ReviewHost interactions with Segmented Filamentous Bacteria: An unusual trade-off that drives the post-natal maturation of the gut immune system
Introduction
During their billions of years of coevolution, prokaryotes and eukaryotes have established multiple and fascinating cooperations [1]. The partnership developed between mammalian hosts and their complex intestinal microbiota has become the focus of considerable attention following compelling evidence of the broad influence of intestinal bacteria on multiple host pathways in and beyond the gut [1]. Challenging issues remain such as to delineate the rules that govern the reciprocal adaptation and to define whether and how they might be manipulated for the host's benefit. One arbiter at the core of host-microbiota interactions is the immune system. The presence of a considerable number of bacteria in the intestinal lumen is indeed a potential major threat for the hosts, who therefore have evolved robust protective mechanisms for monitoring and controlling the microbial ecosystem (reviewed in [2], [3]). Conversely, commensal bacteria capable of using energetic resources available in the intestinal environment must have adapted to cope with host immune responses in order to maintain their intestinal niche. One interesting symbiont, Segmented Filamentous Bacterium (SFB), a bacterium widely present among vertebrate species, provides a remarkable example of such a trade-off. Herein, we examine how the SFB life-style in close contact with the epithelium may underlie its outstanding immunostimulatory capacities and discuss costs and benefits for the host and for the bacterium.
Section snippets
SFB life-cycle: a need for a niche at the ileal epithelium surface
The name SFB or “Candidatus Arthromitus” (Greek for “jointed thread”) is a collective name used to describe filamentous bacteria in the gut of a large number of both invertebrate and vertebrate animals that intimately attach to the epithelial lining of the digestive tract [4], [5]. SFB were first described over 100 years ago by the physician and naturalist Joseph Leidy in the gut of termites and other arthropods and 16S rRNA gene amplification of capillary picked single filaments from the
SFB sequence analysis: a genome between obligate and facultative symbionts
The genome of rat SFB and a number of mouse SFBs have recently been sequenced [8], [21], [26], [27]. The SFB genome from both species is highly similar but do contain several species SFB-specific genes of unknown function that may be involved in the species-specificity of SFB colonization. SFB has a small genome size of 1.5–1.62 Mbp, a low GC-content (27.9%) and relatively small number of genes (1420–1534 for mouse SFB). This reduced genome leaves SFB with highly auxotrophic needs. The
SFB-host intimate interactions: a threat or a benefit for the host?
A characteristic feature of SFB is its host-specific attachment that suggests a receptor-ligand type of interaction [8], [26], [27]. In addition, transmission electron micrographs show SFB strongly anchored into epithelial cells with condensed actin underneath the holdfast [13], [22], suggesting a specific host response. The SFB genome only codes for a Sec and signal recognition particle (SRP) secretion system and is devoid of most protein motifs that are often found in cell-wall attached
SFB: a strong inducer of intestinal IgA responses
The first evidence of a selective role of SFB in the post-natal maturation of the gut immune system was provided by Klaasen and coworkers [37]. In line with pioneering studies demonstrating that post-natal expansion of intestinal IgA plasma cells is driven by intestinal colonization [38], [39], Klaassen et al. observed that the numbers of intestinal and spleen IgA-secreting cells (IgA-SC) and the concentrations of IgA in serum and intestinal secretions increased more in mice monocolonized by
SFB is a strong activator of intraepithelial lymphocytes
The first formal demonstration of the selective role of SFB in the stimulation of intestinal T cells was provided by Umesaki et al. who observed that, after 28 days of colonization by SFB, the epithelium contained twice as many γδ T cell receptor (TCR) intraepithelial lymphocytes (IEL) and 15-fold more CD8+ αβTCR IEL, than germ-free mice [11], [36] (Fig. 2). Small intestinal IEL displayed cytolytic activity in the presence of anti-αβTCR antibody and the induction of MHC class II molecules on
SFB: a potent stimulus of intestinal homeostatic innate and effector CD4 T cell responses
It has recently become clear that SFB is also a potent activator of gut CD4+ T effector cells and can notably initiate gut homeostatic CD4+ TH17 responses (Fig. 2). Indeed, in contrast with TH1, TH2 and FoxP3 regulatory T (Tregs) cells, which are present in small numbers in the gut mucosa of germ-free mice, TH17 CD4+ T cells only develop after intestinal colonization and represent approximately 2–5% of CD4+ LP T cells in the small intestine and colon of conventional mice at steady state. The
Host gut immune responses keep in check but do not eliminate SFB
Several recent studies suggest that innate immune responses can prevent SFB overgrowth. A marked increase in mucosa-associated SFB was observed in mice lacking Reg3γ [58], an antimicrobial C-type lectin, which specifically targets Gram-positive bacteria. Since SFB colonization induced a substantial and rapid up-regulation of Reg3γ [30], [45], [54], this peptide might in turn restrict the access of SFB to the ileal mucosa (Fig. 2). A role for ILC3-derived IL-22 was also recently suggested in Ahr
SFB-induced colonization resistance: altruistic consequence of a “self-interested” behavior?
