PLEASE_COMBO
Inflammation, Antibiotics, and Diet as Concurrent Environmental Stressors of the Gut Microbiome in Pediatric Crohn's Disease
Pediatric Crohn's disease patients were treated with TNF-alpha or enteral nutrition and compared to healthy pediatric control subjects. Feces from both were sequenced with WGS.
Dysbiosis in the human intestines, an alteration in the normal composition of the microbiota, characterizes a wide spectrum of diseases, such as infections, irritable bowel syndrome, Crohn's disease. Dysbiosis has been studied extensively but typically characterized cross-sectionally and as alterations in bacterial taxonomic proportions.  The longitudinal contributions of diet, antibiotic use, and inflammation on the evolution of dysbiosis during therapy for Crohn's disease have not been well characterized. Here we used shot-gun metagenomic sequencing of fecal samples collected from a longitudinal prospective cohort of pediatric Crohn's disease subjects to analyze the representation and gene content of all types of organisms present, including bacteria, fungi, archaea and viruses.  Patients initiated treated with either antibodies directed against tumor necrosis factor alpha or enteral nutrition per the treating physician.  Multivariate analysis showed that microbiome composition was associated with three environmental stressors--intestinal inflammation, antibiotic use, and diet.  Bacterial gene signatures suggested that communities in Crohn's samples were responding to oxidative stress. Antibiotic use was associated with a more dysbiotic composition of the bacterial microbiota as well as a distinctive increase in fungal organisms and human DNA content. In contrast, the abundance of tailed phage and archaea was similar in feces of children with Crohn's disease and healthy controls.  Composition of the bacterial and fungal communities were highly correlated. Dysbiosis in bacterial and fungal communities was reduced in patients with reduction of intestinal inflammation by either therapy. Diet had an independent and rapid effect on gut microbiota composition within one week of initiation. Evidently dysbiosis characteristic of Crohn's disease results in part from inflammation and antibiotic use, and involves correlated changes in bacterial and eukaryotic community members.  Notably, the three stressors were independently associated with different bacteria and different gene pathways, reflecting concurrent disruption of normal homeostasis by multiple mechanisms. Thus, while dysbiosis in general is common to multiple disease states, the nature of the dysbiosis is unique to the environmental stressor.