Bioderived materials that disarm the gut mucosal immune system: Potential lessons from commensal microbiota

Over the course of evolution, mammals and gut commensal microbes have adapted to coexist with each other. This homeostatic coexistence is dependent on an intricate balance between tolerogenic and inflammatory responses directed towards beneficial, commensal microbes and pathogenic intruders, respectively. Immune tolerance towards the gut microflora is largely sustained by immunomodulatory molecules produced by the commensals, which protect the bacteria from immune advances and maintain the gut's unique tolerogenic microenvironment, as well as systemic homeostasis. The identification and characterization of commensal-derived, tolerogenic molecules could lead to their utilization in biomaterials-inspired delivery schemes involving nano/microparticles or hydrogels, and potentially lead to the next generation of commensal-derived therapeutics. Moreover, gut-on-chip technologies could augment the discovery and characterization of influential commensals by providing realistic in vitro models conducive to finicky microbes. In this review, we provide an overview of the gut immune system, describe its intricate relationships with the microflora and identify major genera involved in maintaining tolerogenic responses and peripheral homeostasis. More relevant to biomaterials, we discuss commensal-derived molecules that are known to interface with immune cells and discuss potential strategies for their incorporation into biomaterial-based strategies aimed at culling inflammatory diseases. We hope this review will bridge the current findings in gut immunology, microbiology and biomaterials and spark further investigation into this emerging field. STATEMENT OF SIGNIFICANCE: Despite its tremendous potential to culminate into revolutionary therapeutics, the synergy between immunology, microbiology, and biomaterials has only been explored at a superficial level. Strategic incorporation of biomaterial-based technologies may be necessary to fully characterize and capitalize on the rapidly growing repertoire of immunomodulatory molecules derived from commensal microbes. Bioengineers may be able to combine state-of-the-art delivery platforms with immunomodulatory cues from commensals to provide a more holistic approach to combating inflammatory disease. This interdisciplinary approach could potentiate a neoteric field of research - "commensal-inspired" therapeutics with the promise of revolutionizing the treatment of inflammatory disease.