A pivotal role of SFB in the barrier effect of the microbiota is a long-standing hypothesis suggested by correlative observations linking protection against pathogens with the presence of SFB in the microbiota or at the ileal surface. SFB was thus suggested to confer protection against intestinal colonization by Salmonella enteritidis in rats [19], enteropathogenic Escherichia coli O103 in rabbits [64], and Salmonella enterica serovar Typhimurium in mice [49], [65]. More recently, the barrier
SFB stimulation of the gut immune barrier: an as yet poorly understood consequence of SFB attachment to the ileal mucosa?
The immunological stimulation that follows SFB colonization may occur through sensing by the host of bacterial products, bacterial-induced changes in the host cell upon attachment, injection of bacterial products into the host cell or through uptake of SFB remnants and sampling of bacterial antigens [70], [71]. Reports indicating that rat SFB can grow in the mouse intestine but can neither attach to the mucosal surface nor recapitulate the strong adaptive immune response induced by mouse SFB
SFB influences immune responses beyond the gut
Evidence that the microbiota influences the immune system at a distance from the gut is now compelling and abundant experimental data have highlighted how microbiota-derived signals foster steady-state activation of peripheral innate (neutrophils [80], macrophages [81], NK cells [82], and iTNK cells [83]) and adaptive (T cells [84], [85]) immune cells, and shape host systemic immune responses. Outcome is variable and depends on host immune status, on the type of immune responses but also on the
SFB: a unique or an archetypical example of gut immunostimulatory symbionts?
Overall SFB provides an unusual example of the trade-off set up by resident bacteria with their host to establish and maintain their ecological niche in the intestine. As a likely consequence of its life-style in close contact with the small intestinal epithelium, SFB triggers innate and adaptive IgA and effector T cell responses, that are sufficiently robust to limit bacterial overgrowth but insufficient to eliminate the bacterium and to induce host tissue damage. The robust adaptive immune
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
The authors and their work are supported by Institut National Pour la Santé et la Recherche, Institut National de la Recherche Agronomique and Université Paris Descartes, and by grants from the French National Agency for Research and from Fondation Princesse Grace. P. Schnupf was supported by post-doctoral fellowships from the European FP7 TORNADO excellence program and from the French National Agency for Research.
References (102)
- et al.
A scanning electron microscope study of the caecal tonsil: the identification of a bacterial attachment to the villi of the caecal tonsil and the possible presence of lymphatics in the caecal tonsil
Poult Sci
(1978) - et al.
Complete genome sequences of rat and mouse segmented filamentous bacteria, a potent inducer of th17 cell differentiation
Cell Host Microbe
(2011) - et al.
The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment
Cell Host Microbe
(2011) - et al.
Induction of intestinal Th17 cells by segmented filamentous bacteria
Cell
(2009) - et al.
The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses
Immunity
(2009) - et al.
Gut immune maturation depends on colonization with a host-specific microbiota
Cell
(2012) - et al.
