PHILADELPHIA - Different treatments for Crohn's disease in children affects their gut microbes in distinct ways, which has implications for future development of microbial-targeted therapies for these patients, according to a study led by researchers from the Perelman School of Medicine at the University of Pennsylvania. Their work revealed that an imbalance in the normally diverse array of microorganisms that populate the intestines of children is more complex than previously thought in pediatric Crohn's patients. Therapeutic strategies in Crohn's disease range from therapeutic diets to immunosuppressant drugs and antibiotics. However, effects of these treatments on the imbalanced, or dysbiotic, intestinal microbiome remain unclear. The Penn team, in collaboration with the Children's Hospital of Philadelphia, Seattle Children's Hospital, and Canada's IWK Health Centre and Hospital for Sick Children, published their work online this week in Cell Host and Microbe.
The Crohn's and Colitis Foundation of America estimates that as many as 80,000 children in the United States may have inflammatory bowel disease, a broader term for Crohn's disease and the related disease ulcerative colitis. Crohn’s disease is a debilitating disorder for all patients, but its early onset in children can cause additional problems such as stunted growth and delayed puberty, making the identification of effective treatments even more vital. Because immunsuppressant drugs can cause serious side-effects, there is great interest in developing new treatments that target the microbes living in the gut. This requires a better understanding of how gut microbes respond to different therapeutic approaches, the main objective of the current study.
"While antibiotics, inflammation and diet each impacted the composition of the gut microbiome, the effects were largely independent of each other," said co-first author James D. Lewis, MD, a professor of Epidemiology and Biostatistics. "From this we concluded that the dysbiosis in Crohn’s has many origins."
The researchers used genomic sequencing to analyze fecal samples from 90 children with Crohn's disease as well as from 26 healthy children, tracking symptoms, inflammation, and microbial changes over eight weeks. The Crohn's patients were all undergoing treatment with a diet formula or immunosuppressant medications. "In all, we collected more than half a trillion bases of DNA sequence information, then used the data to characterize the behavior of gut microbes over time," said co-senior author Frederic Bushman, PhD, chair of the department of Microbiology.
Each treatment had a distinct effect on the gut microbial community. The use of antibiotics, for example, suppressed bacterial growth but consequently facilitated the growth of fungi. The formula diet helped to reduce symptoms and decrease inflammation, but not by correcting the imbalance of the bacterial population. Under immunosuppressant therapy, inflammation and bacterial dysbiosis were reduced, but fungal dysbiosis persisted.
"The formula-based diet helped the children to improve their symptoms and inflammation despite making the microbiota initially more dysbiotic," explained co-senior author Gary Wu, MD, a professor of Gastroenterology. “This is an intriguing finding implying that it may not be necessary to completely restore a healthy microbiome to provide a beneficial effect.”
The study confirms that while dysbiosis is an important part of Crohn's disease, the reaction of gut microbes to different treatments can vary significantly. The discovery identifies important new research avenues to find novel treatment approaches and biomarkers that could be used to choose the right therapy for the right patient.
"We are currently conducting a study designed to assess the impact of diet, including formula-based diets, and gut microbiome on metabolites found in feces and blood," Lewis said. The new insights on mechanisms of dysbiosis and their interactions with treatments promise better therapies and symptom management to find a better quality of life for children and adults with Crohn's disease.
This work was funded by Project UH3DK083981; the Crohn’s and Colitis Foundation of America, Penn Digestive Disease Center (P30 DK050306); The Joint Penn-CHOP Center for Digestive, Liver, and Pancreatic Medicine; the Penn-CHOP Microbiome Program (S10RR024525; UL1RR024134, K24- DK078228) and the University of Pennsylvania Center for AIDS Research (P30 AI 045008).
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