From the AGA Journals

Testing phagocytes might better characterize IBD dysbiosis

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Inflammation-promoting bacteria could invade the mucosa
Klaus H. Kaester, PhD, MS

Dysbiosis, or pathological changes in the composition or abundance of gut microbiota, has been linked to inflammatory bowel disease in multiple studies, although cause and effect relationships are sometimes difficult to establish. One issue is whether the analysis of the microbiome from stool samples or even whole colonic biopsies is the optimal method to assess its impact of altered bacterial colonization on disease, or whether it might be more informative to analyze the microbiota that are in direct contact with lamina propria phagocytes. Phagocytes, i.e. cells of the innate immune system including macrophages, monocytes, and neutrophils, are the “first responders” to bacteria that invade the ileal or colonic epithelium and thus might be a better reflection of the disease-relevant microbes than stool or whole mucosal specimens commonly analyzed.
Indeed, major differences between phagocyte-associated microbiota and those found in whole biopsy samples were discovered. Importantly, several of the phagocyte-associated phyla, such as Prevotella species, are known to promote Th-17 mediated mucosal inflammation. Thus, it appears that selective invasion of the mucosa by inflammation-promoting bacteria could modify the immune response and thus degrees of progression. In addition, there are striking differences between the phagocyte-associated microbiome in inflamed tissue from ulcerative colitis or Crohn’s patients. Thus, for the first time it appears that microbiota are different between the two diseases in the setting of inflammation. Future research is needed to generalize these findings, and to compare the phagocyte-associated microbiome from IBD patients to that of healthy individuals.

Klaus H. Kaestner, PhD, MS, is an investigator in the department of genetics and Center for Molecular Studies in Digestive and Liver Diseases at the Perelman School of Medicine of the University of Pennsylvania in Philadelphia, codirector of Penn’s Digestive Disease Research Center, and co-Editor-in-Chief of Cellular and Molecular Gastroenterology and Hepatology. He has no conflicts.



For patients with inflammatory bowel disease, 16S ribosomal gene sequencing of lamina propria phagocytes identified microbiota closely associated with inflamed intestinal tissue, according to the results of a pilot study.

This microbiome differed from that of the intestinal mucosa, containing a markedly higher concentration of Proteobacteria, reported Rishu Dheer, PhD, of the University of Miami, and associates. The microbiota also differed between Crohn’s disease and ulcerative colitis, while inflammatory gene expression did not. “The approach used in this study can narrow the spectrum of potentially dysbiotic bacterial populations” in patients with inflammatory bowel disease, the researchers wrote in Cellular and Molecular Gastroenterology and Hepatology.

Recent studies have confirmed intestinal dysbiosis in patients with inflammatory bowel disease, but little is known about disease susceptibility or severity or how microbiota correlate with inflammatory gene expression, the researchers said. They obtained ileal and colonic punch biopsy specimens from 32 patients with inflammatory bowel disease (20 with Crohn’s disease and 12 with ulcerative colitis) and performed 16S ribosomal RNA sequencing of CD11+ phagocytic cells from the lamina propria. They also performed innate immune gene expression profiling. For comparison, they also studied the microbiota of the intestinal mucosa of the same patients.

Compared with mucosal microbiota, the lamina propria microbiota was enriched in Proteobacteria — the “defining phyla” associated with dysbiosis in inflammatory bowel disease, the investigators wrote. Gene profiling revealed extensive functional and metabolic differences between the lamina propria microbiota and the mucosal microbiota, regardless of whether patients had Crohn’s disease or ulcerative colitis.

The microbiota associated with phagocytes was similar in inflamed and uninflamed tissue from the same patients, but it significantly differed between inflamed tissue from patients with Crohn’s disease and inflamed tissue from patients with ulcerative colitis. “These results suggest that the phagocyte-associated microbiota distinguishes Crohn’s disease and ulcerative colitis in the setting of inflammation,” the researchers wrote.

The oncostatin M (OSM) gene, which is part of the IL6 cytokine family of genes, was “highly upregulated” in inflamed CD11b+ cells from the patients, the researchers said. An adjusted analysis did not find statistically significant correlations between specific microbes and inflammatory genes, but clusters of genes were expressed at higher and lower levels in cells from inflamed versus noninflamed tissue, and these gene clusters correlated with specific bacterial genera.

“These results suggest that the variation in the abundance of specific groups of microbiota may affect gene expression levels in host lamina propria phagocyte cell types,” the researchers said. They added that their study method enabled them to “amplify and detect bacteria that are found at very low abundance in the gastrointestinal tract [and that] may participate in initiating or promoting inflammatory bowel disease.”

The study was supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Crohn’s & Colitis Foundation of America, Micky & Madeleine Arison Family Foundation Crohn’s & Colitis Discovery Laboratory, and the Martin Kaiser Chair in Gastroenterology at the University of Miami. The senior investigator disclosed ties to Prometheus, Takeda, Pfizer, AbbVie, Janssen, and several other companies. The other researchers reported having no conflicts of interest.

SOURCE: Dheer R et al. Cell Mol Gastroenterol Hepatol. 2020. doi: 10.1016/j.jcmgh.2019.10.013.

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