Surgery for Crohn's Disease Is Associated With a Dysbiotic Microbiome and Metabolome: Results From Two Prospective Cohorts.

BACKGROUND & AIMS: Crohn's disease is associated with alterations in the gut microbiome and metabolome described as dysbiosis. We characterized the microbial and metabolic consequences of ileal resection, the most common Crohn's disease surgery. METHODS: Patients with and without intestinal resection were identified from the Diet to Induce Remission in Crohn's Disease and Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease studies. Stool samples were analyzed with shotgun metagenomics sequencing. Fecal butyrate was measured with 1H nuclear magnetic resonance spectroscopy. Fecal bile acids and plasma 7α-hydroxy-4-cholesten-3-one (C4) was measured with mass spectrometry. RESULTS: Intestinal resection was associated with reduced alpha diversity and altered beta diversity with increased Proteobacteria and reduced Bacteroidetes and Firmicutes. Surgery was associated with higher representation of genes in the KEGG pathway for ABC transporters and reduction in genes related to bacterial metabolism. Surgery was associated with reduced concentration of the But gene but this did not translate to reduced fecal butyrate concentration. Surgery was associated with decreased abundance of bai operon genes, with increased plasma C4 concentration, increased primary bile acids and reduced secondary bile acids, including isoLCA. Additionally, Egerthella lenta, Adlercreutzia equalofaciens, and Gordonibacter pamelaeae were lower in abundance among patients with prior surgery in both cohorts. CONCLUSIONS: In 2 different populations, prior surgery in Crohn's disease is associated with altered fecal microbiome. Patients who had undergone ileal resection had reduction in the potentially beneficial bacteria E lenta and related actinobacteria and secondary bile acids, including isoLCA, suggesting that these could be biomarkers of patients at higher risk for disease progression.

Disruption of intestinal oxygen balance in acute colitis alters the gut microbiome.

The juxtaposition of well-oxygenated intestinal colonic tissue with an anerobic luminal environment supports a fundamentally important relationship that is altered in the setting of intestinal injury, a process likely to be relevant to diseases such as inflammatory bowel disease. Herein, using two-color phosphorometry to non-invasively quantify both intestinal tissue and luminal oxygenation in real time, we show that intestinal injury induced by DSS colitis reduces intestinal tissue oxygenation in a spatially defined manner and increases the flux of oxygen from the tissue into the gut lumen. By characterizing the composition of the microbiome in both DSS colitis-affected gut and in a bioreactor containing a stable human fecal community exposed to microaerobic conditions, we provide evidence that the increased flux of oxygen into the gut lumen augments glycan degrading bacterial taxa rich in glycoside hydrolases which are known to inhabit gut mucosal surface. Continued disruption of the intestinal mucus barrier through such a mechanism may play a role in the perpetuation of the intestinal inflammatory process.

Effects of dietary zinc on the gut microbiome and resistome of the gestating cow and neonatal calf.

Zinc is an essential trace element required in the diet of all species. While the effects of zinc have been studied in growing calves, little is known about the effect of zinc on the microbiota of the gestating cow or her neonatal calf. Understanding factors that shape the gut health of neonatal animals and evaluating the effect of dietary supplements in adult gestating animals is important in promoting animal health and informing feeding practices. The aims of this study were to determine the effect of dietary zinc on the microbiota and resistome of the gestating cow and calf. Gestating cows received standard (40 ppm) or high (205 ppm) dietary zinc levels from dry off to calving. Fecal samples were collected from cows upon enrollment and at calving and from neonatal calves. Fecal samples underwent 16S rRNA sequencing and a subset also underwent shotgun metagenomic sequencing. The effect of zinc supplementation on the diversity and composition of the cow and calf microbiome and resistome was assessed. Alpha and beta diversity and composition of the microbiota were significantly altered over time but not by treatment in the cows, with alpha diversity decreasing and 14 genera found at significantly higher relative abundances at calving compared to enrollment. Levels of 27 antimicrobial resistance genes significantly increased over time. Only a small number of taxa were differentially expressed at calving in treatment and control groups, including Faecalibacterium, Bacteroides, Turicibacter, and Bifidobacterium pseudolongum. No effect of the dam's treatment group was observed on the diversity or composition of the neonatal calf microbiota. The calf resistome, which was relatively rich and diverse compared to the cow, was also unaffected by the dam's treatment group. The impact of high levels of dietary zinc thus appeared to be minimal, with no observed changes in alpha or beta diversity, and few changes in the relative abundance of a small number of taxa and antimicrobial resistance genes.

The evolutionarily ancient FOXA transcription factors shape the murine gut microbiome via control of epithelial glycosylation.

Evolutionary adaptation of multicellular organisms to a closed gut created an internal microbiome differing from that of the environment. Although the composition of the gut microbiome is impacted by diet and disease state, we hypothesized that vertebrates promote colonization by commensal bacteria through shaping of the apical surface of the intestinal epithelium. Here, we determine that the evolutionarily ancient FOXA transcription factors control the composition of the gut microbiome by establishing favorable glycosylation on the colonic epithelial surface. FOXA proteins bind to regulatory elements of a network of glycosylation enzymes, which become deregulated when Foxa1 and Foxa2 are deleted from the intestinal epithelium. As a direct consequence, microbial composition shifts dramatically, and spontaneous inflammatory bowel disease ensues. Microbiome dysbiosis was quickly reversed upon fecal transplant into wild-type mice, establishing a dominant role for the host epithelium, in part mediated by FOXA factors, in controlling symbiosis in the vertebrate holobiont.