Under homeostatic conditions, bidirectional interactions between the gastrointestinal and the immune system allow production of both inflammatory and anti-inflammatory responses designed to prevent undesirable inflammation and to respond efficiently to potential insults. This balanced regulation can be disrupted in disorders that affect tissues remote to the gastrointestinal tract, as seen in autoimmune diseases. Recent reports have described a variety of B lymphocyte-mediated functions that likely contribute to gastrointestinal homeostasis to a greater extent than previously thought. Studies have shown that early B cell development takes place within the intestine, and that self-reactive B cells are rendered tolerant using mechanisms known to occur in the bone marrow, indicating that the gastrointestinal tract contributes to maintaining immune tolerance to self. Relatedly, continuous bacterial stimulation is essential for maintaining regulatory B cell functions and for mediating mucosal homeostasis. In studies of neuro-inflammation, intestinal IgA+ B cells, which constitute a prominent source of lymphocytes in the organism, can migrate to inflamed tissues and exert regulatory functions that attenuate inflammation in the central nervous system, indicating that, in addition to its local effects in the intestin, gut microbiota-B cell crosstalk can exert long-range beneficial effects. At the translational level, metabolites produced by gut microbiota can act as B cell-intrinsic epigenetic modulators, reducing inflammation in the skin and kidneys of mice suffering from experimental lupus. Given the significant impact of B cell-intestinal microbiota interactions, there is a momentum for improving our understanding of these pathways in autoinflammatory diseases and for designing novel therapeutic strategies for systemic autoimmune diseases where B cells play key roles.