Segmented Filamentous Bacteria Are Potent Stimuli of a Physiologically Normal State of the Murine Gut Mucosal Immune System

Abstract

Segmented filamentous bacteria (SFB) are autochthonous bacteria inhabiting the intestinal tracts of many species, including humans. We studied the effect of SFB on the mucosal immune system by monoassociating formerly germfree C3H/HeN mice with SFB. At various time points during 190 days of colonization, fragment cultures of small intestine and Peyer’s patches (PP) were analyzed for total immunoglobulin A (IgA) and SFB-specific IgA production. Also, phenotypic changes indicating germinal center reactions (GCRs) and the activation of CD4+ T cells in PP were determined by using fluorescence-activated cell sorter analyses. A second group of SFB-monoassociated mice was colonized with a gram-negative commensal,Morganella morganii, to determine if the mucosal immune system was again stimulated and to evaluate the effect of prior colonization with SFB on the ability of M. morganii to translocate to the spleen and mesenteric lymph nodes. We found that SFB stimulated GCRs in PP from day 6 after monoassociation, that GCRs only gradually waned over the entire length of colonization, that natural IgA production was increased to levels 24 to 63% of that of conventionally reared mice, and that SFB-specific IgA was produced but accounted for less than 1.4% of total IgA. Also, the proportion of CD4+, CD45RBlow T cells, indicative of activated cells, gradually increased in the PP to the level found in conventionally reared mice. Secondary colonization with M. morganii was able to stimulate GCRs anew, leading to a specific IgA antibody response. Previous stimulation of mucosal immunity by SFB did not prevent the translocation of M. morganii in the double-colonized mice. Our findings generally indicate that SFB are one of the single most potent microbial stimuli of the gut mucosal immune system.

Segmented filamentous bacteria‐induced immune responses: a balancing act between host protection and autoimmunity

“…Examination of the transcriptional programming induced in IECs by SFB adhesion revealed that serum amyloid A (SAA) proteins are important factors in Th17 programming . The molecular trigger of SAA following SFB adhesion was reported to include the transcription factor CCAAT/enhancer‐binding protein δ induced by reorganization of the actin skeleton in epithelial cells . Epithelial secretion of SAA1 and SAA2 induced by SFB adhesion acts on CD11c + cells to stimulate cytokine production that shapes the tissue microenvironment to potentiate the induction of Th17 cells.…”

“…Epithelial secretion of SAA1 and SAA2 induced by SFB adhesion acts on CD11c + cells to stimulate cytokine production that shapes the tissue microenvironment to potentiate the induction of Th17 cells. Interleukin‐23 produced by antigen‐presenting cells (APCs) upon recognition of SFB also initiates an IL‐23R/IL‐22 circuit in type 3 ILCs (ILC3) to promote SAA secretion from the epithelium; however, this appears to occur independent of SFB adhesion …”

“…Of the immunomodulatory effects driven by SFB colonization, the most recognized is the ability to drive postnatal maturation of the intestinal immune system, including IL‐17‐producing CD4 + T cells (Th17 cells), which have antimicrobial effects and promote barrier function to protect the host from infection with extracellular pathogens. SFB also influence a number of other protective immune responses including the development of lymphoid tissue and IgA production, and innate lymphoid cell (ILC)‐mediated barrier protection . This protection can come at a cost, however, as SFB‐induced Th17 cells can trigger autoimmunity in susceptible hosts.…”

Colonization and distribution of segmented filamentous bacteria (SFB) in chicken gastrointestinal tract and their relationship with host immunity

“…In SFB‐monoassociated mice, the immunological characteristics of the small intestine are almost converted to that in conventional mice without the assistance of other bacteria (Umesaki et al ., ). GF mice, after being solely colonized with SFB, show fully developed thymus‐dependent IELs with an increase in IgA‐producing cells and IgA titers (Klaasen et al ., , b; Umesaki et al ., , ; Snel et al ., ; Talham et al ., ). These results indicate that SFB could stimulate the mucosal immune system to a greater extent than other autochthonous gut bacteria (Klaasen et al ., , b).…”

Incorporating the gut microbiota into models of human and non‐human primate ecology and evolution

“…mediated by antibodies produced by B cells) to recognize cells and tag pathogenic invaders for destruction, and IgA‐secreting cells are significantly reduced in germ‐free animals and absent in neonates (Benveniste et al, ,; Macpherson et al, ). Only colonization with specifically‐selected bacteria during a window of host development provokes the complete restoration of immune activity (Talham et al, ; Round and Mazmanian, ). These interactions are important for promoting immune development, decreasing the risk of autoimmune diseases, and establishing host tolerance of the gut microbiota.…”