The gut microbiome engages in constant interactions with the immune system, laying fundamentals for what we perceive as health or disease. The microbiome acts locally in the gut and distally in other organs (for example, the lungs or the brain). These wide-ranging effects are achieved, at least in part, through microbial metabolites released into circulation. Prime examples are short-chain fatty acids (SCFAs), shown to protect against various conditions. However, SCFAs, along with a handful of other compounds, constitute only a small fraction of microbial products known for their immunomodulatory activity. This underlines an urgent need for discoveries of new metabolites, defining their mechanisms of action and testing them in different disease settings. Our research program aims to identify immunosuppressive metabolites active in the lungs and the brain, explain their mechanisms of action, and tailor them toward the formulation of therapeutics against acute respiratory distress syndrome and multiple sclerosis. We believe this strategy may pave the way to harnessing microbial metabolites for human health benefits.