Commensal-derived probiotics as anti-inflammatory agents

Indigenous bacteria in the mammalian gastrointestinal tract comprise a rich ecosystem of organisms and secreted factors with direct effects on intestinal immunity. Commensal constituents of the gastrointestinal microbiota include the lactic acid bacteria such as Lactobacillus species. The genus Lactobacillus includes a restricted set of intestine-indigenous species from a pool of more than 100 Lactobacillus species. Scientific challenges include the abilities to define commensal species and specific bacterial clones with specific immunomodulatory activities. Our studies have resulted in the identification of Lactobacillus strains from mice and humans with potent anti-inflammatory effects. Commensal-derived Lactobacillus strains were isolated from healthy mice lacking evidence of intestinal inflammation and identified as candidate probiotics due to immunomodulatory activities. Less than 10% of commensal strains isolated from humans and mice had potent tumor necrosis factor (TNF)-α-inhibitory activity. These strains down-regulated the production of TNF-α by macrophage cell lines and successfully suppressed inflammation in mouse colitis models. Human-derived Lactobacillus reuteri strains have been identified with potent human TNF-α-inhibitory effects on lipopolysaccharide (LPS)-activated human myeloid cell lines and primary monocyte-derived macrophages from children with Crohn's disease. Human commensal-derived probiotics suppressed the transcription of human TNF-α by inhibition of MAP kinase signaling via AP-1. Alternatively, commensal-derived human L. reuteri strains suppressed nuclear factor (NF)-κB signaling in TNF-α-stimulated human myeloid cells. Suppression of NF-κB signaling in TNF-α-activated immune cells promotes apoptosis of activated immune cells and provides a novel mechanism for anti-inflammatory action in the mammalian intestine. In summary, commensal-derived probiotics provide opportunities for understanding mechanisms of microbial-host interactions in the gastrointestinal tract. By understanding mechanisms of probiosis, novel therapeutic strategies may be developed for prevention and treatment of inflammatory bowel disease and other intestinal disorders.