title: Intestinal dysbiosis contributes to the delayed gastrointestinal transit in high-fat diet fed mice.
abstract: OBJECTIVE
  High-fat diet (HFD) feeding is associated with gastrointestinal motility disorders. We recently reported delayed colonic motility in mice fed a HFD mice for 11 weeks. In this study, we investigated the contributing role of gut microbiota in HFD-induced gut dysmotility.
  
  
  METHODS
  Male C57BL/6 mice were fed a HFD (60% kcal fat) or a regular/control diet (RD) (18% kcal fat) for 13 weeks. Serum and fecal endotoxin levels were measured, and relative amounts of specific gut bacteria in the feces assessed by real time PCR. Intestinal transit was measured by fluorescent-labeled marker and bead expulsion test. Enteric neurons were assessed by immunostaining. Oligofructose (OFS) supplementation with RD or HFD for 5 weeks was also studied.In vitrostudies were performed using primary enteric neurons and an enteric neuronal cell line.
  
  
  RESULTS
  HFD-fed mice had reduced numbers of enteric nitrergic neurons and exhibited delayed gastrointestinal transit compared to RD-fed mice. HFD-fed mice had higher fecal Firmicutes andEscherichia coliand lower Bacteroidetes compared to RD-fed mice. OFS supplementation protected against enteric nitrergic neurons loss in HFD-fed mice, and improved intestinal transit time. OFS supplementation resulted in a reductions in fecal Firmicutes andEscherichia coliand serum endotoxin levels.In vitro, palmitate activation of TLR4 induced enteric neuronal apoptosis in a p-JNK1 dependent pathway. This apoptosis was prevented by a JNK inhibitor and in neurons fromTLR4-/-mice.
  
  
  CONCLUSIONS
  Together our data suggest that intestinal dysbiosis in HFD fed mice contribute to the delayed intestinal motility by inducing a TLR4-dependant neuronal loss. Manipulation of gut microbiota with OFS improved intestinal motility in HFD mice.
authors.affiliation: Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA.
authors.forename: Mallappa
authors.initials: M
authors.lastname: Anitha
authors.affiliation: Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA.
authors.forename: François
authors.initials: F
authors.lastname: Reichardt
authors.affiliation: Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA.
authors.forename: Sahar
authors.initials: S
authors.lastname: Tabatabavakili
authors.affiliation: Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA.
authors.forename: Behtash Ghazi
authors.initials: BG
authors.lastname: Nezami
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Medical Sciences, Georgia State University, GA, USA.
authors.forename: Benoit
authors.initials: B
authors.lastname: Chassaing
authors.affiliation: Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Mwangi
authors.affiliation: Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA.
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Medical Sciences, Georgia State University, GA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gewirtz
authors.affiliation: Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Srinivasan
keywords: LPS; Myenteric neurons; TLR4; colon transit; gut microbiota; palmitate