What is already known
Ulcerative colitis is a type of inflammatory bowel disease that causes inflammation and sores in the digestive tract. Previous studies have found microbial signatures in people with ulcerative colitis, but the mechanisms underlying the disease are still unclear.
What this research adds
Researchers analyzed stool and plasma samples from children newly diagnosed with ulcerative colitis. Children with severe disease showed changes in many metabolites, including altered levels of specific bile acids as well as increased levels of plasma polyamines. Further experiments linked Veillonella parvula with the increased production of immunomodulatory metabolites. V. parvula appeared to also metabolize immunosuppressive drugs, potentially impairing their therapeutic efficacy.
Conclusions
The findings suggest that the gut microbiota contributes to alterations in the levels of metabolites associated with ulcerative colitis.
Ulcerative colitis is a type of inflammatory bowel disease that causes inflammation and sores in the digestive tract, but the mechanisms underlying the condition are still unclear. Now, researchers have identified key microbial metabolites as well as host-microbe interactions underlying disease course in children with ulcerative colitis.
The findings, published in Cell Host & Microbe, suggest that the gut microbiota contributes to alterations in the levels of metabolites associated with the disease. The work, the researchers say, also highlights the importance of these interactions in disease pathology and treatment.
Previous research has identified microbial signatures in people with ulcerative colitis. Some studies have found that the disease is linked with an expansion of mouth-dwelling bacteria and a reduction in Clostridiales bacteria. Other studies have associated ulcerative colitis with higher levels of Bifidobacterium breve and Clostridium symbiosum as well as with gut inflammation driven by oral Klebsiella strains.
“However, differences in microbial signatures between cohorts and across disease duration, as well as differences in treatment history, complicate the identification of disease mechanisms,” the researchers say.
So the team, led by Melanie Schirmer at The Broad Institute of MIT and Harvard in Cambridge, Massachusetts, set out to analyze stool and plasma samples from children newly diagnosed with ulcerative colitis.
Differentially abundant metabolites
The researchers recruited children aged 4 to 17 years who received an ulcerative colitis diagnosis and followed them for 1 year, during which they collected clinical data and biological samples. The team focused on 95 children with mild or moderate/severe disease at diagnosis and collected stool and blood samples up to 4 time points per child.
Compared with children with inactive disease, those with moderate or severe disease had higher levels of bacteria typical of the oral cavity, including three Veillonella species, Haemophilus parainfluenzae and Klebsiella pneumoniae, as well as lower levels of Bifidobacteria, including B. longum, B. adolescentis and B. bifidum.
The researchers also found that 72% of the metabolites in stool were differentially abundant in children with moderate or severe disease compared with inactive disease, and 41% of the metabolites in plasma were significantly altered in moderate or severe disease.
Immune overactivation
Children with severe disease showed altered levels of specific bile acids such as tauro-conjugated bile acids. One tauro-conjugated bile acid called taurocholate, which was present at high levels in these children, is known to increase the production of reactive oxygen species — molecules that can provoke damage to cells. Taurochenodeoxycholate, another tauro-conjugated bile acid that was enriched in children with severe disease, is known to decrease the viability of biliary epithelial cells and induce cell death at high concentrations.
Children with severe disease also showed lowered levels of plasma tryptophan metabolites and polyamines. Microbial tryptophan metabolites suppress inflammation and polyamines attenuate immune responses. “The loss of these metabolites and their protective effects may contribute to immune system overactivation in [ulcerative colitis],” the researchers say.
Further experiments linked Veillonella parvula with the increased production of immunomodulatory metabolites. V. parvula appeared to also metabolize immunosuppressive drugs, potentially impairing their therapeutic efficacy.
