Role of intestinal microbiota in driving injury mechanisms in short bowel syndrome

肠道微生物群在驱动短肠综合征损伤机制中的作用

• 批准号: 10580044
• 负责人: Ajay K. Jain
• 金额: $ 21.4万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-25 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580044
• 关键词: Address; Aliquot; Animal Model; Animal Nutrition; Animals; Atrophic; Automobile Driving; Bacteroidetes; Bile Acid Biosynthesis Pathway; Bile Acids; Bilirubin; Catheters; Cholestasis; Classification; Data; Dependence; Distal; Duodenum; Dyslipidemias; Enteral Feeding; Enteral Nutrition; Enterohepatic Circulation; Etiology; Excision; FGF19 gene; Failure; Feces; Fibroblast Growth Factor Receptors; Firmicutes; G-Protein-Coupled Receptors; GLP-2; GPBAR1 gene; Glucose Intolerance; Gut Mucosa; Hepatic; Hepatobiliary; Hepatotoxicity; Histology; Human; Inflammation; Inflammatory; Injury; Intestinal permeability; Intestines; Intravenous; Life; Ligands; Lipids; Liver; Liver diseases; Measures; Messenger RNA; Metagenomics; Modeling; Monitor; Nutritional; Operative Surgical Procedures; Pathology; Pathway interactions; Patients; Play; Population Control; Process; Property; Publishing; Pump; Receptor Activation; Research; Rodent; Role; Schedule; Secondary to; Serology; Short Bowel Syndrome; Shotguns; Signal Transduction; Signaling Molecule; Somatotropin; System; Testing; Therapeutic; Total Parenteral Nutrition; Villous; cytokine; deprivation; glucagon-like peptide; gut microbes; gut microbiota; hepatoprotective; improved; insight; liver injury; microbial; microbiota; microbiota transplantation; novel; nutrition; porcine model; prevent; receptor; restoration; serological marker; side effect

PROJECT SUMMARY / ABSTRACT Patients with Short Bowel Syndrome (SBS) require intravenous nutrition via a process called Total Parenteral Nutrition (TPN) as they cannot sustain nutritional needs through regular enteral nutrition (EN) due to insufficient intestines. Worldwide, tens of thousands of patients require TPN. Unfortunately, side effects in SBS include potentially fatal liver and gut injury from a likely multifactorial etiology. While many prior studies have focused on the possible detrimental effects induced by TPN constituents, we instead postulate the novel hypothesis that the state of luminal content deprivation as occurring in SBS alters gut-systemic signals driving injury mechanisms. Further analyzing these pathways, using a novel ambulatory SBS piglet model developed by us, which recapitulates human SBS (SLU#2346,43-R-011), we have shown gut microbial shifts in SBS with a significant increase in the Bacteroidetes phylum and decrease in the Firmicutes phylum as well as significant sub phylum changes. Pertinently, in SBS we have also published decreased synthesis of hepato-protective Fibroblast Growth Factor 19 (FGF19) secondary to inadequate gut Farnesoid X Receptor (FXR) activation and a decrease in the gut growth hormone, glucagon like peptide – 2 (GLP-2) due to a lack of gut receptor TGR5 activation. Indeed, during normal enterohepatic circulation, primary bile acids (FXR ligands), synthesized by the liver undergo transformation to secondary bile acids (TGR5 ligands) by the gut microbiota and thus we highlight a novel mechanism by which gut microbes modulate bile acid signaling properties and thus alter the course of injury in SBS. Thus, we note that an altered gut microbiota, has a prominent role in driving injury in SBS and hypothesize that its restoration in SBS animals by intestinal microbiota transplant (IMT), obtained from EN animals, will mitigate injury. Using our model, as proof of concept, we have noted mitigation of hepatic and gut injury in SBS upon IMT, attesting to its therapeutic role. As detailed in the research plan; with Aim 1 we will test the impact of rigorously monitored IMT to SBS and evaluate gut injury. We shall objectively classify and quantify stool microbiota using culture-independent targeted amplicon sequencing and shotgun metagenomics, assess serological gut injury markers, histology and perform gut morphometric analysis to gain mechanistic insights. Aim 2 relates to assessing the impact of IMT in SBS on hepatic injury. We will thus assess liver injury serological markers, hepato-toxic cytokine profiles and liver histology to assess impact of IMT. Aim 3 will focus on understanding mechanisms along the gut-systemic signaling axis driving injury in SBS. We will evaluate key hepatobiliary receptors, transporters and signaling molecules along the FXR-FGF19 and TGR5-GLP-2 gut-systemic axis to gain insights into microbial modulators and their mechanisms driving SBS injury. This project, using a highly translatable SBS model will help advance strategies to mitigate serious complications and provide critical insights into microbiota driven modulation of injury in SBS.

项目摘要/摘要

项目成果

The Effect of a Merit Point Incentive System on the Willingness to Donate Organs.

功绩点激励制度对器官捐献意愿的影响。

• DOI: 10.1016/j.transproceed.2023.09.023
• 发表时间: 2023
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Nazzal,Mustafa;Engelhardt,Annabel;Hallcox,Taylor;VanGorp,Luke;Parrish,Paul;Okeke,Raymond;Kumanan,Krithika;Buchanan,Paula;Schnitzler,Mark;Rub,FadeeAbuAl;Caliskan,Yasar;Shacham,Enbal;Fleetwood,Vidyaratna;Lentine,KristaL;Jain,
• 通讯作者: Jain,