Tumor Necrosis Factor Induces Developmental Stage-Dependent Structural Changes in the Immature Small Intestine

Abstract

Background. Premature infants are commonly subject to intestinal inflammation. Since the human small intestine does not reach maturity until term gestation, premature infants have a unique challenge, as either acute or chronic inflammation may alter the normal development of the intestinal tract. Tumor necrosis factor (TNF) has been shown to acutely alter goblet cell numbers and villus length in adult mice. In this study we tested the effects of TNF on villus architecture and epithelial cells at different stages of development of the immature small intestine. Methods. To examine the effects of TNF-induced inflammation, we injected acute, brief, or chronic exposures of TNF in neonatal and juvenile mice. Results. TNF induced significant villus blunting through a TNF receptor-1 (TNFR1) mediated mechanism, leading to loss of villus area. This response to TNFR1 signaling was altered during intestinal development, despite constant TNFR1 protein expression. Acute TNF-mediated signaling also significantly decreased Paneth cells. Conclusions. Taken together, the morphologic changes caused by TNF provide insight as to the effects of inflammation on the developing intestinal tract. Additionally, they suggest a mechanism which, coupled with an immature immune system, may help to explain the unique susceptibility of the immature intestine to inflammatory diseases such as NEC.

The role of intestinal epithelial barrier function in the development of NEC

“…Coutinho, et. al, found decreased numbers of [93][94][95] While Salzman, et. al, showed increased Paneth cell numbers, defensin production from these cells was deficient.…”

The Paneth Cell: The Curator and Defender of the Immature Small Intestine

“…As the microbiome becomes more dysbiotic, it suppresses anti-inflammatory mechanisms creating a cycle of increasing intestinal inflammation (136). This increasing inflammation can then impact Paneth cell biology leading to a loss in Paneth cells (14,129,137). In an already dysbiotic environment, this combination is exactly the milieu that is modeled in our animal model and predisposes to development of injury.…”

“…This creates a feedback loop for sustaining and increasing the pro-inflammatory state in the immature intestine. Previous work from our lab has shown that intestinal inflammation can reduce intestinal mucus production and cause loss of Paneth cells (112,129). (C) Loss of these important chemical and physical aspects of innate immunity allows bacteria to move from the mucus layer of the intestinal lumen and gain closer proximity to the epithelial surface, (D) followed eventually by attachment and invasion of the epithelium.…”

“…As the proportion of commensal bacteria such as Firmicutes and Bacteroidetes decrease, the production of anti-inflammatory mediators also decreases which further facilitates increased inflammation and dysbiosis. Our laboratory has previously shown that in the immature murine small intestine, exposure to inflammation can significantly decrease the density and function of Paneth cells (129)(130)(131).…”

The Role of Interleukin-6 and Interleukin-8 Circulating Cytokines in Differentiating between Feeding Intolerance and Necrotizing Enterocolitis in Preterm Infants

“…NEC is predominantly a syndrome of acute intestinal necrosis with intestinal inflammation, affecting 5 to 15% of very low birth weight (VLBW) infants with an overall mortality rate of 10 to 30%. [3][4][5][6] The relationship, if any, of NEC to FI is unknown, but because of their similar initial clinical courses, FI is also referred to as stage I or suspect NEC. Early symptoms of NEC are often nonspecific, and the diagnosis of NEC can be challenging.…”