ABSTRACT

Complications of short bowel syndrome (SBS) include malabsorption and bacterial overgrowth, requiring prolonged dependence on parenteral nutrition (PN). We hypothesized that the intolerance of whole food in some SBS patients might be due to the effect of dietary fiber on the gut microbiome. Shotgun metagenomic sequencing and targeted metabolomics were performed using biospecimens collected from 55 children with SBS and a murine dietary fiber model. Bioinformatic analyses were performed on these datasets as well as from a healthy human dietary intervention study. Compared to healthy controls, the gut microbiota in SBS had lower diversity and increased Proteobacteria, a pattern most pronounced in children on PN and inversely correlated with whole food consumption. Whole food intake correlated with increased glycoside hydrolases (GH) and bile salt hydrolases (BSH) with reduced fecal conjugated bile acids suggesting that dietary fiber regulates BSH activity via GHs. Mechanistic evidence supporting this notion was generated via fecal and plasma bile acid profiling in a healthy human fiber-free dietary intervention study as well as in a dietary fiber mouse experiment. Gaussian mixture modeling of fecal bile acids was used to identify three clinically relevant SBS phenotypes. Dietary fiber is associated with bile acid deconjugation likely via an interaction between gut microbiota BSHs and GHs in the small intestine, which may lead to whole food intolerance in patients with SBS. This mechanism not only has potential utility in clinical phenotyping and targeted therapeutics in SBS based on bile acid metabolism but may have relevance to other intestinal disease states.

摘要

短肠综合征 (SBS) 的并发症包括吸收不良和细菌过度生长，需要长期依赖肠外营养 (PN)。我们假设一些 SBS 患者对全食物的不耐受可能是由于膳食纤维对肠道微生物组的影响。使用从 55 名 SBS 儿童和鼠膳食纤维模型收集的生物样本进行鸟枪法宏基因组测序和靶向代谢组学。对这些数据集以及健康的人类饮食干预研究进行了生物信息学分析。与健康对照组相比，SBS 中的肠道微生物群具有较低的多样性和增加的变形菌，这种模式在 PN 的儿童中最为明显，并且与全食物摄入量呈负相关。全食物摄入与糖苷水解酶 (GH) 和胆盐水解酶 (BSH) 增加相关，而粪便结合胆汁酸减少，表明膳食纤维通过 GH 调节 BSH 活性。支持这一观点的机制证据是通过在健康的人类无纤维饮食干预研究以及膳食纤维小鼠实验中的粪便和血浆胆汁酸分析产生的。粪便胆汁酸的高斯混合模型用于鉴定三种临床相关的 SBS 表型。膳食纤维可能通过肠道微生物群 BSH 和小肠中的 GH 之间的相互作用与胆汁酸去结合有关，这可能导致 SBS 患者的全食物不耐受。