In people with inflammatory bowel disease, the composition of the gut microbiome – the community of microorganisms living in the intestine – is often altered. However, it is frequently unclear which bacteria actually contribute to inflammation. The microbiome varies considerably from person to person, making it difficult to determine whether certain bacteria cause inflammation or simply become more abundant as a result of the disease.
Identifying Disease-Promoting Gut Bacteria
Together with researchers at the University of Calgary, Dr. Mager's team developed a method to identify disease-promoting bacteria in individual patients. To do so, the researchers compared stool samples collected from patients before and after treatment with antibiotics or fecal microbiota transplantation. The gut microorganisms from these samples were transferred into germ-free mice to investigate their effects on inflammation. The team then used antibodies produced by the immune system to isolate potentially harmful bacteria and assess their effects.
Two Bacterial Species Promote Inflammation
The researchers identified two bacterial species capable of triggering or exacerbating intestinal inflammation in susceptible hosts: Sarcina perfringens and Hathewaya massiliensis. Both activate cells of the innate immune system, thereby promoting inflammatory responses.
Additional analyses of international patient datasets showed elevated levels of Sarcina perfringens in approximately 25 to 30 percent of people with IBD, while Hathewaya massiliensis was found at elevated levels in around five percent. Experiments using intestinal organoids – miniature tissue models grown from human cells – provided further evidence that the bacteria promote inflammation through immune responses and can impair the function of intestinal epithelial cells.
"Inflammatory bowel disease does not have the same triggers in every patient. Our findings show that we can specifically identify bacteria that contribute to inflammation in individual patients. This is an important step towards more personalized treatment," explains Dr. Lukas Mager.
Targeted Inhibition Instead of Broad-Spectrum Antibiotics
The research team then screened 1,518 previously approved compounds. They identified five substances capable of selectively inhibiting the growth of the two bacterial species without substantially affecting other common gut bacteria.
The antibiotic compound oxolinic acid proved particularly promising. In a mouse model, the compound reduced intestinal inflammation promoted by Sarcina perfringens with an efficacy comparable to that of the broad-spectrum antibiotic metronidazole. Unlike metronidazole, however, oxolinic acid had only a minor impact on the remaining bacterial community examined. This suggests that it may eventually be possible to selectively inhibit disease-promoting bacteria while largely preserving beneficial members of the gut microbiota.
Towards Personalized Therapies
Current treatments for inflammatory bowel disease primarily focus on controlling inflammatory responses. The new approach could complement these therapies by directly targeting specific bacterial triggers of inflammation.
Further research is needed before the approach can be used in clinical practice. In particular, researchers must establish whether selectively targeting these bacteria is also safe and effective in humans.
The study was conducted in collaboration between University Hospital Tübingen, the Faculty of Medicine at the University of Tübingen, and the University of Calgary in Canada. In Tübingen, Mahana Sabachvili, the M3 Research Center, the Department of Internal Medicine I, and the Clusters of Excellence CMFI and iFIT made substantial contributions. In Calgary, Spencer Abbott and Carolyn Thomson were among the key contributors to the study. The research was supported, among others, by the European Research Council (ERC) through Lukas Mager's Starting Grant SOAR.
