A Disease-Associated Microbial and Metabolomics State in Relatives of Pediatric Inflammatory Bowel Disease Patients

Abstract

Background & AimsMicrobes may increase susceptibility to inflammatory bowel disease (IBD) by producing bioactive metabolites that affect immune activity and epithelial function. We undertook a family based study to identify microbial and metabolic features of IBD that may represent a predisease risk state when found in healthy first-degree relatives.MethodsTwenty-one families with pediatric IBD were recruited, comprising 26 Crohn’s disease patients in clinical remission, 10 ulcerative colitis patients in clinical remission, and 54 healthy siblings/parents. Fecal samples were collected for 16S ribosomal RNA gene sequencing, untargeted liquid chromatography–mass spectrometry metabolomics, and calprotectin measurement. Individuals were grouped into microbial and metabolomics states using Dirichlet multinomial models. Multivariate models were used to identify microbes and metabolites associated with these states.ResultsIndividuals were classified into 2 microbial community types. One was associated with IBD but irrespective of disease status, had lower microbial diversity, and characteristic shifts in microbial composition including increased Enterobacteriaceae, consistent with dysbiosis. This microbial community type was associated similarly with IBD and reduced microbial diversity in an independent pediatric cohort. Individuals also clustered bioinformatically into 2 subsets with shared fecal metabolomics signatures. One metabotype was associated with IBD and was characterized by increased bile acids, taurine, and tryptophan. The IBD-associated microbial and metabolomics states were highly correlated, suggesting that they represented an integrated ecosystem. Healthy relatives with the IBD-associated microbial community type had an increased incidence of elevated fecal calprotectin.ConclusionsHealthy first-degree relatives can have dysbiosis associated with an altered intestinal metabolome that may signify a predisease microbial susceptibility state or subclinical inflammation. Longitudinal prospective studies are required to determine whether these individuals have a clinically significant increased risk for developing IBD.

Trace Amines and Their Receptors

“…Consistent with this, TAAR1 has been proposed to play a role in the susceptibility to fibromyalgia (Smith et al, 2012), TAAR6 implicated in treatment outcomes 598 in asthma (Chang et al, 2015), and TAAR2, TAAR5, and TAAR9 among the most highly upregulated genes in the inflamed zones of patients with Crohn disease (Taquet et al, 2012), an effect that allowed discrimination of these patients from those with irritable bowel syndrome. As previously indicated, two recent unbiased metabolomic studies have also identified elevated endogenous TAAR1 ligands in Crohn disease fecal samples (Jacobs et al, 2016;Santoru et al, 2017). Together, these studies indicate that a careful, systematic investigation of the ability of TAAR isoforms to regulate the immune system is warranted.…”

“…Recent unbiased metabolomics studies indicated that elevated fecal PEA levels are present in patients with Crohn disease (Jacobs et al, 2016;Santoru et al, 2017), an effect that was suggested to contribute to the ability to discriminate these patients from healthy controls (Santoru et al, 2017). Similarly elevated TYR levels were reported in ulcerative colitis fecal samples (Santoru et al, 2017).…”

Whole-blood taurine concentrations in cats with intestinal disease

“…2 Similarly, feces from humans with inflammatory bowel disease contained more bile acids and taurine, and this metabolite pattern was highly correlated with a characteristic shift in the microbiota. 15 One study documented that the increased conjugated and sulfated bile acids in the feces of humans with Crohn's disease was attributed to the decreased capacity of the microbiome in these patients to deconjugate and desulfate bile acids, resulting in decreased production in the colon of secondary bile acids, which are normally anti-inflammatory. 16 Therefore, the increase in fecal taurine seen in human and animal models of inflammatory bowel disease likely results from a perturbation in microbiota, and consequently, bile acids may form the link between the dysbiosis and inflammation seen in these diseases.…”

Disease-Associated Microbial Communities in Healthy Relatives: A Bacteria-Filled Crystal Ball?

“…In a new study published in this issue of Cellular and Molecular Gastroenterology and Hepatology , Jacobs et al 3 do exactly that. Performing a thorough analysis of fecal microbial profiles from 36 IBD patients in remission (26 with Crohn’s disease and 10 with ulcerative colitis) and 54 healthy first-degree relatives, they showed that it is possible to identify an IBD-like intestinal microbiome in at-risk healthy individuals who do not have clinically detectable inflammation.…”

“…Going forward, prospective longitudinal studies in an expanded and more diverse cohort will be essential to determine whether the microbial signatures described by Jacobs et al 3 are indeed markers for a predisease state. Furthermore, because evidence suggests that mucosa-adherent microbes may correlate more tightly with the disease state than fecal communities, 5 it would be interesting to see whether typing using these communities could provide even more sensitive measures of susceptibility.…”