Anitha Mallappa, Reichardt François, Tabatabavakili Sahar, Nezami Behtash Ghazi, Chassaing Benoit, Mwangi Simon, Vijay-Kumar Matam, Gewirtz Andrew, Srinivasan Shanthi
Department of Digestive Diseases, Emory University School of Medicine, Atlanta & Atlanta VA Medical Center, Decatur, GA, USA.
Center for Inflammation, Immunity & Infection, Institute for Biomedical Medical Sciences, Georgia State University, GA, USA.
Cell Mol Gastroenterol Hepatol. 2016 May;2(3):328-339. doi: 10.1016/j.jcmgh.2015.12.008.
BACKGROUND & AIMS: 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.
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. studies were performed using primary enteric neurons and an enteric neuronal cell line.
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 and and 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 and and serum endotoxin levels. , 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 from mice.
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.
高脂饮食（HFD）与胃肠动力障碍有关。我们最近报道，喂食HFD 11周的小鼠出现结肠动力延迟。在本研究中，我们调查了肠道微生物群在HFD诱导的肠道运动障碍中的作用。
雄性C57BL/6小鼠喂食HFD（60%千卡脂肪）或常规/对照饮食（RD）（18%千卡脂肪）13周。测量血清和粪便内毒素水平，并通过实时PCR评估粪便中特定肠道细菌的相对含量。通过荧光标记物和珠子排出试验测量肠道转运。通过免疫染色评估肠神经元。还研究了用RD或HFD补充低聚果糖（OFS）5周的情况。使用原代肠神经元和肠神经元细胞系进行研究。
与喂食RD的小鼠相比，喂食HFD的小鼠肠内一氧化氮能神经元数量减少，胃肠转运延迟。与喂食RD的小鼠相比，喂食HFD的小鼠粪便中厚壁菌门含量更高，拟杆菌门含量更低。补充OFS可防止喂食HFD的小鼠肠内一氧化氮能神经元丢失，并改善肠道转运时间。补充OFS可降低粪便中厚壁菌门含量和血清内毒素水平。棕榈酸酯激活TLR4通过p-JNK1依赖性途径诱导肠神经元凋亡。JNK抑制剂和来自[具体小鼠品系未提及]小鼠的神经元可预防这种凋亡。
我们的数据共同表明，喂食HFD的小鼠肠道菌群失调通过诱导TLR4依赖性神经元丢失导致肠道动力延迟。用OFS调节肠道微生物群可改善HFD小鼠的肠道动力。
