Dataset Information

Preclinical Evaluation of Oral Urolithin-A for the Treatment of Acute Campylobacteriosis in Campylobacter jejuni Infected Microbiota-Depleted IL-10^-/- Mice.

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.

SUBMITTER: Mousavi S

PROVIDER: S-EPMC7823290 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Preclinical Evaluation of Oral Urolithin-A for the Treatment of Acute Campylobacteriosis in Campylobacter jejuni Infected Microbiota-Depleted IL-10-/- Mice.

Mousavi Soraya S Weschka Dennis D Bereswill Stefan S Heimesaat Markus M MM

Pathogens (Basel, Switzerland) 20201223 1

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 incl ...[more]

PMID: 33374868

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Project description:Campylobacter jejuni infection produces a spectrum of clinical presentations in humans--including asymptomatic carriage, watery diarrhea, and bloody diarrhea--and has been epidemiologically associated with subsequent autoimmune neuropathies. This microorganism is genetically variable and possesses genetic mechanisms that may contribute to variability in nature. However, relationships between genetic variation in the pathogen and variation in disease manifestation in the host are not understood. We took a comparative experimental approach to explore differences among different C. jejuni strains and studied the effect of diet on disease manifestation in an interleukin-10 deficient mouse model.In the comparative study, C57BL/6 interleukin-10-/- mice were infected with seven genetically distinct C. jejuni strains. Four strains colonized the mice and caused disease; one colonized with no disease; two did not colonize. A DNA:DNA microarray comparison of the strain that colonized mice without disease to C. jejuni 11168 that caused disease revealed that putative virulence determinants, including loci encoding surface structures known to be involved in C. jejuni pathogenesis, differed from or were absent in the strain that did not cause disease. In the experimental study, the five colonizing strains were passaged four times in mice. For three strains, serial passage produced increased incidence and degree of pathology and decreased time to develop pathology; disease shifted from watery to bloody diarrhea. Mice kept on an ~6% fat diet or switched from an approximately 12% fat diet to an approximately 6% fat diet just before infection with a non-adapted strain also exhibited increased incidence and severity of disease and decreased time to develop disease, although the effects of diet were only statistically significant in one experiment.C. jejuni strain genetic background and adaptation of the strain to the host by serial passage contribute to differences in disease manifestations of C. jejuni infection in C57BL/6 IL-10-/- mice; differences in environmental factors such as diet may also affect disease manifestation. These results in mice reflect the spectrum of clinical presentations of C. jejuni gastroenteritis in humans and contribute to usefulness of the model in studying human disease.

Project description:Campylobacter jejuni is the most common bacterial cause of foodborne zoonosis in the European Union. Infections are often linked to the consumption and handling of poultry meat. The aim of the present study was to investigate the caecal microbiota of birds infected with C. jejuni at different ages. Therefore, a total of 180 birds of the laying hybrid Lohmann Brown-Classic were housed in 12 subgroups of 15 animals each in three performed repetitions. Three birds per subgroup were experimentally infected with C. jejuni at an age of about 21 days and about 78 days (4.46 ± 0.35 log10 CFU/bird). Twenty-one days after experimental infection, microbiome studies were performed on 72 caecal samples of dissected birds (three primary infected and three further birds/subgroup). Amplification within the hypervariable region V 4 of the 16S rRNA gene was performed and sequenced with the Illumina MiSeq platform. Statistical analyses were performed using SAS® Enterprise Guide® (version 7.1) and R (version 3.5.2). Both factors, the experimental replication (p < 0.001) and the chickens' age at infection (p < 0.001) contributed significantly to the differences in microbial composition of the caecal samples. The factor experimental replication explained 24% of the sample's variability, whereas the factor age at infection explained 14% thereof. Twelve of 32 families showed a significantly different count profile between the two age groups, whereby strongest differences were seen for seven families, among them the family Campylobacteraceae (adjusted p = 0.003). The strongest difference between age groups was seen for a bacterial species that is assigned to the genus Turicibacter which in turn belongs to the family Erysipelotrichaceae (adjusted p < 0.0001). Correlation analyses revealed a common relationship in both chicken ages at infection between the absolute abundance of Campylobacteraceae and Alcaligenaceae, which consists of the genus Parasutterella. In general, concentrations of particular volatile fatty acids (VFA) demonstrated a negative correlation to absolute abundance of Campylobacteraceae, whereby the strongest link was seen for n-butyrate (-0.51141; p < 0.0001). Despite performing consecutive repetitions, the factor experimental replication contributed more to the differences of microbial composition in comparison to the factor age at infection.

