Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, MO, USA.
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
Ann Med. 2022 Dec;54(1):1701-1713. doi: 10.1080/07853890.2022.2081871.
Total Parenteral Nutrition (TPN) provides lifesaving nutritional support to patients unable to maintain regular enteral nutrition (EN). Unfortunately, cholestasis is a significant side effect affecting 20-40% of paediatric patients. While the aetiology of TPN-associated injury remains ill-defined, an altered enterohepatic circulation in the absence of gut luminal nutrient content during TPN results in major gut microbial clonal shifts, resulting in metabolic endotoxemia and systemic inflammation driving liver injury and cholestasis.
To interrogate the role of gut microbiota, using our novel ambulatory TPN piglet model, we hypothesized that clonal reduction of bacteria in phylum (predominant in EN) and an increase in pathogenic Gram-negative bacteria during TPN correlates with an increase in serum lipopolysaccharide and systemic inflammatory cytokines, driving liver injury.
Upon institutional approval, 16 animals were allocated to receive either TPN ( = 7) or EN only ( = 9). The TPN group was subdivided into a low systemic inflammation (TPN-LSI) and high systemic inflammation (TPN-HSI) based on the level of serum lipopolysaccharide. Culture-independent identification of faecal bacterial populations was determined by 16S rRNA.
Piglets on TPN, in the TPN-HSI group, noted a loss of enterocyte protective Firmicutes bacteria and clonal proliferation of potent inflammatory and lipopolysaccharide containing pathogens: , and compared to EN animals. Within the TPN group, the proportion of phylum correlated with lower portal lipopolysaccharide levels ( = -0.89). The TPN-LSI had a significantly lower level of serum bile acids compared to the TPN-HSI group (7.3 60.4 mg/dL; = .018), increased day 14 weight (5.67 5.07 kg; = .017) as well as a 13.7-fold decrease in serum conjugated bilirubin.
We demonstrate a novel relationship between the gut microbiota and systemic inflammation in a TPN animal model. Pertinently, the degree of gut dysbiosis correlated with the severity of systemic inflammation. This study underscores the role of gut microbiota in driving liver injury mechanisms during TPN and supports a paradigm change in therapeutic targeting of the gut microbiota to mitigate TPN-related injury. KEY MESSAGESThis study identified a differential link between gut microbiota and inflammation-the higher the dysbiosis, the worse the systemic inflammatory markers.Higher levels of species correlated with reduced inflammation.
全胃肠外营养（TPN）为无法维持常规肠内营养（EN）的患者提供救命的营养支持。不幸的是，胆汁淤积是一种重要的副作用，影响 20-40%的儿科患者。虽然 TPN 相关损伤的病因仍不清楚，但 TPN 期间缺少肠道腔内容物的情况下，会导致肠肝循环改变，从而导致主要的肠道微生物克隆转移，导致代谢内毒素血症和全身炎症，从而导致肝损伤和胆汁淤积。
为了研究肠道微生物群的作用，我们使用新型的门诊 TPN 仔猪模型，假设在 TPN 期间，门（主要存在于 EN 中）的细菌克隆减少和致病性革兰氏阴性菌增加与血清内毒素和全身炎症细胞因子的增加有关，从而导致肝损伤。
在获得机构批准后，将 16 只动物分配到接受 TPN（n=7）或仅接受 EN（n=9）。根据血清内毒素水平，TPN 组分为低全身炎症（TPN-LSI）和高全身炎症（TPN-HSI）亚组。通过 16S rRNA 确定粪便细菌种群的无偏倚鉴定。
TPN 组仔猪在 TPN-HSI 组中观察到肠上皮保护Firmicutes 细菌丢失和强效炎症和内毒素含有的病原体的克隆增殖：、和，与 EN 动物相比。在 TPN 组内，门的比例与较低的门静脉内毒素水平相关（r=-0.89）。TPN-LSI 组的血清胆汁酸水平明显低于 TPN-HSI 组（7.3±60.4μg/dL；=0.018），第 14 天体重增加（5.67±5.07kg；=0.017），血清结合胆红素降低 13.7 倍。
我们在 TPN 动物模型中证明了肠道微生物群与全身炎症之间的新关系。重要的是，肠道菌群失调的程度与全身炎症的严重程度相关。这项研究强调了肠道微生物群在 TPN 期间驱动肝损伤机制的作用，并支持改变治疗靶点，以减轻 TPN 相关损伤的治疗模式。关键信息：本研究确定了肠道微生物群与炎症之间的差异联系-菌群失调程度越高，全身炎症标志物越差。高水平的属与炎症减少相关。
