Intraduodenal fecal microbiota transplantation ameliorates gut atrophy and cholestasis in a novel parenteral nutrition piglet model.

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-11-01 Epub Date: 2024-08-20 DOI:10.1152/ajpgi.00012.2024
Chandrashekhara Manithody, Christine Denton, Shaurya Mehta, Jasmine Carter, Kento Kurashima, Ashlesha Bagwe, Marzena Swiderska-Syn, Miguel Guzman, Sherri Besmer, Sonali Jain, Matthew McHale, Kamran Qureshi, Mustafa Nazzal, Yasar Caliskan, John Long, Chien-Jung Lin, Chelsea Hutchinson, Aaron C Ericsson, Ajay Kumar Jain
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Abstract

Total parenteral nutrition (TPN) provides lifesaving nutritional support intravenously; however, it is associated with significant side effects. Given gut microbial alterations noted with TPN, we hypothesized that transferring fecal microbiota from healthy controls would restore gut-systemic signaling in TPN and mitigate injury. Using our novel ambulatory model (US Patent: US 63/136,165), 31 piglets were randomly allocated to enteral nutrition (EN), TPN only, TPN + antibiotics (TPN-A), or TPN + intraduodenal fecal microbiota transplant (TPN + FMT) for 14 days. Gut, liver, and serum were assessed through histology, biochemistry, and qPCR. Stool samples underwent 16 s rRNA sequencing. Permutational multivariate analysis of variance, Jaccard, and Bray-Curtis metrics were performed. Significant bilirubin elevation in TPN and TPN-A versus EN (P < 0.0001) was prevented with FMT. IFN-G, TNF-α, IL-β, IL-8, and lipopolysaccharide (LPS) were significantly higher in TPN (P = 0.009, P = 0.001, P = 0.043, P = 0.011, P < 0.0001), with preservation upon FMT. Significant gut atrophy by villous-to-crypt ratio in TPN (P < 0.0001) and TPN-A (P = 0.0001) versus EN was prevented by FMT (P = 0.426 vs. EN). Microbiota profiles using principal coordinate analysis demonstrated significant FMT and EN overlap, with the largest separation in TPN-A followed by TPN, driven primarily by Firmicutes and Fusobacteria. TPN-altered gut barrier was preserved upon FMT; upregulated cholesterol 7 α-hydroxylase and bile salt export pump in TPN and TPN-A and downregulated fibroblast growth factor receptor 4, EGF, farnesoid X receptor, and Takeda G Protein-coupled Receptor 5 (TGR5) versus EN was prevented by FMT. This study provides novel evidence of prevention of gut atrophy, liver injury, and microbial dysbiosis with intraduodenal FMT, challenging current paradigms into TPN injury mechanisms and underscores the importance of gut microbes as prime targets for therapeutics and drug discovery.NEW & NOTEWORTHY Intraduodenal fecal microbiota transplantation presents a novel strategy to mitigate complications associated with total parenteral nutrition (TPN), highlighting gut microbiota as a prime target for therapeutic and diagnostic approaches. These results from a highly translatable model provide hope for TPN side effect mitigation for thousands of chronically TPN-dependent patients.

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十二指肠内粪便微生物群移植可改善新型肠外营养仔猪模型的肠道萎缩和胆汁淤积症
背景:全胃肠外营养(TPN)通过静脉注射提供救命的营养支持,但其副作用很大。鉴于 TPN 会导致肠道微生物改变,我们假设从健康对照组转移粪便微生物群将恢复 TPN 的肠道系统信号传导并减轻损伤:利用我们的新型流动模型(美国专利:US 63/136,165),31 头仔猪被随机分配到肠内营养(EN)、仅 TPN、TPN + 抗生素(TPN-A)或 TPN + 十二指肠内粪便微生物群移植(TPN-FMT),为期 14 天。通过组织学、生物化学和 qPCR 对肠道、肝脏和血清进行评估。粪便样本进行了 16s rRNA 测序。进行了 PERMANOVA、Jaccard 和 Bray-Curtis 指标分析:结果:TPN 和 TPN-A 与 EN 相比,胆红素显著升高(p):这项研究提供了新的证据,证明十二指肠内 FMT 可预防肠道萎缩、肝损伤和微生物菌群失调,对当前 TPN 损伤机制的范式提出了挑战,并强调了肠道微生物作为治疗和药物发现的主要靶点的重要性。
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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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