In the study published in the journal Pharmaceutics, the researchers took a two-step approach to fighting ulcerative colitis. First, they reduced inflammation in gut microbiota from a mouse with an anti-inflammatory drug candidate delivered by lipid nanoparticles. Then, they orally administered the end products of these treated microbiota to the same mouse, resulting in a new, effective way to prevent ulcerative colitis.

The findings report the nano formulation, M13/nLNP, shifted the inflamed microbiota composition toward being non-inflamed. This altered microbiota composition induced significant changes in the chemical profiles of secreted metabolites (end products of metabolic reactions), and when these metabolites were orally administered to mice, they established strong protection against the formation of chronic inflammation.

Ulcerative colitis is a form of chronic inflammatory bowel disease (IBD) that affects more than five million patients worldwide. Studies have shown that irregular gut microbiota composition is associated with the progression of ulcerative colitis. Altering the composition of gut microbiota is an effective approach to treating a variety of chronic diseases, including ulcerative colitis. However, current methods such as fecal microbiota transplants pose a risk of serious infections because they involve the transmission of drug-resistant organisms.

In this study, the researchers developed an organism-free strategy in which gut microbiota were altered in test tubes, and then microbiota-secreted metabolites were transferred back to the host. By collecting feces from mice with chronic ulcerative colitis, the researchers determined that a natural lipid nanoparticle-encapsulated drug candidate modified the composition of inflamed gut microbiota, which were cultured outside of the host, and the secreted metabolites.

“Our study demonstrates that modifying microbiota outside of the host using M13/nLNP effectively reshaped the microbial secreted metabolites,” said Dr. Didier Merlin, a Distinguished University Professor in the Institute for Biomedical Sciences at Georgia State and a senior research career scientist at Atlanta Veterans Affairs Medical Center. “Oral transfer of these metabolites might be an effective and safe therapeutic approach for preventing chronic ulcerative colitis.”

A limitation of the study is that alteration of the microbiota composition could be affected by the accumulation of secreted metabolites. A dynamic flowing device must be developed to continuously eliminate the secreted metabolites from the medium so the metabolites themselves will not affect how the drug formulation changes the composition of cultured microbiota. In addition, other key factors, such as the drug concentration, culture time and anaerobic gas composition, can be further optimized.

“Our strategy to tackle the progression of ulcerative colitis might offer an alternative and complementary approach for better managing this disease,” said Dr. Chunhua Yang, a research assistant professor at the Institute for Biomedical Sciences at Georgia State. “Although this study demonstrates the anti-inflammatory effects of metabolites modified outside of the organism, further investigations are required to characterize the specific bacteria that contribute to the anti-inflammatory metabolites and to identify anti-inflammatory metabolite structures.”

Co-authors of the study include Chunhua Yang (first author) and Didier Merlin of the Institute for Biomedical Sciences at Georgia State and the Atlanta Veterans Affairs Medical Center; Junsik Sung and Dingpei Long of the Institute for Biomedical Sciences at Georgia State; and Zahra Alghoul of the Institute for Biomedical Sciences and Department of Chemistry at Georgia State.

The study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, the Department of Veterans Affairs and the Crohn’s and Colitis Foundation.