Weiss Scott L, Bittinger Kyle, Lee Jung-Jin, Friedman Elliot S, Mattei Lisa M, Graham Kathryn, Zhang Donglan, Bush Jeny, Balamuth Fran, McGowan Francis X, Bushman Frederic D, Baldassano Robert N, Wu Gary D, Wallace Douglas C, Collman Ronald G
Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
Pediatric Sepsis Program at the Children's Hospital of Philadelphia, Philadelphia, PA.
Crit Care Explor. 2021 Mar 17;3(3):e0360. doi: 10.1097/CCE.0000000000000360. eCollection 2021 Mar.
The intestinal microbiome can modulate immune function through production of microbial-derived short-chain fatty acids. We explored whether intestinal dysbiosis in children with sepsis leads to changes in microbial-derived short-chain fatty acids in plasma and stool that are associated with immunometabolic dysfunction in peripheral blood mononuclear cells.
Prospective observational pilot study.
Single academic PICU.
Forty-three children with sepsis/septic shock and 44 healthy controls.
Stool and plasma samples were serially collected for sepsis patients; stool was collected once for controls. The intestinal microbiome was assessed using 16S ribosomal RNA sequencing and alpha- and beta-diversity were determined. We measured short-chain fatty acids using liquid chromatography, peripheral blood mononuclear cell mitochondrial respiration using high-resolution respirometry, and immune function using ex vivo lipopolysaccharide-stimulated whole blood tumor necrosis factor-α. Sepsis patients exhibited reduced microbial diversity compared with healthy controls, with lower alpha- and beta-diversity. Reduced microbial diversity among sepsis patients (mainly from lower abundance of commensal obligate anaerobes) was associated with increased acetic and propionic acid and decreased butyric, isobutyric, and caproic acid. Decreased levels of plasma butyric acid were further associated with lower peripheral blood mononuclear cell mitochondrial respiration, which in turn, was associated with lower lipopolysaccharide-stimulated tumor necrosis factor-α. However, neither intestinal dysbiosis nor specific patterns of short-chain fatty acids were associated with lipopolysaccharide-stimulated tumor necrosis factor-α.
Intestinal dysbiosis was associated with altered short-chain fatty acid metabolites in children with sepsis, but these findings were not linked directly to mitochondrial or immunologic changes. More detailed mechanistic studies are needed to test the role of microbial-derived short-chain fatty acids in the progression of sepsis.
肠道微生物群可通过产生微生物衍生的短链脂肪酸来调节免疫功能。我们探讨了脓毒症患儿的肠道生态失调是否会导致血浆和粪便中微生物衍生的短链脂肪酸发生变化，这些变化与外周血单核细胞的免疫代谢功能障碍有关。
前瞻性观察性试点研究。
单一学术性儿科重症监护病房。
43例脓毒症/脓毒性休克患儿和44例健康对照。
对脓毒症患者连续采集粪便和血浆样本；对照仅采集一次粪便。使用16S核糖体RNA测序评估肠道微生物群，并确定α和β多样性。我们使用液相色谱法测量短链脂肪酸，使用高分辨率呼吸测定法测量外周血单核细胞线粒体呼吸，使用体外脂多糖刺激全血肿瘤坏死因子-α测量免疫功能。与健康对照相比，脓毒症患者的微生物多样性降低，α和β多样性均较低。脓毒症患者中微生物多样性降低（主要源于共生专性厌氧菌丰度降低）与乙酸和丙酸增加以及丁酸、异丁酸和己酸减少有关。血浆丁酸水平降低进一步与外周血单核细胞线粒体呼吸降低相关，而外周血单核细胞线粒体呼吸降低又与脂多糖刺激的肿瘤坏死因子-α降低相关。然而，肠道生态失调和短链脂肪酸的特定模式均与脂多糖刺激的肿瘤坏死因子-α无关。
肠道生态失调与脓毒症患儿短链脂肪酸代谢产物改变有关，但这些发现与线粒体或免疫变化无直接关联。需要更详细的机制研究来检验微生物衍生的短链脂肪酸在脓毒症进展中的作用。
