title: SMAD4 haploinsufficiency associates with augmented colonic inflammation in select humans and mice.
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.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Reka
authors.initials: R
authors.lastname: Szigeti
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Pangas
authors.forename: Dorottya
authors.initials: D
authors.lastname: Nagy-Szakal
authors.forename: Scot E
authors.initials: SE
authors.lastname: Dowd
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Shulman
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Olive
authors.forename: Edwina J
authors.initials: EJ
authors.lastname: Popek
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.forename: Richard
authors.initials: R
authors.lastname: Kellermayer
mesh_terms: D000818:Animals; D002648:Child; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000382:microbiology*; D016264:Dextran Sulfate / Q000008:administration & dosage / Q000633:toxicity; D016983:Enterococcus / Q000235:genetics*; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000601:surgery*; D008297:Male; D054892:Metagenome / Q000235:genetics*; D051379:Mice; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics*; D013045:Species Specificity; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D012336:RNA, Ribosomal, 16S; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; D016264:Dextran Sulfate