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Toll-Like Receptor-4 Dependent Intestinal and Systemic Sequelae Following Peroral Campylobacter coli Infection of IL10 Deficient Mice Harboring a Human Gut Microbiota.

ABSTRACT: 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.

SUBMITTER: Klove S

PROVIDER: S-EPMC7281621 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Toll-Like Receptor-4 Dependent Intestinal and Systemic Sequelae Following Peroral Campylobacter coli Infection of IL10 Deficient Mice Harboring a Human Gut Microbiota.

Kløve Sigri S Genger Claudia C Mousavi Soraya S Weschka Dennis D Bereswill Stefan S Heimesaat Markus M MM

Pathogens (Basel, Switzerland) 20200518 5

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 campylobacteri ...[more]

PMID: 32443576

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Project description:BackgroundWithin seven days following peroral high dose infection with Toxoplasma gondii susceptible conventionally colonized mice develop acute ileitis due to an underlying T helper cell (Th) -1 type immunopathology. We here addressed whether mice harboring a human intestinal microbiota developed intestinal, extra-intestinal and systemic sequelae upon ileitis induction.Methodology/principal findingsSecondary abiotic mice were generated by broad-spectrum antibiotic treatment and associated with a complex human intestinal microbiota following peroral fecal microbiota transplantation. Within three weeks the human microbiota had stably established in the murine intestinal tract as assessed by quantitative cultural and culture-independent (i.e. molecular 16S rRNA based) methods. At day 7 post infection (p.i.) with 50 cysts of T. gondii strain ME49 by gavage human microbiota associated (hma) mice displayed severe clinical, macroscopic and microscopic sequelae indicating acute ileitis. In diseased hma mice increased numbers of innate and adaptive immune cells within the ileal mucosa and lamina propria and elevated intestinal secretion of pro-inflammatory mediators including IFN-γ, IL-12 and nitric oxide could be observed at day 7 p.i. Ileitis development was accompanied by substantial shifts in intestinal microbiota composition of hma mice characterized by elevated total bacterial loads and increased numbers of intestinal Gram-negative commensals such as enterobacteria and Bacteroides / Prevotella species overgrowing the small and large intestinal lumen. Furthermore, viable bacteria translocated from the inflamed ileum to extra-intestinal including systemic compartments. Notably, pro-inflammatory immune responses were not restricted to the intestinal tract as indicated by increased pro-inflammatory cytokine secretion in extra-intestinal (i.e. liver and kidney) and systemic compartments including spleen and serum.Conclusion/significanceWith respect to the intestinal microbiota composition "humanized" mice display acute ileitis following peroral high dose T. gondii infection. Thus, hma mice constitute a suitable model to further dissect the interactions between pathogens, human microbiota and vertebrate host immunity during acute intestinal inflammation.

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.

Project description:We have recently shown that following peroral low-dose Toxoplasma gondii infection susceptible mice develop subacute ileitis within 10 days. Data regarding long-term intestinal and extra-intestinal sequelae of infection are scarce, however. We therefore challenged conventional C57BL/6 mice with one cyst of T. gondii ME49 strain by gavage and performed a comprehensive immunopathological survey 10, 36, and 57 days later. As early as 10 days post-infection, mice were suffering from subacute ileitis as indicated by mild-to-moderate histopathological changes of the ileal mucosa. Furthermore, numbers of apoptotic and proliferating/regenerating epithelial cells as well as of T and B lymphocytes in the mucosa and lamina propria of the ileum were highest at day 10 post-infection, but declined thereafter, and were accompanied by enhanced pro-inflammatory mediator secretion in ileum, colon and mesenteric lymph nodes that was most pronounced during the early phase of infection. In addition, subacute ileitis was accompanied by distinct shifts in the commensal gut microbiota composition in the small intestines. Remarkably, immunopathological sequelae of T. gondii infection were not restricted to the intestines, but could also be observed in extra-intestinal tissues including the liver, kidneys, lungs, heart and strikingly, in systemic compartments that were most prominent at day 10 post-infection. We conclude that the here provided long-term kinetic survey of immunopathological sequalae following peroral low-dose T. gondii infection provides valuable corner stones for a better understanding of the complex interactions within the triangle relationship of (parasitic) pathogens, the host immunity and the commensal gut microbiota during intestinal inflammation. The low-dose T. gondii infection model may be applied as valuable gut inflammation model in future pre-clinical studies in order to test potential treatment options for intestinal inflammatory conditions in humans.

Project description:The World Health Organization has rated multi-drug resistant (MDR) Pseudomonas aeruginosa as serious threat for human health. It is, however, unclear, whether intestinal MDR P. aeruginosa carriage is associated with inflammatory responses in intestinal or even systemic compartments. In the present study, we generated with respect to their microbiota "humanized" mice by human fecal microbiota transplantation of secondary abiotic mice. Following peroral challenge with a clinical P. aeruginosa isolate on two consecutive days, mice harboring a human or murine microbiota were only partially protected from stable intestinal P. aeruginosa colonization given that up to 78% of mice were P. aeruginosa-positive at day 28 post-infection (p.i.). Irrespective of the host-specificity of the microbiota, P. aeruginosa colonized mice were clinically uncompromised. However, P. aeruginosa colonization resulted in increased intestinal epithelial apoptosis that was accompanied by pronounced proliferative/regenerative cell responses. Furthermore, at day 7 p.i. increased innate immune cell populations such as macrophages and monocytes could be observed in the colon of mice harboring either a human or murine microbiota, whereas this held true at day 28 p.i. for adaptive immune cells such as B lymphocytes in both the small and large intestines of mice with murine microbiota. At day 7 p.i., pro-inflammatory cytokine secretion was enhanced in the colon and mesenteric lymph nodes, whereas the anti-inflammatory cytokine IL-10 was down-regulated in the former at day 28 p.i. Strikingly, cytokine responses upon intestinal P. aeruginosa colonization were not restricted to the intestinal tract, but could also be observed systemically, given that TNF and IFN-? concentrations were elevated in spleens as early as 7 days p.i., whereas splenic IL-10 levels were dampened at day 28 p.i. of mice with human microbiota. In conclusion, mere intestinal carriage of MDR P. aeruginosa by clinically unaffected mice results in pro-inflammatory sequelae not only in intestinal, but also systemic compartments.

Dataset Information

Toll-Like Receptor-4 Dependent Intestinal and Systemic Sequelae Following Peroral Campylobacter coli Infection of IL10 Deficient Mice Harboring a Human Gut Microbiota.

Publications

Toll-Like Receptor-4 Dependent Intestinal and Systemic Sequelae Following Peroral <i>Campylobacter coli</i> Infection of IL10 Deficient Mice Harboring a Human Gut Microbiota.

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