bacterium Campylobacter jejuni (C. jejuni) are among the most frequent causes of bacterial gastroenteritis worldwide. The aim was to evaluate the relationship between epithelial barrier disruption, mucosal immune activation, and vitamin D (VD) treatment during C. jejuni infection, using intestinal epithelial cells and mouse models focused on the interaction of C. jejuni with the VD signaling pathway and VD treatment to improve C. jejuni-induced barrier dysfunction. Our RNA-Seq data from campylobacteriosis patients demonstrate inhibition of VD receptor (VDR) downstream targets, consistent with suppression of immune function. Barrier-preserving effects of VD addition were identified in C. jejuni-infected epithelial cells and IL-10-/- mice. Furthermore, interference of C. jejuni with the VDR pathway was shown via VDR/retinoid X receptor (RXR) interaction. Paracellular leakiness of infected epithelia correlated with tight junction (TJ) protein redistribution off the TJ domain and apoptosis induction. Supplementation with VD reversed barrier impairment and prevented inhibition of the VDR pathway, as shown by restoration of transepithelial electrical resistance and fluorescein (332 Da) permeability. We conclude that VD treatment restores gut epithelial barrier functionality and decreases bacterial transmigration and might, therefore, be a promising compound for C. jejuni treatment in humans and animals.

Campylobacteriose ­ eine zoonotische Infektionskrankheit.

Campylobacter jejuni represents an important zoonotic pathogen that is causing foodborne enteric infections. In the human gut, C. jejuni bacteria induce intestinal campylobacteriosis which can develop into systemic post-infectious sequelae such as Guillain-Barré syndrome or rheumatoid arthritis. Here, we review the pathobiology and molecular mechanisms of C. jejuni infections as well as promising strategies to combat campylobacteriosis within the "One World - One Health" approach.

Antibiotic use during pregnancy increases offspring asthma severity in a dose-dependent manner.

BACKGROUND: The use of antibiotics during pregnancy is associated with increased allergic asthma risk in the offspring, and given that approximately 25% of pregnant women are prescribed antibiotics, it is important to understand the mechanisms contributing to this phenomenon. Currently, there are no studies that directly test this association experimentally. Our objective was to develop a mouse model in which antibiotic treatment during pregnancy results in increased offspring asthma susceptibility. METHODS: Pregnant mice were treated daily from gestation day 8-17 with an oral solution of the antibiotic vancomycin, and three concentrations were tested. At weaning, offspring were subjected to an adjuvant-free experimental asthma protocol using ovalbumin as an allergen. The composition of the gut microbiome was determined in mothers and offspring with samples collected from five different time points; short-chain fatty acids were also analyzed in allergic offspring. RESULTS: We found that maternal antibiotic treatment during pregnancy was associated with increased offspring asthma severity in a dose-dependent manner. Furthermore, maternal vancomycin treatment during pregnancy caused marked changes in the gut microbiome composition in both mothers and pups at several different time points. The increased asthma severity and intestinal microbiome changes in pups were also associated with significantly decreased cecal short-chain fatty acid concentrations. CONCLUSION: Consistent with the "Developmental Origins Hypothesis," our results confirm that exposure to antibiotics during pregnancy shapes the neonatal intestinal environment and increases offspring allergic lung inflammation.

Microbiota changes associated with ADNP deficiencies: rapid indicators for NAP (CP201) treatment of the ADNP syndrome and beyond.

Activity-dependent neuroprotective protein (ADNP) and its protein snippet NAP (drug candidate CP201) regulate synapse formation and cognitive as well as behavioral functions, in part, through microtubule interaction. Given potential interactions between the microbiome and brain function, we now investigated the potential effects of the ADNP-deficient genotype, mimicking the ADNP syndrome on microbiota composition in the Adnp+/- mouse model. We have discovered a surprising robust sexually dichotomized Adnp genotype effect and correction by NAP (CP201) as follows. Most of the commensal bacterial microbiota tested were affected by the Adnp genotype and corrected by NAP treatment in a male sex-dependent manner. The following list includes all the bacterial groups tested-labeled in bold are male Adnp-genotype increased and corrected (decreased) by NAP. (1) Eubacteriaceae (EubV3), (2) Enterobacteriaceae (Entero), (3) Enterococcus genus (gEncocc), (4) Lactobacillus group (Lacto), (5) Bifidobacterium genus (BIF), (6) Bacteroides/Prevotella species (Bac), (7) Clostridium coccoides group (Coer), (8) Clostridium leptum group (Cluster IV, sgClep), and (9) Mouse intestinal Bacteroides (MIB). No similarities were found between males and females regarding sex- and genotype-dependent microbiota distributions. Furthermore, a female Adnp+/- genotype associated decrease (contrasting male increase) was observed in the Lactobacillus group (Lacto). Significant correlations were discovered between specific bacterial group loads and open-field behavior as well as social recognition behaviors. In summary, we discovered ADNP deficiency associated changes in commensal gut microbiota compositions, a sex-dependent biomarker for the ADNP syndrome and beyond. Strikingly, we discovered rapidly detected NAP (CP201) treatment-dependent biomarkers within the gut microbiota.