Project description:Human Campylobacter jejuni-infections are progressively increasing worldwide. Despite their high prevalence and socioeconomic impact the underlying mechanisms of pathogen-host-interactions are only incompletely understood. Given that the innate immune receptor nucleotide-oligomerization-domain-2 (Nod2) is involved in clearance of enteropathogens, we here evaluated its role in murine campylobacteriosis. To address this, we applied Nod2-deficient IL-10-/- (Nod2-/- IL-10-/-) mice and IL-10-/- counterparts both with a depleted intestinal microbiota to warrant pathogen-induced enterocolitis. At day 7 following peroral C. jejuni strain 81-176 infection, Nod2 mRNA was down-regulated in the colon of secondary abiotic IL-10-/- and wildtype mice. Nod2-deficiency did neither affect gastrointestinal colonization nor extra-intestinal and systemic translocation properties of C. jejuni. Colonic mucin-2 mRNA was, however, down-regulated upon C. jejuni-infection of both Nod2-/- IL-10-/- and IL-10-/- mice, whereas expression levels were lower in infected, but also naive Nod2-/- IL-10-/- mice as compared to respective IL-10-/- controls. Remarkably, C. jejuni-infected Nod2-/- IL-10-/- mice were less compromised than IL-10-/- counterparts and displayed less distinct apoptotic, but higher regenerative cell responses in colonic epithelia. Conversely, innate as well as adaptive immune cells such as macrophages and monocytes as well as T lymphocytes and regulatory T-cells, respectively, were even more abundant in large intestines of Nod2-/- IL-10-/- as compared to IL-10-/- mice at day 7 post-infection. Furthermore, IFN-? concentrations were higher in ex vivo biopsies derived from intestinal compartments including colon and mesenteric lymph nodes as well as in systemic tissue sites such as the spleen of C. jejuni infected Nod2-/- IL-10-/- as compared to IL10-/- counterparts. Whereas, at day 7 postinfection anti-inflammatory IL-22 mRNA levels were up-regulated, IL-18 mRNA was down-regulated in large intestines of Nod2-/- IL-10-/- vs. IL-10-/- mice. In summary, C. jejuni-infection induced less clinical signs and apoptosis, but more distinct colonic pro- and (of note) anti-inflammatory immune as well as regenerative cell responses in Nod2 deficient IL-10-/- as compared to IL-10-/- control mice. We conclude that, even though colonic Nod2 mRNA was down-regulated upon pathogenic challenge, Nod2-signaling is essentially involved in the well-balanced innate and adaptive immune responses upon C. jejuni-infection of secondary abiotic IL-10-/- mice, but does neither impact pathogenic colonization nor translocation.

