Computer-guided design of optimal microbial consortia for immune system modulation

The role of the immune system is to protect the body from infection. It does this by using a powerful toolkit that isolates pathogens and removes damaged tissue. When directed against bacteria and viruses, the system helps to keep the body safe, but an imbalance of the components of the immune system can lead to inflammatory or allergic diseases. The body has built-in mechanisms to shut off the immune response. For example, regulatory T-cells are immune cells with an anti-inflammatory effect, meaning they can switch off inflammation after the immune system has cleared an invasion. If their numbers are too low, it can contribute to unwanted inflammation. In ulcerative colitis, for instance, an unbalanced immune system mistakenly attacks healthy tissue. This causes inflammation and ulcers in the intestine, resulting in bleeding and weight loss. Previous studies revealed that bacteria in the gut might help to control regulatory T-cell numbers. Certain combinations of bacteria can stimulate these regulatory T-cells and potentially dampen inflammation. Tweaking the different populations of microbes in the gut could provide a new way to treat diseases like ulcerative colitis. But, identifying the best combination to use is a major challenge. Testing them all one by one would be extremely challenging. Now, Stein, Tanoue et al. present a mathematical model designed to predict the best microbe-mix to use. The model incorporated data from regulatory T-cells and microbes gathered from mice to estimate the contribution that different strains of bacteria make to regulatory T-cell numbers. This then fed into an ecological model predicted how different combinations of bacteria would behave in mice. The model aimed to fulfill two key criteria. First, to find combinations that can form stable, long-term bacterial colonies alone and when faced with competing microbes. Second, to boost regulatory T-cell numbers, helping them to expand to correct the immune imbalance. To test the predictions, mice received combinations of bacteria suggested by the model. The model had predicted some combinations to be 'weak' at inducing regulatory T-cells, some 'intermediate' and some 'strong'. The results matched the predictions, validating the method. This new model allows the rapid design of microbes that could dampen the immune response in the gut and paves the way for new treatments to correct imbalances of the immune system. By using already available data, it should be possible to expand the model to other diseases with imbalance in the immune system. In future, similar models could also find combinations for other medical uses. For example, to optimise the delivery of cancer immunotherapy, or to modulate the immune system after an organ transplant.