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The intestinal tract is a host to 100 trillion of microbes that have co-evolved with mammals over the millennia. These commensal organisms are critical to the host survival. The roles that symbiotic microorganisms play in the digestion, absorption, and metabolism of nutrients have been clearly demonstrated. Additionally, commensals are indispensable in regulating host immunity. This is evidenced by the poorly developed gut immune system of germ-free mice, which can be corrected by transplantation of specific commensal bacteria. Recent advances in our understanding of the mechanism of host–microbial interaction have provided the basis for this interaction. This paper reviews some of these key studies, with a specific focus on the effect of the microbiome on the immune organ development, nonspecific immunity, specific immunity, and inflammation.