• Do Relatives of Patients With IBD Also Have Intestinal Dysbiosis?

Do Relatives of Patients With IBD Also Have Intestinal Dysbiosis?

The intestinal microbiota of many healthy, first-degree relatives of patients with inflammatory bowel diseases (IBD) is dysbiotic, signifying a pre-disease state, low-level inflammation, and susceptibility to IBD, researchers report in the November issue of Cellular and Molecular Gastroenterology and Hepatology.

Changes in the intestinal microbiome are involved in the pathogenesis of IBD. Patients have reduced intestinal microbial diversity, with alterations in composition and function. Environmental factors such as diet help determine microbial composition and can affect IBD risk. However, risk is determined by a combination of environmental and genetic factors that affect the intestinal mucosa and determine microbial composition.

The authors found a statistically significant difference in abundance between OTU types 2 and 1 in multivariate DESeq2 models. Effect size is represented as the log2 fold-change between OTU types 2 and 1. Dot size is proportional to the abundance of that OTU after normalization in DESeq2. Only OTUs with a mean normalized abundance greater than 10-4 are included. Color signifies whether the OTU also is differentially abundant in patients with CD, UC, or both. The genus of each OTU is shown on the horizontal axis, ordered by the log2 fold-change between OTU types 2 and 1 of the genus as a whole. OTUs are grouped into families.

Jonathan P. Jacobs et al compared the intestinal microbiome and metabolome of pediatric patients with IBD with those of unaffected, first-degree relatives. They aimed to determine whether the relatives’ microbiota could be in a pre-disease state, characterized by sub-clinical inflammation, due to the genetic and environmental factors they shared with the patients.

Jacobs et al studied 21 families of patients with pediatric IBD; their analysis comprised 26 patients with Crohn’s disease (CD) in clinical remission, 10 patients with ulcerative colitis (UC) in clinical remission, and 54 healthy siblings or parents. Fecal samples were collected and analyzed by 16S ribosomal RNA gene sequencing and liquid chromatography–mass spectrometry metabolomics. The authors also measured levels of calprotectin, as a marker of inflammation.

In agreement with findings from previous studies, patients with CD had lower microbial diversity than patients with UC or healthy individuals. Samples formed a gradient by IBD status and microbial diversity, each of which were significantly associated with overall composition.

Based on the participants’ microbiomes, the authors identified 2 groups, which they called operational taxonomic unit or OTU types (see figure). They associated OTU type 2 with IBD—particularly with CD. Nineteen of the 21 families included at least 1 individual with IBD who carried OTU type 2, indicating that the association of this microbial community state with IBD was not a family-specific trait.  Most healthy relatives had OTU type 1, but 10 carried OTU type 2.

This IBD-associated microbiome was characterized by lower microbial diversity, with increased Enterobacteriaceae, consistent with dysbiosis. This finding is supported by studies of mice with deletion of Toll-like receptor 5 or NLRP6, in which colitis susceptibility associates with blooms of Enterobacteriaceae and Prevotellaceae, respectively.

Jacobs et al also identified a metabotype associated with IBD, characterized by increased bile acids, taurine, and tryptophan. The authors found the IBD-associated microbial and metabolomics states to correlate, indicating an integrated ecosystem.

The authors validated their findings in an independent pediatric cohort.

A higher proportion of healthy relatives with the IBD-associated microbial community type had increased fecal levels of calprotectin, compared to relatives without this microbiome, indicating low-level intestinal inflammation. Nevertheless, most individuals with the IBD-associated OTU type and metabotype had normal levels of fecal calprotectin.

Jacobs et al conclude that, in healthy individuals, an IBD-associated OTU type and metabotype can indicate intestinal dysbiosis and changes in metabolic products that lead to IBD. Although unaffected family members were not evaluated endoscopically for IBD, the study design includes periodic monitoring for acquisition of clinical disease.

The authors speculate that healthy individuals with an IBD-associated microbial community type and metabotype have a pre-disease state that increases the risk for subclinical and overt IBD. Validating this interpretation will require prospective longitudinal studies to assess the incidence of IBD in individuals stratified by OTU type, metabotype, and calprotectin level, and to assess the stability of OTU types and metabotypes across time and with different diets.

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