he intestinal tract is the first barrier from the externaltotheinternalenvironment.Assuch,itplaysakeyrolenotonlyinnutrientabsorptionbutalsoinprotectionfromtoxinsandimmunity.However,thegutisnotaloneinthisregulatory role. The mammalian intestinal tract is colo-nized by trillions of microorganisms collectively referredto as the microbiome. These bacteria have a symbioticrelationship with the host and contribute to many vitalintestinalfunctions(1,2).Thesefunctionsincludehomeo-stasis of the immune system, including protection againstpathogens, intestinal cell development and proliferation,xenobiotic metabolism, bone mineral density, behavior,and metabolism (1, 2).That the gut microbiota plays a critical role in main-taining not only intestinal but also host homeostasis as awhole has been well described (3). Its role in disease hasbecomemoreapparentoverthelastseveralyearscoincid-ing with advances in technology that allow for compre-hensive high-throughput sequencing analysis of the mi-crobiome. Data suggest that shifting of the microbiotapopulationsaltersthebalanceofthemicrobiome(dysbio-sis), and this increases the risk of intestinal infection (4)and intestinal disorders such as irritable bowel syndromeandinflammatoryboweldisease(5).Moreover,dysbiosisis implicated in diseases thought to be unrelated to intes-tinal function, including cardiovascular disease (6), obe-sity (2, 7), diabetes (8), autism (9), and even cancer (5).Conversely,correctionofdysbiosisisalsothoughttobeamechanism for the drastic weight loss and metabolic im-provements seen with bariatric surgery (10).Given the wide-ranging implications for alterations inthe microbiota, determining what regulates their differ-entiation is critical but, at present, is not completely un-derstood.Variationofthemicrobiotaisinfluencedinformor function by the introduction of probiotics (11), antibi-otics(12),anddiet(13)aswellasdevelopmentandaging(5), altogether demonstrating the role of the environmentinregulatingmicrobiomecomposition.Althoughgeneticsdoes play a role (14), internal pressures dictated by hostphysiology also influence the local colonization. Panethcells, which are secretory epithelial cells, regulate devel-opment of the barrier between intestinal microbes andmucosalepithelialcellsandalsosecreteantimicrobialpep-tides (15), gene-encoded antibiotics (16). Antimicrobialpeptides, in turn, target intruding pathogens but also res-identmicrobiotaofthesmallintestine(17,18),thusshap-ingthecompositionofthemicrobiota.Understandingreg-ulationofPanethcellsand/orantimicrobialpeptidescouldprovideanewpipelinefortherapeutictargetingofawiderange of chronic diseases.Anewstudyinthisissueof