Project description:Campylobacter jejuni is a major foodborne pathogen that is increasingly found worldwide and that is transmitted to humans through meat or dairy products. A detailed understanding of the prevalence and characteristics of C. jejuni in dairy cattle farms, which are likely to become sources of contamination, is imperative and is currently lacking. In this study, a total of 295 dairy cattle farm samples from 15 farms (24 visits) in Korea were collected. C. jejuni prevalence at the farm level was 60% (9/15) and at the animal level was 23.8% (68/266). Using the multivariable generalized estimating equation (GEE) model based on farm-environmental factors, we estimated that a high density of cattle and average environmental temperature (7 days prior to sampling) below 24°C affects the presence and survival of C. jejuni in the farm environment. Cattle isolates, together with C. jejuni from other sources (chicken and human), were genetically characterized based on analysis of 10 virulence and survival genes. A total of 19 virulence profile types were identified, with type 01 carrying eight genes (all except hcp and virB11) being the most prevalent. The prevalence of virB11 and hcp was significantly higher in isolates from cattle than in those from other sources (p < 0.05). Multilocus sequence typing (MLST) of C. jejuni isolates from three different sources mainly clustered in the CC-21 and CC-48. Within the CC-21 and CC-48 clusters, cattle isolates shared an indistinguishable pattern with human isolates according to pulsed-field gel electrophoresis (PFGE) and flaA-restriction fragment length polymorphism (RFLP) typing. This suggests that CC-21 and CC-48 C. jejuni from dairy cattle are genetically related to clinical campylobacteriosis isolates. In conclusion, the farm environment influences the presence and survival of C. jejuni, which may play an important role in cycles of cattle re-infection, and dairy cattle represent potential reservoirs of human campylobacteriosis. Thus, environmental management practices could be implemented on cattle farms to reduce the shedding of C. jejuni from cattle, subsequently reducing the potential risk of the spread of cattle-derived C. jejuni to humans through the food chain.

Project description:Human campylobacteriosis constitutes a zoonotic food-borne disease and a progressively rising health burden of significant socioeconomic impact. We have recently shown that conventional mice are protected from Campylobacter jejuni infection, which was not the case for human microbiota associated (hma) mice indicating that the host-specific gut microbiota composition primarily determines susceptibility to or resistance against C. jejuni infection. In our present preclinical intervention study we addressed whether gut microbiota changes in stably C. jejuni infected hma mice following murine fecal microbiota transplantation (mFMT) could alleviate pathogen-induced immune responses. To accomplish this, secondary abiotic C57BL/6 mice were generated by broad-spectrum antibiotic treatment, perorally reassociated with a complex human gut microbiota and challenged with C. jejuni by gavage. Seven days later C. jejuni infected hma mice were subjected to peroral mFMT on 3 consecutive days. Within a week post-mFMT fecal pathogenic burdens had decreased by two orders of magnitude, whereas distinct changes in the gut microbiota composition with elevated numbers of lactobacilli and bifidobacteria could be assessed. In addition, mFMT resulted in less C. jejuni induced apoptotic responses in colonic epithelia, reduced numbers of macrophages and monocytes as well as of T lymphocytes in the large intestinal mucosa and lamina propria and in less distinct intestinal pro-inflammatory cytokine secretion as compared to mock challenge. Strikingly, inflammation dampening effects of mFMT were not restricted to the intestinal tract, but could also be observed systemically as indicated by elevated serum concentrations of pro-inflammatory cytokines such as TNF-α, IL-12p70, and IL-6 in C. jejuni infected hma mice of the mock, but not the mFMT cohort. In conclusion, our preclinical mFMT intervention study provides evidence that changes in the gut microbiota composition which might be achieved by pre- or probiotic formulations may effectively lower intestinal C. jejuni loads, dampen both, pathogen-induced intestinal and systemic inflammatory sequelae and may represent a useful tool to treat continuous shedding of C. jejuni by asymptomatic carriers which is critical in the context of food production, hospitalization and immunosuppression.

Dataset Information

Preclinical Evaluation of Oral Urolithin-A for the Treatment of Acute Campylobacteriosis in Campylobacter jejuni Infected Microbiota-Depleted IL-10^-/- Mice.

Publications

Preclinical Evaluation of Oral Urolithin-A for the Treatment of Acute Campylobacteriosis in <i>Campylobacter jejuni</i> Infected Microbiota-Depleted IL-10<sup>-/-</sup> Mice.

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