A Gut Feeling: The mammalian gut is colonized by many nonpathogenic, commensal microbes. In order to prevent the body from mounting inappropriate immune responses to these microbes, plasma cells in the gut produce large amounts of immunoglobulin A (IgA) specific for commensal bacteria. Because of the difficulties of uncoupling IgA production from microbial colonization, how commensal bacteria shape the gut IgA response is not well understood. Hapfelmeier et al. (p. 1705 ; see the Perspective by Cerutti ) have now devised a way to get around this problem by developing a reversible system of gut bacterial colonization in mice. Commensal-specific IgA responses were able to persist for long periods of time in the absence of microbial colonization and required the presence of high microbial loads in the gut for their induction. IgA responses upon bacterial reexposure did not resemble the synergistic prime-boost effect seen in classical immunological memory responses but rather exhibited an additive effect that matched the current bacterial content present in the gut. The body thus constantly adapts the commensal-specific immune response to the microbial species present in the gut, which contrasts with the systemic immune response, which persists in the absence of pathogenic microbes.

The overall composition of the mammalian intestinal microbiota varies between individuals: within each individual there are differences along the length of the intestinal tract related to host nutrition, intestinal motility and secretions. Mucus is a highly regenerative protective lubricant glycoprotein sheet secreted by host intestinal goblet cells; the inner mucus layer is nearly sterile. Here we show that the outer mucus of the large intestine forms a unique microbial niche with distinct communities, including bacteria without specialized mucolytic capability. Bacterial species present in the mucus show differential proliferation and resource utilization compared with the same species in the intestinal lumen, with high recovery of bioavailable iron and consumption of epithelial-derived carbon sources according to their genome-encoded metabolic repertoire. Functional competition for existence in this intimate layer is likely to be a major determinant of microbiota composition and microbial molecular exchange with the host.

Maintaining Mutual Ignorance: Our gut is colonized by trillions of bacteria that do not activate the immune system because of careful compartmentalization. Such compartmentalization means that our immune system is “ignorant” of these microbes and thus it has been proposed that loss of compartmentalization might result in an immune response to the colonizing bacteria. Microorganisms are sensed by cells that express pattern recognition receptors, such as Toll-like receptors, which recognize patterns specific to those microbes. Slack et al. (p. 617 ) show that Toll-like receptor–dependent signaling is required to maintain compartmentalization of bacteria to the gut of mice. In the absence of Toll-dependent signaling, intestinal bacteria disseminated throughout the body and the mice mounted a high-titer antibody response against them. This antibody response was of great functional importance because, despite the loss of systemic ignorance to intestinal microbes, the mice were tolerant of the bacteria. Thus, in the absence of innate immunity, the adaptive immune system can compensate so that host and bacterial mutualism can be maintained.

The liver forms a firewall that protects against vascular-borne gut microbes and is commonly impaired in liver disease.