The article discusses the fundamental role of the microbiota in the induction, training, and function of the host immune system. The immune system, in turn, has evolved to maintain a symbiotic relationship with these diverse microbes. When functioning optimally, this alliance allows for the induction of protective responses against pathogens and the maintenance of regulatory pathways that ensure tolerance to harmless antigens. However, in high-income countries, factors such as overuse of antibiotics, dietary changes, and the elimination of certain microbial partners like nematodes have led to a microbiota that lacks the resilience and diversity needed to establish balanced immune responses, contributing to the rise in autoimmune and inflammatory disorders. The article highlights the importance of early interactions between the host and commensal microbes during fetal development and neonatal life, which set the tone for long-term immune system development. These interactions are crucial for the establishment of a durable and homeostatic relationship between the host and the microbiota. The immune system's role in maintaining this relationship is multifaceted, including the production of antimicrobial peptides, the formation of the "mucosal firewall," and the induction of regulatory T cells (Treg) to prevent excessive inflammation. The microbiota also plays a critical role in inducing regulatory responses, such as the induction of Treg cells, which are essential for maintaining oral tolerance and preventing autoimmune diseases. Commensals can produce metabolites like short-chain fatty acids (SCFA), which regulate the function and activation of Treg cells. Additionally, commensals can control the function of inflammatory cells and modulate the immune response to pathogens, both directly and by influencing the immune system's response to infection. The article also explores how the microbiota can induce protective immune responses, including colonization resistance against pathogens, the promotion of adaptive immunity, and the systemic control of immunity. It emphasizes the importance of specific microbes, known as "keystone species," in shaping immune responses and their potential therapeutic applications, such as in the treatment of multidrug-resistant infections. Overall, the article underscores the complex and dynamic nature of the host-microbiota relationship, highlighting the need for a holistic understanding of how these interactions influence health and disease.The article discusses the fundamental role of the microbiota in the induction, training, and function of the host immune system. The immune system, in turn, has evolved to maintain a symbiotic relationship with these diverse microbes. When functioning optimally, this alliance allows for the induction of protective responses against pathogens and the maintenance of regulatory pathways that ensure tolerance to harmless antigens. However, in high-income countries, factors such as overuse of antibiotics, dietary changes, and the elimination of certain microbial partners like nematodes have led to a microbiota that lacks the resilience and diversity needed to establish balanced immune responses, contributing to the rise in autoimmune and inflammatory disorders. The article highlights the importance of early interactions between the host and commensal microbes during fetal development and neonatal life, which set the tone for long-term immune system development. These interactions are crucial for the establishment of a durable and homeostatic relationship between the host and the microbiota. The immune system's role in maintaining this relationship is multifaceted, including the production of antimicrobial peptides, the formation of the "mucosal firewall," and the induction of regulatory T cells (Treg) to prevent excessive inflammation. The microbiota also plays a critical role in inducing regulatory responses, such as the induction of Treg cells, which are essential for maintaining oral tolerance and preventing autoimmune diseases. Commensals can produce metabolites like short-chain fatty acids (SCFA), which regulate the function and activation of Treg cells. Additionally, commensals can control the function of inflammatory cells and modulate the immune response to pathogens, both directly and by influencing the immune system's response to infection. The article also explores how the microbiota can induce protective immune responses, including colonization resistance against pathogens, the promotion of adaptive immunity, and the systemic control of immunity. It emphasizes the importance of specific microbes, known as "keystone species," in shaping immune responses and their potential therapeutic applications, such as in the treatment of multidrug-resistant infections. Overall, the article underscores the complex and dynamic nature of the host-microbiota relationship, highlighting the need for a holistic understanding of how these interactions influence health and disease.