The data described are consistent with a model where the loss of bacterial compartmentalization initiates an immediate immune inhibitor Vorinostat response from days 5 to 15 as demonstrated by elevated epithelial-derived chemokines and cytokines as well as recruitment of CD3+ T cells, F4/80 macrophages and GR-1/Ly-6g positive granulocytes into the colon. The accumulation and location of bacteria in the tissue correlates with the peak in immune cell infiltration into the tissue on day 21 and subsequent reduction in bacterial numbers. Figure 3 Infiltration of colon by immune cells assessed by immunohistochemistry following DSS damage. Interdependence of bacterial infiltration and host immune response The correlation of bacterial infiltration and immune cell recruitment into the colon led us to examine the causal relationships between the bacteria and the host immune response in the chronic inflammatory phase.

We treated mice with DSS and allowed them to recover to the approximate end of the acute inflammatory phase on day 15. At this time, mice were treated with either dexamethasone to suppress inflammation or with an antibiotic cocktail targeting the bacteria followed by assessment of histological and clinical parameters on day 22 (Figure S3). Both treatments significantly improved the condition of the mice. The gross pathological readouts of inflammation like colon length as well as the associated histological scores significantly improved with either treatment. As expected, antibiotic treatment reduced detection of tissue-associated bacteria.

Interestingly, inhibition of the immune response with dexamethasone also significantly decreased tissue-associated bacterial levels. These data demonstrate interdependence of the tissue-associated bacteria and chronic inflammation observed in the mice day 21 post-DSS – the chronic inflammatory state supports the residence of the commensal flora within the tissue and the resident bacteria play a significant role in the pathologic consequences of inflammation within the host. Nod2 regulates tissue-associated bacterial loads independent of host immunity Having established a clear correlation between environmental damage of the epithelium, host inflammation and the interaction between the commensal flora and the host, we turned our attention to host genetic factors regulating host/commensal interactions.

Pattern recognition receptors (PRR) play an important role in the detection of foreign organisms that Batimastat penetrate host defences and likely play an important role in the recognition and clearance of the tissue-associated bacteria observed in this model. Nod2 is a cytoplasmic PRR that is genetically-associated with Crohn’s disease and has been demonstrated to play an important role in pathogen defence in mouse models [25], [26]. Previous reports have demonstrated that deletion of Nod2 has no impact on the severity of DSS-induced colitis in mice; observations that we reproduced (not shown) [14].