Leptin receptor modulation of the gut-microbiota interaction

描述(由申请人提供)：肠上皮与肠道菌群沟通以维持健康平衡的机制尚不清楚，该平衡能够容忍共生细菌，同时对特定病原体快速反应。微生物区系和宿主之间的动态相互作用调节细胞增殖、分泌细胞的产生和肠道相关免疫细胞。这种相互作用的失调可能是炎症性肠病的发病机制之一。更多的证据也支持微生物区系的代谢作用，这些微生物区系发酵原本无法消化的饮食营养，使它们可供宿主吸收。这些共生菌群的缺乏，就像在无菌动物中所看到的那样，减少了从饮食中摄取的卡路里，并防止了暴露在高热量密度饮食中的动物肥胖。给无菌小鼠接种正常的肠道微生物群，可以恢复它们对肥胖的敏感性。宿主因素也明显地调节肠道菌群和从饮食中吸收营养的效率。肠道潘氏细胞产生抗菌肽(除了防御肠道病原体外)，控制特定肠道微生物的相对丰富。此外，荷尔蒙瘦素(由脂肪细胞按能量储存比例产生，因此在饥饿时减少)可能有助于调节肠道菌群。与对照组相比，瘦素缺乏(ob/ob)小鼠的肠道微生物环境发生了变化，ob/ob菌群促进了从肠道更有效地吸收营养。为了了解瘦素如何调节肠道及其相关菌群，我们研究了小鼠的肠道，以确定通过瘦素受体(LepRb)-揭示LepRb在回肠远端Paneth细胞中的表达-直接发挥瘦素作用的可能性。因此，我们假设瘦素通过潘氏细胞上的LepRb直接作用于肠道上皮和微生物区系之间的相互作用，从而控制肠道菌群中微生物的相对平衡。瘦素的这种作用可能不仅对正常的Paneth细胞-肠道菌群相互作用很重要，而且对新陈代谢也很重要，因为影响宿主细菌群落整体效率的变化可能会影响从食物摄入的热量提取。该项目的目标是了解瘦素/LepRb与饮食因素相关的在潘氏细胞功能和肠道菌群控制中的作用。因此，我们将利用小鼠的各种饮食和遗传操作来确定瘦素在潘氏细胞功能和肠道菌群平衡中的重要性。我们还将通过研究潘氏细胞中LepRb缺失的小鼠模型，来确定潘氏细胞LepRb在这些测量和代谢中的作用。这项工作将加深我们对肠道上皮和微生物区系之间复杂相互作用的理解，这可能有助于病原体防御、养分吸收和宿主的能量平衡。 公共卫生相关性：肠道微生物群的变化与各种人类疾病有关，如肠炎/结肠炎、炎症性肠病和肥胖症。肠上皮细胞与肠腔细菌沟通和调节的机制尚不清楚。我们最近已经在潘氏细胞上发现了脂肪激素瘦素的受体，特别是在回肠末端。我们的主要目的是确定瘦素信号在回肠Paneth细胞中的生理作用，并验证瘦素通过Paneth细胞分泌抗菌肽来调节肠道微生物区系的假设。这些研究将有助于我们理解回肠弹性细胞对微生物的调节，并确定这种环境的变化是否可能通过改变营养吸收来促进肥胖症的发展。

DESCRIPTION (provided by applicant): The mechanisms by which intestinal epithelium communicates with the gut flora to maintain a healthy equilibrium capable of tolerating commensal bacteria while swiftly responding to specific pathogens is not well understood. Dynamic interactions between microbiota and the host modulate cellular proliferation, production of secretory cells, and gut-associated immune cells. Dysregulation of this interaction may contribute to the pathogenesis of inflammatory bowel disease. Additional evidence also supports a metabolic role for microbiota that ferment otherwise indigestible dietary nutrients, rendering them available for host absorption. The absence of these symbiotic flora, as seen in germ free animals, decreases caloric uptake from the diet and prevents obesity in animals exposed to high caloric density diets. Inoculation of germ free mice with normal gut microbiota restores their susceptibility to obesity. Host factors clearly modulate gut flora and the efficiency of nutrient uptake from the diet, as well. Gut Paneth cells produce antimicrobial peptides that (in addition to defending against gut pathogens) control the relative abundance of specific gut microbes. Additionally, the hormone leptin (which is produced by adipocytes in proportion to energy stores, and is thus reduced in starvation) may contribute to the regulation of gut flora. Leptin-deficient (ob/ob) mice display an altered gut microbial environment relative to controls, and the ob/ob flora promote more efficient nutrient uptake from the gut. To understand how leptin might modulate the gut and its associated flora, we examined the intestines of mice to determine the potential for direct leptin action via the leptin receptor (LepRb)- revealing LepRb expression in the Paneth cells of the distal ileum. We thus hypothesize that leptin acts directly via LepRb on Paneth cells to modulate interactions between the gut epithelium and microbiota and thus to control the relative balance of organisms in the gut flora. This role of leptin may be important not only for normal Paneth cell - gut flora interaction but also for metabolism as changes affecting overall efficiency of the bacterial community in the host can affect caloric extraction from dietary intake. The goal of this project is to understand roles for leptin/LepRb relative to dietary factors in the control of Paneth cell function and gut flora. We will thus utilize a variety of dietary and genetic manipulations in mice to determine the importance of leptin in Paneth cell function and in the balance of intestinal flora. We will also determine the role for Paneth cell LepRb in these measures and in metabolism by studying a mouse model in which LepRb is deleted from Paneth cells. This work will increase our understanding of the complex interactions between gut epithelium and microbiota which may contribute to pathogen defense, nutrient absorption and energy balance of the host. PUBLIC HEALTH RELEVANCE: Changes in gut microflora have been implicated in various human diseases such as enteritis/colitis, inflammatory bowel disease and obesity. The mechanisms by which intestinal epithelial cells communicate with and regulate luminal bacteria are poorly understood. We have recently identified receptors for the adiposity hormone leptin on Paneth cells specifically within the terminal ileum. Our primary aim is to determine the physiologic role of leptin signaling in ileal Paneth cells and test the hypothesis that leptin moderates gut microflora through Paneth cell secretion of antimicrobial peptides. These studies will aid in our understanding of ileal eplithlial cell regulation of microbiata and determine if alterations in this environment could contribute to the development of obesity, possibly through alterations in nutrient absorption.