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Andrew J Macpherson

Publications and source records attributed to Andrew J Macpherson.

14 recordsLinked to original sources
PubMed2025

A global survey of taxa-metabolic associations across mouse microbiome communities.

Host-microbiota mutualism is rooted in the exchange of dietary and metabolic molecules. Microbial diversity broadens the metabolite pool, with each taxon contributing distinct compounds in varying proportions. In the human microbiome, high variability in consortial composition is largely compensated by similar metabolic functions across different taxa. However, the extent of compensation in lower diversity mouse models, and whether vivaria are metabolically equivalent, is unknown. We provide a searchable resource of microbiome composition variability across 51 murine vivaria and 12 wild mouse colonies worldwide, with vivarium-specific variants mapped according to predicted 3D structures for each microbial species. Our matched metabolomics data show that realized metabolic potential has relatively low variability, providing functional evidence for metabolic compensation. Additionally, variability is related to taxonomic composition rather than vivarium, revealing taxa-metabolite associations that are potentially relevant to phenotypic differences between vivaria. Collectively, this resource offers tools to strengthen microbiome studies and collaborative science.

Animals↗
PubMed2006

Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota.

Vertebrates are essentially born germ-free but normally acquire a complex intestinal microbiota soon after birth. Most of these organisms are non-pathogenic to immunocompetent hosts; in fact, many are beneficial, supplying vitamins for host nutrition and filling the available microbiological niche to limit access and consequent pathology when pathogens are encountered. Thus, mammalian health depends on mutualism between host and flora. This is evident in inflammatory conditions such as inflammatory bowel disease, where aberrant responses to microbiota can result in host pathology. Studies with axenic (germ-free) or deliberately colonised animals have revealed that commensal organisms are required for the development of a fully functional immune system and affect many physiological processes within the host. Here, we describe the technical requirements for raising and maintaining axenic and gnotobiotic animals, and highlight the extreme diversity of changes within and beyond the immune system that occur when a germ-free animal is colonized with commensal bacteria.

Animals↗
PubMed2006

Adaptation of solitary intestinal lymphoid tissue in response to microbiota and chemokine receptor CCR7 signaling.

Besides Peyer's patches, solitary intestinal lymphoid tissue (SILT) provides a structural platform to efficiently initiate immune responses in the murine small intestine. SILT consists of dynamic lymphoid aggregates that are heterogeneous in size and composition, ranging from small clusters of mostly lineage-negative cells known as cryptopatches to larger isolated lymphoid follicles rich in B cells. In this study, we report that in chemokine receptor CCR7-deficient mice SILT is enlarged, although unchanged in frequency and cellular composition compared with wild-type mice. This phenotype is conferred by bone marrow-derived cells and is independent of the presence of intestinal bacteria. Remarkably, particularly small-sized SILT predominates in germfree wild-type mice. Colonization of wild-type mice with commensal bacteria provokes an adjustment of the spectrum of SILT to that observed under specific pathogen-free conditions by the conversion of pre-existing lymphoid structures into larger-sized SILT. In conclusion, our findings establish that intestinal microbes influence the manifestation of gut-associated lymphoid tissues and identify CCR7 signaling as an endogeneous factor that controls this process.

Adaptation, Physiological↗
PubMed2006

Mechanisms of neonatal mucosal antibody protection.

Following an abrupt transition at birth from the sterile uterus to an environment with abundant commensal and pathogenic microbes, neonatal mammals are protected by maternal Abs at mucosal surfaces. We show in mice that different Ab isotypes work in distinct ways to protect the neonatal mucosal surface. Secretory IgA acts to limit penetration of commensal intestinal bacteria through the neonatal intestinal epithelium: an apparently primitive process that does not require diversification of the primary natural Ab repertoire. In contrast, neonatal protection against the exclusively luminal parasite Heligmosomoides polygyrus required IgG from primed females. This immune IgG could either be delivered directly in milk or retrotransported via neonatal Fc receptor from the neonatal serum into the intestinal lumen to exert its protective effect.

Animals↗
PubMed2006

Mesenteric lymph nodes at the center of immune anatomy.

The surface of the intestinal mucosa is constantly assaulted by food antigens and enormous numbers of commensal microbes and their products, which are sampled by dendritic cells (DCs). Recent work shows that the mesenteric lymph nodes (MLNs) are the key site for tolerance induction to food proteins and that they also act as a firewall to prevent live commensal intestinal bacteria from penetrating the systemic immune system.

Administration, Oral↗
PubMed2005

Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria.

Animals contain an enormous load of non-pathogenic bacteria in the lower intestine, which exploit an environment with a stable temperature and abundant carbon sources. Our load of bacteria outnumbers our own cells. In order to survive with such a high number of organisms in very close proximity to host tissues the intestinal mucosa and its immune system is highly adapted. Mucosal immune responses are induced by small numbers of live commensal organisms penetrating the Peyer's patches and persisting in dendritic cells (DC). These DC can induce immunoglobulin A+ (IgA+) B cells, which recirculate through the lymph and bloodstream to populate the lamina propria and secrete protective IgA. Because DC loaded with commensal bacteria do not penetrate further than the mesenteric lymph nodes, immune induction to commensals is confined to the mucosa, allowing strong mucosal immune responses to be induced whilst the systemic immune system remains relatively ignorant of these organisms.

Adaptation, Physiological↗
PubMed2005

Comparison of Salmonella enterica serovar Typhimurium colitis in germfree mice and mice pretreated with streptomycin.

