Abstract
Colonizing bacteria interacting with the immature, unlike the mature, human intestine favors inflammation over immune homeostasis. As a result, ten percent of premature infants under 1500 grams weight develop an inflammatory necrosis of the intestine after birth, e.g., necrotizing enterocolitis (NEC). NEC is a major health problem in this population causing extensive morbidity and mortality and an enormous expenditure of health care dollars. NEC can be prevented by giving preterm infants their mother’s expressed breast milk or ingesting selective probiotic organisms. Vaginally delivered, breast fed newborns develop health promoting bacteria (“pioneer” bacteria) which preferentially stimulate intestinal host defense and anti-inflammation. One such “pioneer” organism is Bacteroides fragilis with a polysaccharide (PSA) on its capsule. B. fragilis has been shown developmentally in intestinal lymphocytes and dendritic cells to produce a balanced T-helper cell (TH1/TH2) response and to reduce intestinal inflammation by activity through the TLR2 receptor stimulating IL-10 which inhibits IL-17 causing inflammation. No studies have been done on the role of B. fragilis PSA on fetal enterocytes and its increased inflammation. Accordingly, using human and mouse fetal intestinal models, we have shown that B. fragilis with PSA and PSA alone inhibits IL-1β-induced IL-8 inflammation in fetal and NEC intestine. We have also begun to define the mechanism for this unique inflammation noted in fetal intestine. We have shown that B. fragilis PSA anti-inflammation requires both the TLR2 and TLR4 receptor and is in part mediated by the AP1 transcription factor (TLR2) which is developmentally regulated. These observations may help to devise future preventative treatments of premature infants against NEC.
Highlights
Colonizing bacteria interacting with the immature human intestine, unlike the mature intestine, favors inflammation over homeostasis [1,2]
In order to confirm that the B. fragilis-PSA effect existed in a primary cell line isolated from the resected small intestine of a necrotizing enterocolitis (NEC) patient at surgery, NEC-IECs were incubated with PSA and stimulated with IL-1β
This study shows for the first time that Bacteroides fragilis with PSA and PSA alone has an antiinflammatory effect on IL-1β stimulation of IL-8 in fetal human enterocytes, NEC enterocytes and fetal mouse small intestine
Summary
Colonizing bacteria interacting with the immature human intestine, unlike the mature intestine, favors inflammation over homeostasis [1,2]. Certain commensal bacteria used as probiotics, when given to newborn prematures can prevent or lessen the severity of NEC [6,7] What is it about the immature intestine interacting with colonizing bacteria that causes this paradoxical response? We hypothesize that commensal bacteria interacting with immature enterocytes can result in either an excessive inflammatory response or an inhibition of inflammation depending on the composition of the immature signaling pathways in the enterocyte. We have shown that a secreted factor from Bifidobacterium infantis (a probiotic preventative of NEC) preferentially downregulates an IL-1β inflammatory stimulus in fetal enterocytes [4,11] These observations suggest that immature enterocytes interacting with commensal bacteria or their secretions have unique inflammatory or anti-inflammatory pathways
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