In the human body, immune system activity needs to be set at just the right level. Like a volume dial that must be set loud enough to hear, but not so loud that the neighbours come knocking, immune responses can be neither too high nor too low. High activity means the body starts attacking its own healthy tissues, and low activity means the immune system may fail to eliminate harmful invaders. In either of these cases, tissues can be injured, resulting in inflammation – which may be the starting point of many diseases. So if scientists knew how to control immune system activity – turning it up or down at will – they could profoundly influence disorders such as asthma, food allergy, inflammatory bowel disease, obesity, and heart disease.

In a recent Nature Medicine news article, Roxanne Khamsi reported on research around the world that investigates how the gut microbiota exerts an influence on the human immune system and inflammation. The proximity of the gut microbiota to immune cells in the gut doesn’t prove its influence. So the big question that scientists are setting out to answer is this: by what mechanisms can bacteria interact with immune cells?

The most promising line of research finds that bacteria probably don’t do the heavy lifting themselves when it comes to interacting with the immune system. They have assistants: the metabolites they produce. These compounds, produced when bacteria carry out their daily activities, often seem to be responsible for affecting key immune cells and tuning inflammation up or down.

Stanley Hazen of Cleveland Clinic, USA, for example, studies how bacteria produce trimethylamine (TMA) when they feast on choline, a nutrient found in abundantly in eggs and meat. TMA is further metabolized to produce trimethylamine N-oxide (TMAO), which is linked to inflammation and atherosclerosis. Mice who can’t change TMA into TMAO are protected against the disease. This suggests that TMAO is an undesirable metabolite that kick-starts the inflammatory process, resulting in a higher risk of heart disease.

Other research points to desirable metabolites that may affect inflammation. Chief among them are the short-chain fatty acids (SCFAs) such as butyrate, produced when microbes break down fiber. Animal research shows that these SCFAs lend a helping hand to immune-modulating regulatory T cells that reduce inflammation. More work is needed to see whether this mechanism holds true in humans, but data does suggest that people who consume a high-fiber diet have more SCFA production by their bacteria and less inflammation.

The research so far only scratches the surface. Scientists may discover many other metabolites that positively or negatively affect the immune system. And as the evidence grows that the gut microbiota do indeed have ways of altering immune function, how can we change it at will?

To date it has proven hard to find short-term interventions that change the microbiota in humans for the long term – it seems to keep coming back to its baseline state. Khamsi reports, though, that scientists are learning how specific probiotics and prebiotics could alter microbial communities.

Finding out how to maximize the efficacy of probiotics involves learning more about the ecosystem of the gut. It seems probiotics have a greater chance of taking hold in the digestive tract if multiple strains of bacteria are delivered at once.

Meanwhile, other researchers – in Belgium and elsewhere – are investigating prebiotics as a way to change the microbiota and alter the immune system in ways that change disease trajectories. Prebiotics – as ‘fertilizer’ for growing more of the desired gut bacteria – may have the most immediate therapeutic promise for modulating the microbiota and controlling inflammation, according to Stanley Hazen.

Adding bacteria to the gut, or adding food to help bacteria grow on their own, could one day help us tune immunity up or down. When we begin to understand this exceedingly complex process, it will help us turn down the volume on our future risk of disease.