Role of the bacterial gut microbiota and innate immunity in Campylobacter jejuni-enteritis: Investigations in gnotobiotic mouse models of inflammation

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Enteritis caused by C. jejuni is one of the most widespread diarrhoeal diseases worldwide. In industrialized nations, the clinical spectrum of C. jejuni-infection is most commonly characterized by acute severe inflammatory responses in the lower intestinal tract accom-panied by watery diarrhoea including bloody stools, fever and abdominal pain. The inflam-mation is initiated by infiltration of the intestinal mucosa with granulocytes and macropha-ges. These innate immune cells trigger inflammatory responses and perpetuate tissue de-struction leading to a severe disturbance of the intestinal barrier functions presented by the healthy mucosa to defend against non-pathogenic bacteria of the natural commensal inte-stinal flora. In consequence, not only C. jejuni but also other translocating gut bacteria infil-trate submucosal tissues sites and are coming in direct contact with immune cells thereby aggravating inflammation. This suggests that the innate immune system and the normal gut flora might play a key role in C. jejuni-induced immunopathology by taking part in the modulation of the inflammatory process. Several clinical studies have shown that in patients suffering from inflammatory bowel diseases non-pathogenic commensal bacteria of the normal intestinal flora might represent critical components in the perpetuation of intestinal inflammation. However, such aspects of intestinal ecology and innate immunity have not been studied in C. jejuni-enteritis so far. Bacterial molecules aggravate or sup-press inflammatory responses by binding to Toll-like receptors (TLRs) or the NOD2-pro-tein, both of which are expressed at high levels by cells of the innate immune system such as granulocytes, macrophages or Paneth cells, respectively. The resulting signal transduc-tion events initiate pro-inflammatory or anti-inflammatory cytokine responses modulating the reactivity of innate and adaptive immunity, including T- and B-cells. Actual research in our group and others has demonstrated that TLRs and NOD2 play important roles in the modulation of acute and chronic inflammatory processes in the gastrointestinal tract. Based upon these findings we hypothesize that both, the commensal bacterial gut micro-flora and the innate immune system, contribute to the perpetuation or suppression of C. jejuni-enteritis. We will use gnotobiotic mouse models to investigate the interplay of the intestinal microflora with C. jejuni colonization and pathogenesis and to study the role of innate immunity in C. jejuni-enteritis. The influences of host innate immunity on C. jejuni-enteritis will be studied in mice with well-defined defects in the TLR2, TLR4, TLR9, or NOD2 genes as well as genes coding for the signal-transducing proteins MyD88 or TRIF. The corres-ponding mechanisms will be further characterized in vitro. C. jejuni-colonization and intestinal inflammation will be investigated in gnotobiotic mice carrying defined gut bacteria or challenged by bacterial compounds. A subsequent treatment of the corresponding animals with purified TLR- and/or NOD2-ligands will be used in order to fulfil the Koch`s postulates and to evaluate if TLR-/NOD-agonists/ antagonists, defined gut bacteria, or modulation of the intestinal flora might be suitable to suppress immune activation and reduce acute inflammatory responses in the course of C. jejuni-enteritis. Finally, we aim to determine the influences of intestinal inflammatory responses on colonization resistance displayed against C. jejuni in our well-established mouse models for ileitis and colitis.