Gastrointestinal commensal microbes usually exist in mutualistic relationship with their mammalian host. This relationship exists even though the mammalian host immune system is equipped with exquisite sensors for microbial chemical structures which trigger powerful immune defense mechanisms. Such beneficial mutualism is specifically maintained at the gut mucosal interface by a variety of physical and bioactive barriers as well as specific immunregulatory mechanisms. In addition, there is a strict compartmentalization between systemic and gut mucosal immunity--at least in inbred mice--which focuses adaptive immunity to gut microbes specifically to the gut tissue and the gut lumen. Only in circumstances of increased gut microbial exposure due to elevated gut epithelial permeability, due to genetic deficiencies in local defense mechanisms, due to imbalances in local immune regulation or in case of gastrointestinal pathogenic bacterial infections this compartmentalization is broken and systemic immune responses to gut microbes are induced, which manifest for example as systemic antibody responses specific for gut microbial antigens. Here we briefly discuss the abundance of systemic antibody responses to commensal gut bacteria in healthy humans and how it is altered in situations with chronic enteropathies such as in inflammatory bowel disease and HIV-1 infection or infection with gut bacterial pathogens.