The human gut microbiome is a complex ecosystem, which contributes essential functions to human physiology. Changes to the microbiome are associated with several chronic diseases characterised by inflammation, including neurodegenerative and autoimmune diseases. Microbiome-derived effector molecules comprising nucleic acids, (poly)peptides and metabolites are present at high levels in the gut but have so far eluded systematic study. I will discuss how integrated multi-omic analyses combined with human organ-on-chip systems can be leveraged to shine light on this molecular “dark matter” with potential for the development of novel diagnostic and therapeutic applications.