Campylobacter concisus Impairs Sodium Absorption in Colonic Epithelium via ENaC Dysfunction and Claudin-8 Disruption.

The epithelial sodium channel (ENaC) can increase the colonic absorptive capacity for salt and water. Campylobacter concisus is a common pathogenic epsilonproteobacterium, causing enteritis and diarrhea. It can induce barrier dysfunction in the intestine, but its influence on intestinal transport function is still unknown. Therefore, our study aimed to characterize C. concisus effects on ENaC using the HT-29/B6-GR/MR (epithelial cell line HT-29/B6 transfected with glucocorticoid and mineralocorticoid receptors) cell model and mouse colon. In Ussing chambers, C. concisus infection inhibited ENaC-dependent Na+ transport as indicated by a reduction in amiloride-sensitive short circuit current (-55%, n = 15, p < 0.001). This occurred via down-regulation of ß- and γ-ENaC mRNA expression and ENaC ubiquitination due to extracellular signal-regulated kinase (ERK)1/2 activation, predicted by Ingenuity Pathway Analysis (IPA). In parallel, C. concisus reduced the expression of the sealing tight junction (TJ) protein claudin-8 and induced claudin-8 redistribution off the TJ domain of the enterocytes, which facilitates the back leakage of Na+ ions into the intestinal lumen. In conclusion, C. concisus caused ENaC dysfunction via interleukin-32-regulated ERK1/2, as well as claudin-8-dependent barrier dysfunction-both of which contribute to Na+ malabsorption and diarrhea.

Curcumin Mitigates Immune-Induced Epithelial Barrier Dysfunction by Campylobacter jejuni.

Campylobacter jejuni (C. jejuni) is the most common cause of foodborne gastroenteritis worldwide. The bacteria induce diarrhea and inflammation by invading the intestinal epithelium. Curcumin is a natural polyphenol from turmeric rhizome of Curcuma longa, a medical plant, and is commonly used in curry powder. The aim of this study was the investigation of the protective effects of curcumin against immune-induced epithelial barrier dysfunction in C. jejuni infection. The indirect C. jejuni-induced barrier defects and its protection by curcumin were analyzed in co-cultures with HT-29/B6-GR/MR epithelial cells together with differentiated THP-1 immune cells. Electrophysiological measurements revealed a reduction in transepithelial electrical resistance (TER) in infected co-cultures. An increase in fluorescein (332 Da) permeability in co-cultures as well as in the germ-free IL-10-/- mouse model after C. jejuni infection was shown. Curcumin treatment attenuated the C. jejuni-induced increase in fluorescein permeability in both models. Moreover, apoptosis induction, tight junction redistribution, and an increased inflammatory response-represented by TNF-α, IL-1ß, and IL-6 secretion-was observed in co-cultures after infection and reversed by curcumin. In conclusion, curcumin protects against indirect C. jejuni-triggered immune-induced barrier defects and might be a therapeutic and protective agent in patients.

Depletion of Cultivatable Gut Microbiota by Broad-Spectrum Antibiotic Pretreatment Worsens Outcome After Murine Stroke.

BACKGROUND AND PURPOSE: Antibiotics disturbing microbiota are often used in treatment of poststroke infections. A bidirectional brain-gut microbiota axis was recently suggested as a modulator of nervous system diseases. We hypothesized that gut microbiota may be an important player in the course of stroke. METHODS: We investigated the outcome of focal cerebral ischemia in C57BL/6J mice after an 8-week decontamination with quintuple broad-spectrum antibiotic cocktail. These microbiota-depleted animals were subjected to 60 minutes middle cerebral artery occlusion or sham operation. Infarct volume was measured using magnetic resonance imaging, and mice were monitored clinically throughout the whole experiment. At the end point, tissues were preserved for further analysis, comprising histology and immunologic investigations using flow cytometry. RESULTS: We found significantly decreased survival in the middle cerebral artery occlusion microbiota-depleted mice when the antibiotic cocktail was stopped 3 days before surgery (compared with middle cerebral artery occlusion specific pathogen-free and sham-operated microbiota-depleted mice). Moreover, all microbiota-depleted animals in which antibiotic treatment was terminated developed severe acute colitis. This phenotype was rescued by continuous antibiotic treatment or colonization with specific pathogen-free microbiota before surgery. Further, infarct volumes on day one did not differ between any of the experimental groups. CONCLUSIONS: Conventional microbiota ensures intestinal protection in the mouse model of experimental stroke and prevents development of acute and severe colitis in microbiota-depleted mice not given antibiotic protection after cerebral ischemia. Our experiments raise the clinically important question as to whether microbial colonization or specific microbiota are crucial for stroke outcome.

