Human TNF and MCP-1 suppression by probiotic L. reuteri was strain-dependent, and the activation of c-Jun and AP-1 represent primary targets for probiotic-mediated suppression of TNF transcription. This report emphasizes the clonal nature of immunoprobiosis and delineation of a specific immunomodulatory mechanism for probiotic strain selection in future inflammatory bowel disease-oriented clinical trials.
Because an increase in flow rate accelerates intestinal transit, a reduction in the flow rate of formula delivery is recommended frequently for treatment of diarrhea that develops during enteral feeding. Because intestinal transit is slowed by nutrient-triggered inhibitory feedback, the rate of intestinal transit during enteral feeding may depend on a balance between the accelerating effect of flow and the inhibiting effect of the nutrient load. The addition of fiber to a formula may alter this balance. By delaying absorption of nutrients, fiber may extend the length of small intestine exposed to nutrients and thereby trigger more intense inhibitory feedback. To determine whether the addition of fiber favors nutrient-triggered inhibition over flow-driven acceleration, we studied intestinal transit after perfusion of a low-residue enteral formula compared with a fiber-supplemented formula at two perfusion rates (50 or 100 mL/h for 2 h) into the duodenum of dogs each with both a duodenal and midgut fistula. With the low-residue formula, intestinal transit accelerated when the flow rate increased from 50 to 100 mL/h (P < 0.05). With the fiber-supplemented formula, however, intestinal transit was inhibited regardless of the flow rate. To determine whether the fiber-supplemented formula inhibited intestinal transit by displacing nutrients distally, we compared intestinal transit when the two formulas, delivered at 100 mL/h, were diverted completely at the midgut fistula. Intestinal transit of the fiber-supplemented formula increased by 400%, eliminating the difference in intestinal transit speed between the two formulas. We concluded that the fiber-supplemented formula slowed intestinal transit by intensifying inhibitory feedback from the distal gut.
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)-a-inhibitory activity. These strains down-regulated the production of TNF-a by macrophage cell lines and successfully suppressed inflammation in mouse colitis models. Human-derived Lactobacillus reuteri strains have been identified with potent human TNF-a-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-a by inhibition of MAP kinase signaling via AP-1. Alternatively, commensal-derived human L. reuteri strains suppressed nuclear factor (NF)-kB signaling in TNF-a-stimulated human myeloid cells. Suppression of NF-kB signaling in TNF-a-activated immune cells promotes apoptosis of activated immune cells and provides a novel mechanism for anti-inflammatory action in the mammalian intestine. In summary, commensalderived probiotics provide opportunities for understanding mechanisms of microbialÁhost 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.
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