Toward the Understanding of Altered Gut Microbiome in Crohn's Disease: Cause or Consequence

Raygoza Garay et al1Raygoza Garay J.A. et al.Gastroenterology. 2023; (May 30)PubMed Google Scholar published a remarkable microbiome study that aimed to identify specific gut microbial features in healthy individuals that may contribute to the onset of Crohn's disease (CD), as opposed to those that could be consequences of the disease. To achieve their objective, Raygoza Garay et al needed to prospectively sample the gut microbiome of a substantial number of healthy individuals and identify unique microbial features in those who later developed CD. By targeting a population at high risk for CD, the healthy first-degree relatives (HFDRs) of patients with CD, the authors effectively decreased the sampling size required for this study. However, as the authors recognized, this design has a pitfall in that the HFDRs share with their diseased relatives many genetic and environmental features that could confound their study. Additionally, 555 individuals with subclinical gut inflammation were included in the healthy control group. These limitations may explain that no difference in microbial genus abundance was observed between the pre-CD individuals and those who remained healthy during the follow-up. Nevertheless, the authors established a microbiome risk score for predicting the risk of developing CD based on the composition of an individual’s microbiome. When examining the abundances of the top 10 important genera contributing to the microbiome risk score model, 7 of these genera exhibited varying trends in the pre-CD group when comparing the discovery and the validation cohorts. The other three genera—Ruminococcus torques (increased), Roseburia (decreased), and Romboutsia (decreased)—displayed similar trends of altered abundances in pre-CD for both cohorts, suggesting that these three genera play more important roles than other genera in the development of CD. Comparing Raygoza Garay et al’s pre-CD study with many of the CD studies with large cohorts,2Quince C. et al.Am J Gastroenterol. 2015; 110 (quiz 1730): 1718-1729Crossref PubMed Scopus (193) Google Scholar including our recent meta-analysis,3Gao S. et al.Gut Microbes. 2023; 152221428Google Scholar the microbial composition in pre-CD differed substantially from that of CD. Apparently, the only consistent change or trend in both pre-CD and CD was a decreased abundance in Roseburia, suggesting that the decrease of Roseburia may play a role in sustaining the intestinal inflammation, which it initially helped to trigger. Observations frequently reported in CD, but not in pre-CD, include the expansion of Escherichia–Shigella.2Quince C. et al.Am J Gastroenterol. 2015; 110 (quiz 1730): 1718-1729Crossref PubMed Scopus (193) Google Scholar, 3Gao S. et al.Gut Microbes. 2023; 152221428Google Scholar, 4Pascal V. et al.Gut. 2017; 66: 813-822Crossref PubMed Scopus (477) Google Scholar, 5Vich Vila A. et al.Sci Transl Med. 2018; 10Crossref PubMed Google Scholar Thus, the expansion of Escherichia–Shigella is likely a consequence of CD. This finding is consistent with the metabolic theory for gut dysbiosis,6Litvak Y. et al.Science. 2018; : 362Google Scholar which proposes that inflammation causes an increase in oxygen in the intestinal lumen, leading to the amplification of aerobic and facultative anaerobic bacteria, including Escherichia–Shigella. However, before we can firmly accept the lack of correlation between Escherichia and CD onset, it is worth noting that a previous study by the same group led by Croitoru found an association between the presence of serum antibody against Escherichia (anti-OmpC) and CD onset in HFDRs.7Lee S.H. et al.Gastroenterology. 2021; 161: 1540-1551Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In conclusion, the study design by Raygoza Garay et al represents a significant milestone in probing for possible causal roles of gut microbes in CD. However, the results obtained so far are controversial, likely owing to the presence of environmental and host genetic confounding factors that can have a profound impact on the gut microbiota. Gut Microbiome Composition Is Associated With Future Onset of Crohn’s Disease in Healthy First-Degree RelativesGastroenterologyVol. 165Issue 3PreviewGut microbiome composition, function, and stool metabolites can identify those more likely to develop Crohn’s disease in a cohort of healthy first-degree relatives of patients with Crohn’s disease. Full-Text PDF