Dataset Information

Less Pronounced Immunopathological Responses Following Oral Butyrate Treatment of Campylobacter jejuni-Infected Mice.

ABSTRACT: 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 10⁹ 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.

SUBMITTER: Du K

PROVIDER: S-EPMC9609162 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Less Pronounced Immunopathological Responses Following Oral Butyrate Treatment of Campylobacter jejuni-Infected Mice.

Du Ke K Foote Minnja S MS Mousavi Soraya S Buczkowski Agnes A Schmidt Sebastian S Bereswill Stefan S Heimesaat Markus M MM

Microorganisms 20220930 10

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. The ...[more]

PMID: 36296229

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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-γ 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:BackgroundCampylobacter jejuni infections constitute serious threats to human health with increasing prevalences worldwide. Our knowledge regarding the molecular mechanisms underlying host-pathogen interactions is still limited. Our group has established a clinical C. jejuni infection model based on abiotic IL-10-/- mice mimicking key features of human campylobacteriosis. In order to further validate this model for unraveling pathogen-host interactions mounting in acute disease, we here surveyed the immunopathological features of the important C. jejuni virulence factors FlaA and FlaB and the major adhesin CadF (Campylobacter adhesin to fibronectin), which play a role in bacterial motility, protein secretion and adhesion, respectively.Methods and resultsTherefore, abiotic IL-10-/- mice were perorally infected with C. jejuni strain 81-176 (WT) or with its isogenic flaA/B (ΔflaA/B) or cadF (ΔcadF) deletion mutants. Cultural analyses revealed that WT and ΔcadF but not ΔflaA/B bacteria stably colonized the stomach, duodenum and ileum, whereas all three strains were present in the colon at comparably high loads on day 6 post-infection. Remarkably, despite high colonic colonization densities, murine infection with the ΔflaA/B strain did not result in overt campylobacteriosis, whereas mice infected with ΔcadF or WT were suffering from acute enterocolitis at day 6 post-infection. These symptoms coincided with pronounced pro-inflammatory immune responses, not only in the intestinal tract, but also in other organs such as the liver and kidneys and were accompanied with systemic inflammatory responses as indicated by increased serum MCP-1 concentrations following C. jejuni ΔcadF or WT, but not ΔflaA/B strain infection.ConclusionFor the first time, our observations revealed that the C. jejuni flagellins A/B, but not adhesion mediated by CadF, are essential for inducing murine campylobacteriosis. Furthermore, the secondary abiotic IL-10-/- infection model has been proven suitable not only for detailed investigations of immunological aspects of campylobacteriosis, but also for differential analyses of the roles of distinct C. jejuni virulence factors in induction and progression of 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.

Dataset Information

Less Pronounced Immunopathological Responses Following Oral Butyrate Treatment of Campylobacter jejuni-Infected Mice.

Publications

Less Pronounced Immunopathological Responses Following Oral Butyrate Treatment of <i>Campylobacter</i> <i>jejuni</i>-Infected Mice.

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Less Pronounced Immunopathological Responses Following Oral Butyrate Treatment of Campylobacter&nbsp;jejuni-Infected Mice.

Publications

Less Pronounced Immunopathological Responses Following Oral Butyrate Treatment of <i>Campylobacter</i> <i>jejuni</i>-Infected Mice.

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OmicsDI is part of the ELIXIR infrastructure

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Less Pronounced Immunopathological Responses Following Oral Butyrate Treatment of Campylobacter jejuni-Infected Mice.