Salmonella enterica subspecies 1 serovar Typhimurium is a common cause of bacterial enterocolitis. Mice are generally protected from Salmonella serovar Typhimurium colonization and enterocolitis by their resident intestinal microflora. This phenomenon is called "colonization resistance" (CR). Two murine Salmonella serovar Typhimurium infection models are based on the neutralization of CR: (i) in specific-pathogen-free mice pretreated with streptomycin (StrSPF mice) antibiotics disrupt the intestinal microflora; and (ii) germfree (GF) mice are raised without any intestinal microflora, but their intestines show distinct physiologic and immunologic characteristics. It has been unclear whether the same pathogenetic mechanisms trigger Salmonella serovar Typhimurium colitis in GF and StrSPF mice. In this study, we compared the two colitis models. In both of the models Salmonella serovar Typhimurium efficiently colonized the large intestine and triggered cecum and colon inflammation starting 8 h postinfection. The type III secretion system encoded in Salmonella pathogenicity island 1 was essential in both disease models. Thus, Salmonella serovar Typhimurium colitis is triggered by similar pathogenetic mechanisms in StrSPF and GF mice. This is remarkable considering the distinct physiological properties of the GF mouse gut. One obvious difference was more pronounced damage and reduced regenerative response of the cecal epithelium in GF mice. Overall, StrSPF mice and GF mice provide similar but not identical models for Salmonella serovar Typhimurium colitis.

Animals↗
PubMed2004

Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria.

The enormous number of commensal bacteria in the lower intestine of vertebrates share abundant molecular patterns used for innate immune recognition of pathogenic bacteria. We show that, even though commensals are rapidly killed by macrophages, intestinal dendritic cells (DCs) can retain small numbers of live commensals for several days. This allows DCs to selectively induce IgA, which helps protect against mucosal penetration by commensals. The commensal-loaded DCs are restricted to the mucosal immune compartment by the mesenteric lymph nodes, which ensures that immune responses to commensal bacteria are induced locally, without potentially damaging systemic immune responses.

Animals↗
PubMed2004

Compartmentalization of the mucosal immune responses to commensal intestinal bacteria.

Mammals coexist with a luxuriant load of bacteria in the lower intestine (up to 10(12) organisms/g of intestinal contents). Although these bacteria do not cause disease if they remain within the intestinal lumen, they contain abundant immunostimulatory molecules that trigger immunopathology if the bacteria penetrate the body in large numbers. The physical barrier consists only of a single epithelial cell layer with overlying mucus, but comparisons between animals kept in germ-free conditions and those colonized with bacteria show that bacteria induce both mucosal B cells and some T cell subsets; these adaptations are assumed to function as an immune barrier against bacterial penetration, but the mechanisms are poorly understood. In mice with normal intestinal flora, but no pathogens, there is a secretory IgA response against bacterial membrane proteins and other cell wall components. Whereas induction of IgA against cholera toxin is highly T help dependent, secretory IgA against commensal bacteria is induced by both T independent and T dependent pathways. When animals are kept in clean conditions and free of pathogens, there is still a profound intestinal secretory IgA response against the commensal intestinal flora. However, T dependent serum IgG responses against commensal bacteria do not occur in immunocompetent animals unless they are deliberately injected intravenously with 10(4) to 10(6) organisms. In other words, unmanipulated pathogen-free mice are systemically ignorant but not tolerant of their commensal flora despite the mucosal immune response to these organisms. In mice that are challenged with intestinal doses of commensal bacteria, small numbers of commensals penetrate the epithelial cell layer and survive within dendritic cells (DC). These commensal-loaded DC induce IgA, but because they are confined within the mucosal immune system by the mesenteric lymph nodes, they do not induce systemic immune responses. In this way the mucosal immune responses to commensals are geographically and functionally separated from systemic immunity.

Animals↗
PubMed2003

Hypergammaglobulinemia and autoantibody induction mechanisms in viral infections.

Polyclonal hypergammaglobulinemia is a characteristic of chronic inflammatory conditions, including persisting viral infections and autoimmune diseases. Here we have studied hypergammaglobulinemia in mice infected with lymphocytic choriomeningitis virus (LCMV), which induces nonspecific immunoglobulins as a result of switching natural IgM specificities to IgG. The process is dependent on help from CD4+ T cells that specifically recognize LCMV peptides presented by B cells on major histocompatibility complex class II molecules. Thus, hypergammaglobulinemia may arise when specific helper T cells recognize B cells that have processed viral antigens irrespective of the B cell receptor specificity. This nonspecific B cell activation may contribute to antibody-mediated autoimmunity.

Animals↗
PubMed2002

The donor splice site mutation in NFkappaB-inducing kinase of alymphoplasia (aly/aly) mice.

The alymphoplasia (aly/aly) mouse has a spontaneous mutation maintained on a C57BL/6xAEJ ( H-2(b)) background that results in an absence of extrasplenic secondary lymphoid tissues. The cDNA defect has previously been shown to reside in a point mutation causing a G855R substitution in NFkappaB-inducing kinase (NIK). Since the aly/aly female cannot lactate, the strain must be bred by intercrossing heterozygous females with homozygous males and the offspring typed by serum IgA levels at the age of 4-6 weeks. We originally determined the genomic location of the alymphoplasia mutation by sequencing boundaries of regions homologous to human NIK exons, although recently the entire genomic sequence of murine C57BL/6 NIK has become available through the mouse genome project. The aly mutation is at position -1 of an intron donor consensus splice site. Exon-connexion PCR confirmed that splicing does occur across this site. Using the genomic information, we also developed a method of PCR typing of aly/aly mice from tail clips, and used this to derive an aly/aly muMT double-mutant strain in which antibody independent typing is essential. Genetic typing should considerably simplify husbandry and manipulation of the aly/aly genetic background, which is widely used as a recipient in lymphocyte transfer experiments to permit examination of the relative role of secondary lymphoid structures in immune responses.

Animals↗