Baseline gut microbiome is associated with disease severity, progression and treatment efficacy in pediatric ulcerative colitis patients

Recent research has involved genetics, altered mucosal immune responses, environmental factors and the gut microbiome as major players in the development of inflammatory bowel disease (IBD). Given that some patients do not respond to conventional treatments, scientists are currently exploring new gut microbiome-targeted therapeutic approaches to improve disease course.

A new study, led by Dr. Ramnik Joseph Xavier from the Department of Molecular Biology at Massachusetts General Hospital (Boston, USA), has found in children with ulcerative colitis that the baseline gut microbiota composition is linked with disease severity, progression and treatment response.

The researchers investigated the role of the gut microbiome in disease severity, progression and treatment response in 405 pediatric (4-17 years old) new-onset ulcerative colitis (UC) patients during the first year of treatment with mesalamine (5ASA) or with corticosteroids (oral or intravenous) followed by 5ASA. Fecal samples and paired rectal biopsies were collected for gut microbiome analysis both at baseline and at different time points. Treatment data, disease activity and serology were also recorded.

For the first year after diagnosis and before initiating treatment, specific taxonomic shifts in gut microbial communities were associated not only with disease severity, but also with its subsequent progression.

Expansion of bacteria from the oral cavity (especially Veillonella species) was observed in patients with severe disease at baseline and follow-up time points, as a result of inflammation or strain-specific niche adaptation that might have been mediated by increased oxygen levels in the UC gut. Many of the microbes that increased or depleted after antibiotic use at baseline were involved in UC severity. Functional changes were also reported when comparing severe and mild disease, although they have a lesser impact when compared with changes in gut microbiota composition.

Associations were also found between the abundance of 21 operational taxonomic units—of which some taxa were also linked to more severe disease—in baseline samples and refractory disease requiring colectomy.

Furthermore, an increase in Ruminococcaceae, Oscillospira and Eggerthella lenta and a decrease in Clostridiales and Sutterella at baseline were all associated with week 52 corticosteroid-free remission.

These findings suggest the role of certain gut microbes in UC severity, refractory disease requiring colectomy and disease remission. However, they also highlight the importance of tracking gut microbiota changes in patients who do not receive treatment for an accurate interpretation of results in the generally under-researched UC microbiome.

On the other hand, analysis of follow-up samples revealed that temporal changes in microbial abundances were associated with disease severity and treatment efficacy.

Microbial taxonomic composition changed over time within individuals and was linked to disease progression and fecal calprotectin levels during treatment. As expected, fecal calprotectin levels increased and microbial community diversity decreased with more severe disease.

The treatment response also relied on baseline gut microbiota composition. This is because for each initial treatment (corticosteroids or 5ASA mesalamine), different microbial shifts were observed in patients that achieved week 4 remission when compared with those with sustained disease. In particular, Haemophilus parainfluenzae levels were higher in patients with severe disease at baseline and the falling of these levels over time was linked with improved disease severity.

A pronounced increase in microbiome variability was also observed prior to colectomy, showing that known interindividual variability in the gut microbiome in IBD is even more pronounced in refractory disease.

Finally, other than microbial changes, some serological markers used in IBD diagnosis (anti-Saccharomyces cerevisiae antibody immunoglobulin A, anti-Saccharomyces cerevisiae antibody immunoglobulin G, antineutrophil cytoplasmic antibodies, anti-flagellin antibodies and anti-outer membrane porin C) correlated—they either increased or decreased—with disease progression. Besides this, the levels of some of these antibodies correlated with microbial species, suggesting a close cross-talk between the gut microbiome, the host immune system and disease progression.

On the whole, this study shows that the baseline gut microbiome in pediatric UC patients may predict disease severity, progression and even treatment efficacy at follow-up. As such, these new findings might help personalize treatments in UC patients based on gut microbiota composition.

Reference:

Schirmer M, Denson L, Vlamakis H, et al. Compositional and temporal changes in the gut microbiome of pediatric ulcerative colitis patients are linked to disease course. Cell Host Microbe. 2018; 24(4):600-10. doi: 10.1016/j.chom.2018.09.009.