The rumen and intestines in the cattle digestive tract house 2 complex, symbiotic microbial communities, which are established early in a calf’s life and have complementary roles in cattle health and productivity. It is unclear how these vital relationships between microbes and host cells are maintained throughout life, but the ability of prokaryotic and eukaryotic cells to communicate with one another by direct contact or through secreted or shed chemical substances may be a factor. Commensal microflora of the intestinal tract shape gut immunity and enteric nervous system development, and are essential for feed assimilation and energy production. Some bacteria produce neurotransmitter substances, and microbial products such as exotoxins and pathogen-associated molecular patterns are recognized by host cells in the intestinal mucosa. The host in turn may influence establishment and maintenance of ruminal and intestinal microbial communities. Neurotransmitters and other chemical signals secreted into the intestinal lumen may influence bacterial growth and virulence. Epithelial cells in the rumen wall and intestinal mucosa are key points of microbe-host contact regulated by nerves and hormones. In the intestinal mucosa, the sympathetic neurotransmitter and stress hormone norepinephrine increases bacterial internalization into Peyer’s patches, the inductive site for gut immunity. Norepinephrine enhances non-intimate adherence of Escherichia coli to colonic epithelial cells and promotes vectorial transport of secretory immunoglobulin A across the small and large intestinal mucosae, which stabilizes mucosa-associated bacteria. Stress activation of the sympatho-adrenomedullary system has profound effects on the digestive tract and on the microbial communities housed within it. Knowledge of the bidirectional communication between host cells and prokaryotic bacteria is steadily increasing for the intestinal tract, but is lacking with respect to the rumen. By understanding the cellular and chemical factors that impact ruminal and intestinal microbial populations, we can potentially identify targets and develop strategies for maintaining the well-being and enhancing the productivity of cattle and other ruminants.