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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #307515
Title: SMAD4 haploinsufficiency associates with augmented colonic inflammation in select humans and mice

Author
item SZIGETI, REKA - Baylor College Of Medicine
item PANGAS, STEPHANIE - Baylor College Of Medicine
item NAGY-SZAKAL, DOROTTYA - Baylor College Of Medicine
item DOWD, SCOT - Molecular Research Lp (MR DNA)
item SHULMAN, ROBERT - Children'S Nutrition Research Center (CNRC)
item OLIVE, ANTHONY - Baylor College Of Medicine
item POPEK, EDWINA - Baylor College Of Medicine
item FINEGOLD, MILTON - Baylor College Of Medicine
item KELLERMAYER, RICHARD - Baylor College Of Medicine

Submitted to: Annals of Clinical and Laboratory Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/1/2012
Publication Date: 10/1/2012
Citation: Szigeti, R., Pangas, S.A., Nagy-Szakal, D., Dowd, S.E., Shulman, R.J., Olive, A.P., Popek, E.J., Finegold, M.J., Kellermayer, R. 2012. SMAD4 haploinsufficiency associates with augmented colonic inflammation in select humans and mice. Annals of Clinical and Laboratory Science. 42(4):401-408.

Interpretive Summary: Some degree of inflammation is normal in the intestine. However, in certain disease states, sometimes worsened by diet, the amount of inflammation in the intestine increases and causes illness. In this study, prompted by observations in humans, we found that a genetic alteration increases the risk of having severe intestinal inflammation in mice. The increased inflammation was associated with an increase in specific types of bacteria in the intestine. This finding will help researchers identify what role nutrition plays on certain bacteria in the intestine.

Technical Abstract: SMAD4 is a common mediator of the TGF-beta signaling pathway. One of the members of this pathway, TGF-beta 1, has an important role in controlling gut inflammation in relation to the continuous stimulation of the intestinal microbiota. SMAD4 haploinsufficiency in humans has been linked to juvenile polyposis hereditary hemorrhagic telangiectasia syndrome (JP/HHT; OMIM#17505). Hematochezia and colonic mucosal inflammation suggestive of inflammatory bowel diseases (IBD) have been reported in JP/HHT. Stimulated by recent experience with two affected pediatric patients presented here, we explored the potential role of Smad4 haploinsufficiency in a murine model of colonic inflammation. Smad4(+/-) mice were maintained on a mixed C57/129SvEv background. Chronic colitis was induced with repeated administration of dextran sulfate sodium (DSS) in drinking water. The colonic mucosal microbiota was interrogated by massively parallel pyrosequencing of the bacterial 16S rRNA gene. 66.7% of Smad4(+/-) mice were sensitive to DSS colitis compared to 14.3% of wild type (Chi-Square p=0.036). The augmented colitis was associated with microbiota separation in the Smad4(+/-) mice. Enterococcus and Enterococcus faecalis specifically was increased in abundance in the colitis-prone animals. Smad4 haploinsufficiency can associate with increased susceptibility to large bowel inflammation in mammals with variable penetrance in association with the colonic mucosal microbiota. These findings may reveal implications not only towards colonic inflammation in the setting of SMAD4 haploinsufficiency, but for colorectal cancer as well.