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Depression is a common mental health condition with a large social and economic impact. While depression etiology is multifactorial, chronic stress is a well-accepted contributor to disease onset. In addition, depression is associated with altered gut microbial signatures that can be replicated in animal models. While targeted restoration of the microbiome has been shown to reduce depressive-like behaviors in mice, the complexity and diversity of the human microbiome has complicated therapeutic intervention in patients. To circumvent these limitations, there is a critical need for identifying pathways responsible for microbiome dysbiosis. Here, for the first time, we identify the changes in host physiology that induce microbiome dysbiosis. Specifically, we show that a component of mucosal layer, the transmembrane protein mucin 13, can regulate microbiome composition. Using a model of chronic stress to induce behavioral and microbial changes in mice, we show a significant reduction in mucin 13 expression across the intestines that occurs independently of the microbiome. Furthermore, deletingMuc13leads to gut dysbiosis, and baseline behavioral changes normally observed after stress exposure. Together, these results validate the hypothesis that mucosal layer disruption is an initiating event in stress-induced dysbiosis and offer mucin 13 as a potential new therapeutic target for microbiome dysbiosis in stress-induced depression. For the first time, our data provide an upstream and conserved target for treating microbiome dysbiosis, a result with sweeping implications for diseases presenting with microbial alterations.