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Background & Aims: The commensal microbiota is believed to have an important role in regulating immune responsiveness and preventing intestinal inflammation. Intestinal microbes produce signals that regulate inflammation via Toll-like receptor (TLR) signaling, but the mechanisms of this process are poorly understood. We investigated the role of the anti-inflammatory cytokine interleukin (IL)-10 in this signaling pathway using a mouse model of colitis. Methods: Clinical, histopathologic, and functional parameters of intestinal inflammation were evaluated in TLR4−/−, IL-10−/−, and TLR4−/− × IL-10−/− mice that were free of specific pathogens and in TLR4−/− × IL-10−/− mice following eradication and reintroduction of Helicobacter hepaticus. Regulatory T-cell (Treg) function was evaluated by crossing each of the lines with transgenic mice that express green fluorescent protein under control of the endogenous regulatory elements of Foxp3. Apoptotic cells in the colonic lamina propria were detected by a TUNEL assay. Results: TLR4-mediated signals have 2 interrelated roles in promoting inflammation in TLR4−/− × IL-10−/− mice. In the absence of TLR4-mediated signals, secretion of proinflammatory and immunoregulatory cytokines is dysregulated. Tregs (Foxp3+) that secrete interferon-γ and IL-17 accumulate in the colonic lamina propria of TLR4−/− × IL-10−/− mice and do not prevent inflammation. Aberrant control of epithelial cell turnover results in the persistence of antigen-presenting cells that contain apoptotic epithelial fragments in the colonic lamina propria of Helicobacter-infected TLR4−/− mice. Conclusions: In mice that lack both IL-10- and TLR4-mediated signals, aberrant regulatory T-cell function and dysregulated control of epithelial homeostasis combine to exacerbate intestinal inflammation. [Copyright &y& Elsevier]