Glycyrrhizic Acid Decreases Gentamicin-Resistance in Vancomycin-Resistant Enterococci.

The resistance of commensal bacteria against first and second line antibiotics has reached an alarming level in many parts of the world and endangers the effective treatment of infectious diseases. Particularly vancomycin-resistant Enterococcus faecium represents an increasing clinical problem in the treatment of infectious diseases and hinders adequate antibiotic stewardship. In consideration of the lack of novel antibiotic compounds, the development of resistance-modifying agents, however, can mitigate the spread of bacterial drug resistance and might possibly extend the useful application indices of an existing licensed antibiotic. Given that saponins modify the local chemical environment at cell membranes and might modify the uptake or mode of action of antibiotics in bacteria, we investigated the influence of the triterpenoid saponin glycyrrhizic acid of Glycyrrhiza glabra on the susceptibility of vancomycin-resistant enterococci against the aminoglycoside antibiotic gentamicin in 47 clinical isolates by applying the checkerboard method. The fractional inhibitory concentration indices values were determined between 0.016 and ≤ 0.5 (synergy is accepted with values ≤ 0.5). Glycyrrhizic acid at the subinhibitory concentration of 2.4 mM was found to reduce the minimal inhibitory concentration of gentamicin in intrinsically resistant E. faecium strains down to 6.25 % of the minimal inhibitory concentration of gentamicin alone, whereas relatively low concentrations of glycyrrhizic acid (18 µM) resulted in increased susceptibilities for some E. faecium isolates to gentamicin. In conclusion, our study points towards a therapeutic potential of glycyrrhizic acid in co-application with gentamicin for defined local bacterial infections caused by vancomycin resistant Enterococcus strains.

Helicobacter pylori protects oncogenically transformed cells from reactive oxygen species-mediated intercellular induction of apoptosis.

Malignant transformation of gastric epithelial cells by chronic Helicobacter pylori infection is caused by several mechanisms including attraction of reactive oxygen species (ROS)-producing neutrophils and cytotoxin-associated antigen A-mediated dysplastic alterations. Here we show that H.pylori protects transformed cells from ROS-mediated intercellular induction of apoptosis. This potential control step in oncogenesis depends on the HOCl and NO/peroxynitrite (PON) signaling pathways. Helicobacter pylori-associated catalase and superoxide dismutase (SOD) efficiently cooperate in the inhibition of HOCl and the NO/PON signaling pathways. Helicobacter pylori catalase prevents HOCl synthesis through decomposition of hydrogen peroxide. Helicobacter pylori-associated SOD interferes with the crucial interactions between superoxide anions and HOCl, as well as superoxide anions and NO. The ratio of bacteria to malignant cells is critical for sufficient protection of transformed cells. Low concentrations of H.pylori more efficiently inhibited ROS-mediated destruction of transformed cells when compared with high concentrations of bacteria. Our data demonstrate the critical role of H.pylori antioxidant enzymes in the survival of transformed cells, modulating an early step of oncogenesis that is distinct from the transformation process per se.

Phage therapy in lung infections caused by multidrug-resistant Pseudomonas aeruginosa - A literature review.

Pulmonary infections of patients with cystic fibrosis (CF) or in intensive care units are frequently caused by the Gram-negative opportunistic pathogen Pseudomonas aeruginosa. Since these bacteria are commonly inherently multidrug-resistant (MDR) and hence, antibiotic treatment options are limited, bacteriophages may provide alternative therapeutic and prophylactic measures in the combat of pneumonia caused by P. aeruginosa. This prompted us to perform a comprehensive literature survey of current knowledge regarding effects of phages applied against pulmonary P. aeruginosa infections. The included 23 studies revealed that P. aeruginosa specific phages lyse and eliminate the bacteria even in case of biofilm production in vitro, whereas application to mice and men resulted in mitigated P. aeruginosa induced clinical signs and enhanced survival. Besides distinct host immune responses, no major adverse effects limiting therapeutic and/or prophylactic phage application were noted. However, the immune system and antibiotics generate synergies with phages due to the mutable sensitivity of P. aeruginosa. In conclusion, results summarized in this review provide evidence that phages constitute promising alternative treatment options for lung infections caused by MDR P. aeruginosa. Further studies are needed, however, to underscore the efficacy and safety aspects of phages application to infected patients including immune-compromised individuals.

Phage therapy in prosthetic joint infections caused by Staphylococcus aureus - A literature review.

