Book excerpt: The intestine has several means for maintaining immune homeostasis and for avoiding inflammation despite massive antigenic stimulation by food components and by commensal bacteria residing in the gut mucosa. These mechanisms include physical and biological barriers such as (i) the intestinal epithelial barrier (IEB); (ii) the gut vascular barrier (GVB) and (iii) the mucus layer. In particular, the mucus layer does not simply act as a diffusion barrier but has important dynamic functions that regulate the type of commensal bacteria residing in the inner mucus layer, enabling the passage of food and bacterial products into the gut tissue and systemic circulation. Importantly, the mucosal layer also has key immune regulatory functions. A healthy mucus structure is fundamental for promoting the presence of beneficial commensal bacteria, such as the short-chain fatty acids (SCFA)-producing bacteria which are known to promote immune tolerance. Moreover, the mucus layer contains anti-microbial peptides (AMPs) and mucins that have key immune modulatory functions. The integrated response of these combined defense systems is fundamental for containing microbes and their products within the intestine; for avoiding their systemic spread and for suppressing their capacity to activate systemic immune and autoimmune responses.