Editors' ChoiceINFLAMMATORY BOWEL DISEASE

Colitis from a chubby colon

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Science Translational Medicine  04 Dec 2019:
Vol. 11, Issue 521, eaaz9760
DOI: 10.1126/scitranslmed.aaz9760

Abstract

Neonatal overfeeding causes disruptions in the microbiome and intestinal homeostasis, which precedes colitis development in adulthood.

Children with obesity are likely to develop inflammatory bowel disease (IBD) later in life; the mechanisms involved are elusive. Maternal obesity, which increases the risk of obesity in the offspring due to developmental programming, also increases the susceptibility of the offspring to develop IBD. Nabhani et al. used mouse models exposed to excessive calorie intake to demonstrate that disrupting intestinal maturation during weaning precedes the development of colitis in adulthood.

In the study, the investigators used different mouse models to study the effects of neonatal overfeeding on colitis development during adulthood. The first model compared mice exposed to a high-fat diet (HFD) before weaning or during adulthood prior to chemical induction of colitis. Mice overfed before weaning showed increased susceptibility to developing colitis. These effects were also reproduced in other models, including mice fed with coconut oil before weaning or mothers caged with small litters (the offspring were fed more milk from their mothers before weaning). In these mouse models, excessive calorie intake disrupted intestinal homeostasis during weaning; the animals showed increased expression of proinflammatory markers and increased intestinal permeability.

To test whether early intestinal inflammation during weaning was essential to the later development of colitis, neonatal mice exposed to HFD were treated with antibodies targeting two proinflammatory cytokines, tumor necrosis factor–α (TNF-α) and interferon-γ (IFN-γ), to limit gut inflammation during weaning. Mice treated with these antibodies were less susceptible in developing colitis in later life. The results were replicated in mice similarly treated with a myosin light chain kinase inhibitor to normalize gut permeability before weaning.

During weaning, the colonizing intestinal microbiota shapes the host immune response, which could be influenced by early-life diet. The authors observed that increased intestinal permeability and inflammation associated with neonatal overfeeding were dependent on the microbiota, since exposure to antibiotics along with HFD normalized these intestinal perturbations. The intestines of neonatal HFD-fed mice displayed expansion of sulfide producing bacteria, which degrades the mucus layer of the intestinal epithelium by reducing disulfide bonds of mucins. Administering 5-aminosalicylic acid, an inhibitor of sulfide production from gut bacteria, successfully normalized the inflammatory responses during weaning and limited the susceptibility of the mice to develop colitis in adulthood. Meanwhile, germ-free neonatal mice orally treated with sodium disulfide mimicked the effects of overfeeding in perturbing intestinal homeostasis during weaning and increased colitis development later in life.

These elegant experiments demonstrate that overfeeding in early life disrupts the microbiome and intestinal homeostasis, which influences colitis development in adulthood. Future experiments should investigate whether these mechanisms of inflammation are replicated in humans. However, the study suggests a potential risk factor and preventative measure for the development of colitis and possibly IBD.

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