背景:全胃肠外营养(TPN)静脉内提供挽救生命的营养支持;然而它与显著的副作用相关。考虑到TPN的肠道微生物改变,我们假设从健康对照组转移粪便微生物群会恢复TPN中的肠道-系统信号并减轻损伤.
方法:使用我们的新型动态模型(美国专利:US63/136,165),31只仔猪随机分配肠内营养(EN),仅限TPN,TPN+抗生素(TPN-A)或TPN+十二指肠内粪便微生物群移植(TPN-FMT)14天。肠子,肝脏,通过组织学评估血清,生物化学,和qPCR。粪便样品进行16srRNA测序。PERMANOVA,进行Jaccard和Bray-Curtis指标。
结果:使用FMT可防止TPN和TPN-A与EN(p<0.0001)中胆红素的显着升高。IFN-G,TNF-α,IL-β,IL-8和LPS在TPN中显著升高(p=0.009/0.001/0.043/0.011/<0.0001),保护FMT。FMT可预防TPN(p<0.0001)和TPN-A(p=0.0001)对EN的绒毛/隐窝比率引起的显着肠萎缩(p=0.426对EN)。使用主坐标分析的微生物区系剖面显示了显著的FMT和EN重叠,TPN-A中分离度最大,其次是TPN,主要由Firmicutes和Fusobacteria驱动。TPN改变的肠屏障在FMT后得以保留。TPN和TPN-A中CYP7A1和BSEP上调,下调FGFR4,EGF,FXR和TGR5vsEN被FMT阻止。
结论:这项研究提供了预防肠道萎缩的新证据,十二指肠内FMT的肝损伤和微生物菌群失调,挑战TPN损伤机制的当前范式,并强调肠道微生物作为治疗和药物发现的主要靶标的重要性。
BACKGROUND: 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.
METHODS: 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 16s rRNA sequencing. PERMANOVA, Jaccard and Bray-Curtis metrics were performed.
RESULTS: Significant bilirubin elevation in TPN and TPN-A vs EN (p<0.0001) was prevented with FMT. IFN-G, TNF-alpha, IL-beta, IL-8 and LPS were significantly higher in TPN (p=0.009/0.001/0.043/0.011/<0.0001), with preservation upon FMT. Significant gut-atrophy by villous/crypt ratio in TPN (p<0.0001) and TPN-A (p=0.0001) vs 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 CYP7A1 and BSEP in TPN and TPN-A, and downregulatedFGFR4, EGF, FXR and TGR5 vs EN was prevented by FMT.
CONCLUSIONS: 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 importance of gut microbes as prime targets for therapeutics and drug discovery.