Prosthetic joint infections (PJIs) are dreaded arthroplasty complications often caused by Staphylococcus aureus. Due to methicillin-resistant S. aureus (MRSA) strains or biofilm formation, successful treatment remains difficult. Currently, two-stage revision surgery constitutes the gold standard therapy of PJIs, sometimes replaced or supplemented by debridement, antibiotics, and implant retention (DAIR). Given the dire consequences of therapeutic failure, bacteriophage therapy might be another treatment option. Here we provide a comprehensive literature review addressing the efficacy of phages applied against S. aureus as causative agent of PJIs. The included 17 publications had in common that the applied phages proved to be effective against various S. aureus isolates including MRSA even in biofilms. Experiments with mice, rats, rabbits, and moth larvae confirmed favorable features of phage preparations in PJI treatment in vivo; including its synergistic with antibiotics. Case reports of PJI patients unanimously described the bacterial eradication following, alongside other measures, intravenous and intra-articular phage administration. Generally, no major side effects occurred, but in some cases elevated liver transaminases were observed. To conclude, our review compiled promising evidence suggesting the safety and suitability of phage therapy as an adjuvant to DAIR in S. aureus PJIs, and thus, underscores the significance of further research.

Therapeutic effects of oral benzoic acid application during acute murine campylobacteriosis.

Serious risks to human health are posed by acute campylobacteriosis, an enteritis syndrome caused by oral infection with the food-borne bacterial enteropathogen Campylobacter jejuni. Since the risk for developing post-infectious autoimmune complications is intertwined with the severity of enteritis, the search of disease-mitigating compounds is highly demanded. Given that benzoic acid is an organic acid with well-studied health-promoting including anti-inflammatory effects we tested in our present study whether the compound might be a therapeutic option to alleviate acute murine campylobacteriosis. Therefore, microbiota-depleted IL-10-/- mice were perorally infected with C. jejuni and received benzoic acid through the drinking water from day 2 until day 6 post-infection. The results revealed that benzoic acid treatment did not affect C. jejuni colonization in the gastrointestinal tract, but alleviated clinical signs of acute campylobacteriosis, particularly diarrheal and wasting symptoms. In addition, benzoic acid mitigated apoptotic cell responses in the colonic epithelia and led to reduced pro-inflammatory immune reactions in intestinal, extra-intestinal, and systemic compartments tested on day 6 post-infection. Hence, our preclinical placebo-controlled intervention trial revealed that benzoic acid constitutes a promising therapeutic option for treating acute campylobacteriosis in an antibiotic-independent fashion and in consequence, also for reducing the risk of post-infectious autoimmune diseases.

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

Incidence rates of human Campylobacter jejuni infections are progressively increasing globally. Since the risk for the development of post-infectious autoimmune diseases correlates with the severity of the preceding enteritis and campylobacteriosis treatment usually involves symptomatic measures, it is desirable to apply antibiotic-independent compounds to treat or even prevent disease. Given its health-promoting including anti-inflammatory properties carvacrol constitutes a promising candidate. This prompted us to test the disease-alleviating including immune-modulatory effects of carvacrol prophylaxis in acute murine campylobacteriosis. Therefore, human gut microbiota-associated IL-10-/- mice were orally challenged with synthetic carvacrol starting a week before C. jejuni infection and followed up until day 6 post-infection. Whereas carvacrol prophylaxis did neither affect gastrointestinal pathogen loads, nor the human commensal gut microbiota composition, it improved the clinical outcome of mice, attenuated colonic epithelial cell apoptosis, and dampened pro-inflammatory immune responses not only in the intestinal tract but also in extra-intestinal organs including the liver and the spleen. In conclusion, our preclinical placebo-controlled intervention study provides convincing evidence that oral carvacrol pretreatment constitutes a promising option to mitigate acute campylobacteriosis and in turn, to reduce the risk for post-infectious complications.

Polyphenolic compounds in the combat of foodborne infections - An update on recent evidence.

In recent years, the incidence of food-borne bacterial enteric diseases has increased worldwide causing significant health care and socioeconomic burdens. According to the World Health Organization, there are an estimated 600 million cases of foodborne illnesses worldwide each year, resulting in 420,000 deaths. Despite intensive efforts to tackle this problem, foodborne pathogenic microorganisms continue to be spread further. Therefore, there is an urgent need to find novel anti-microbial non-toxic compounds for food preservation. One way to tackle this issue may be the usage of polyphenols, which have received increasing attention in the recent years given their pleotropic health-promoting properties. This prompted us to perform a literature search summarizing studies from the past 10 years regarding the potential anti-microbial and disease-alleviating effects of plant-derived phenolic compounds against foodborne bacterial pathogens. The included 16 studies provide evidence that polyphenols show pronounced anti-bacterial and anti-oxidant effects against both Gram-positive and Gram-negative bacterial species. In addition, synergistic anti-microbial effects in combination with synthetic antibiotics were observed. In conclusion, phenolic compounds may be useful as natural anti-microbial agents in the food, agricultural, and pharmaceutical industries in the combat of foodborne infections.