The mammalian intestines harbor trillions of commensal microorganisms composed of thousands of species that are collectively called gut microbiota. Among the microbiota, bacteria are the predominant microorganism, with viruses, protozoa, and fungi (mycobiota) making up a relatively smaller population. The microbial communities play fundamental roles in the maturation and orchestration of the immune landscape in health and disease.Primarily, the gut microbiota modulates the immune system to maintain homeostasis and plays a crucial role in regulating the pathogenesis and pathophysiology of inflammatory, neuronal, and metabolic disorders. The microbiota modulates the host immune system through direct interactions with immune cells or indirect mechanisms such as producing short-chain acids and diverse metabolites. Numerous researchers have put extensive efforts into investigating the role of microbes in immune regulation, discovering novel immunomodulatory microbial species, identifying key effector molecules, and demonstrating how microbes and their key effector molecules mechanistically impact the host immune system. Consequently, recent studies suggest that several microbial species and their immunomodulatory molecules have therapeutic applicability in preclinical settings of multiple disorders. Nonetheless, it is still unclear why and how a handful of microorganisms and their key molecules affect the host immunity in diverse diseases. This review mainly discusses the role of microbes and their metabolites in T helper cell differentiation, immunomodulatory function, and their modes of action.