Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses

By S. Hapfelmeier, Melissa A. E. Lawson, E. Slack, J. Kirundi, M. Stoel, M. Heikenwalder, J. Cahenzli, Yuliya Velykoredko, M. L. Balmer, K. Endt and 4 more. Science, 2010

800 citations recorded by the source corpus.

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. Immunoglobulin responses against nonpathogenic bacteria in the gut are specific for the resident microbial flora. The lower intestine of adult mammals is densely colonized with nonpathogenic (commensal) microbes. Gut bacteria induce protective immune responses, which ensure host-microbial mutualism. The continuous presence of commensal intestinal bacteria has made it difficult to study mucosal immune dynamics. Here, we report a reversible germ-free colonization system in mice that is independent of diet or antibiotic manipulation. A slow (more than 14 days) onset of a long-lived (half-life over 16 weeks), highly specific anticommensal immunoglobulin A (IgA) response in germ-free mice was observed. Ongoing commensal exposure in colonized mice rapidly abrogated this response. Sequential doses lacked a classical prime-boost effect seen in systemic vaccination, but specific IgA induction occurred as a stepwise response to current bacterial exposure, such that the antibody repertoire matched the existing commensal content.

Subfields: Immunology, Infectious Diseases, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/197cc7deb8f492c36b0dd9c95d7b50f9ae3f0d36

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Citations in the corpus

From Vaccines to Memory and Back (2010, background): “A recent study has suggested that there is attrition of previously induced immune responses in the gut because of competition by ongoing responses being continuously generated by the commensal flora (Hapfelmeier et al., 2010).”
The role of gut microbiota in immune homeostasis and autoimmunity (2012, background): “Thus, the gut microbiota is a major driving force for mucosal IgA production; a large dose (10(9) colony-forming unit or CFU) of live bacteria was required to induce a high titer of secretory IgA in GF mice.(56) Mucosal IgA induction lacks a memory response, which explains the recognition of intesti”
The gut microbiome: Relationships with disease and opportunities for therapy (2018, background): “increased IL-22 production (Zelante et al., 2013) Protection against intestinal inflammation in mouse models of colitis (Lamas et al., 2016) IPA (tryptophan metabolism) Clostridium sporogenes Maintenance of intestinal barrier function and mucosal homeostasis (Venkatesh et al., 2014) Increased produc”
Microbiota in health and diseases (2022, methodology): “showed that microbiota-specific sIgA response was observed in GF mice using reversible microbial colonization system.(94) The sIgA induction was confirmed as a gradual response to current bacterial exposure, suggesting a crosstalk between microbiota and immune system.”
Role of the Microbiota in Immunity and inflammation (2014, background): “Indeed, established IgA producing clones are outcompeted by novel anti-bacterial responses allowing the mucosal immune system to respond to a constantly changing microbiota (Hapfelmeier et al., 2010).”
Genetics and pathogenesis of inflammatory bowel disease (2011, background): “Similarly, the gut microbiota induces a dynamic IgA response, with qualitative and/or quantitative defects in IgA production resulting in impaired control of the microbial communitie”
Intestinal bacterial colonization induces mutualistic regulatory T cell responses. (2011, background): “It is also clear that colonization induces secretion of immunoglobulin (Ig) A and almost no other isotype in themucosa (Hapfelmeier et al., 2010).”
The Hologenome Concept: Human, Animal and Plant Microbiota (2014, background): “It should be mentioned that immune response to integral microbiota via IgM differs from its reaction to pathogenic microorganisms (Hapfelmeier et al. 2010).”
Homeostatic immunity and the microbiota (2017, neutral): “One remarkable feature of mucosal IgA responses is that these cells lack classical memory characteristics and are able to respond to flux in commensal microbiota composition allowing the mucosal immune system to respond to a changing microbiota (Hapfelmeier et al., 2010).”
Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour. (2015, background): “Specifically, the absence of bacteria from birth not only alters immune system function and our capacity to fight infection (Hapfelmeier et al., 2010), but also interferes with normal brain function and behaviours including anxiety (Diaz Heijtz et al.”