Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
JPEN J Parenter Enteral Nutr. 2024 Nov;48(8):917-926. doi: 10.1002/jpen.2681. Epub 2024 Aug 26.
Gut microbiota dysbiosis induces intestinal barrier damage during parenteral nutrition (PN). However, the underlying mechanisms remain unclear. This study aimed to investigate gut microbiota dysbiosis, luminal short-chain fatty acids, and autophagy in a mouse model and how these short-chain fatty acids regulate autophagy.
Eight-week-old male specific-pathogen-free mice were randomly divided into a Chow group (standard diet and intravenous normal saline infusion) and a PN group (continuous infusion of PN nutrient solution) for 7 days. Caco-2 cells were also treated with intestinal rinse solutions from Chow and PN mouse models.
Compared with the Chow group, the PN group exhibited increased Proteobacteria and decreased Firmicutes, correlating with decreased propyl acetate. In the PN group, intestinal tissue exhibited elevated adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, LC3II protein levels, and Atg3 and Atg7 messenger RNA levels. P62 protein levels were decreased, indicating an increase of autophagy flux in the PN group. In the Caco-2 cell model, cells treated with PN solution plus propyl acetate exhibited increased Claudin-1 and occluding along with decreased interleukin-6 and tumor necrosis factor α compared with those treated with PN solution alone. Propyl acetate addition inhibited the AMPK-mammalian target of rapamycin (mTOR) pathway, mitigating the excessive autophagy induced by the PN intestinal rinse solution in Caco-2 cells.
PN led to a significant reduction in propyl acetate levels in the intestine, excessive activation of autophagy, and barrier dysfunction. Propyl acetate inhibited excessive autophagy via the AMPK/mTOR signaling pathway and protected the intestinal barrier during PN.
肠菌失调在肠外营养（PN）期间诱导肠道屏障损伤。然而，其潜在机制尚不清楚。本研究旨在研究小鼠模型中的肠菌失调、腔短链脂肪酸和自噬，以及这些短链脂肪酸如何调节自噬。
将 8 周龄雄性无特定病原体小鼠随机分为 Chow 组（标准饮食和静脉生理盐水输注）和 PN 组（连续输注 PN 营养液），共 7 天。还将 Caco-2 细胞用 Chow 和 PN 小鼠模型的肠冲洗液处理。
与 Chow 组相比，PN 组的变形菌门增加，厚壁菌门减少，与丙酸盐减少有关。在 PN 组中，肠组织中腺苷单磷酸激活蛋白激酶（AMPK）磷酸化、LC3II 蛋白水平以及 Atg3 和 Atg7 信使 RNA 水平升高。P62 蛋白水平降低，表明自噬通量增加。在 Caco-2 细胞模型中，与单独用 PN 溶液处理的细胞相比，用 PN 溶液加丙酸盐处理的细胞中 Claudin-1 和闭合蛋白增加，而白细胞介素-6 和肿瘤坏死因子-α减少。丙酸盐的添加抑制了 AMPK-雷帕霉素（mTOR）通路，减轻了 Caco-2 细胞中 PN 肠冲洗液诱导的过度自噬。
PN 导致肠道丙酸盐水平显著降低、自噬过度激活和屏障功能障碍。丙酸盐通过 AMPK/mTOR 信号通路抑制过度自噬，在 PN 期间保护肠道屏障。