Specific gut commensal flora locally alters T cell tuning to endogenous ligands
Immunity
(2013) - et al.
Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora
Immunity
(2013) - et al.
Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine
Cell Host Microbe
(2008) - et al.
Commensal bacteria calibrate the activation threshold of innate antiviral immunity
Immunity
(2012)
Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota
Immunity
Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice
Gastroenterology
Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells
Immunity
Gender bias in autoimmunity is influenced by microbiota
Immunity
An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system
Cell
Animals in a bacterial world, a new imperative for the life sciences
Proc Natl Acad Sci U S A
The immune system and the gut microbiota: friends or foes?
Nat Rev Immunol
Immune adaptations that maintain homeostasis with the intestinal microbiota
Nat Rev Immunol
Intestinal, segmented, filamentous bacteria
FEMS Microbiol Rev
Intestinal, segmented, filamentous bacteria in a wide range of vertebrate species
Lab Anim
On the existence of entophyta in healthy animals, as a natural condition
Proc Acad Natl Sci Phila
’Candidatus Arthromitus’ revised: segmented filamentous bacteria in arthropod guts are members of Lachnospiraceae
Environ Microbiol
The lifestyle of the segmented filamentous bacterium: a non-culturable gut-associated immunostimulating microbe inferred by whole-genome sequencing
DNA Res
Alternatives to binary fission in bacteria
Nat Rev Microbiol
Studies on the effect of system retention time on bacterial populations colonizing a three-stage continuous culture model of the human large gut using FISH techniques
FEMS Microbiol Ecol
Differential roles of segmented filamentous bacteria and clostridia in development of the intestinal immune system
Infect Immun
Comparative analysis of the distribution of segmented filamentous bacteria in humans, mice and chickens
ISME J
Evidence for a complex life cycle and endospore formation in the attached, filamentous, segmented bacterium from murine ileum
J Bacteriol
Electron microscopy of a filamentous, segmented bacterium attached to the small intestine of mice from a laboratory animal colony in Denmark
Acta Pathol Microbiol Scand B
Habitat, succession, attachment, and morphology of segmented, filamentous microbes indigenous to the murine gastrointestinal tract
Infect Immun
Freeze-fracture study of the filamentous, segmented microorganism attached to the murine small bowel
J Bacteriol
Interactions between gut-associated lymphoid tissue and colonization levels of indigenous, segmented, filamentous bacteria in the small intestine of mice
Can J Microbiol
Effect of preventing coprophagy on colonization by segmented filamentous bacteria in the small bowel of mice
Microb Ecol Health Dis
Segmented filamentous bacteria in the rodent small intestine: their colonization of growing animals and possible role in host resistance to Salmonella
Microb Ecol
Actin accumulation at sites of attachment of indigenous apathogenic segmented filamentous bacteria to mouse ileal epithelial cells
Infect Immun
Host specificity of filamentous, segmented microorganisms adherent to the small bowel epithelium in mice and rats
Appl Environ Microbiol
Effect of penicillin on the succession, attachment, and morphology of segmented, filamentous microbes in the murine small bowel
Infect Immun
Segmented filamentous bacteria and increased resistance to infections
Old Herborn Univ Semin Monogr
Single-cell sequencing provides clues about the host interactions of segmented filamentous bacteria (SFB)
Genome Res
Noninvasive measurement of anatomic structure and intraluminal oxygenation in the gastrointestinal tract of living mice with spatial and spectral EPR imaging
Proc Natl Acad Sci U S A
The attachment of filamentous segmented micro-organisms to the distal ileum wall of the mouse: a scanning and transmission electron microscopy study
Lab Anim
Influence of macronutrients on segmented filamentous bacteria in the small intestina of mice
Microb Ecol Health Dis
Influence of a natural-ingredient diet containing Phaseolus vulgaris on the colonization by segmented, filamentous bacteria of the small-bowel of mice
Int J Vitam Nutr Res
Downregulation of Th17 cells in the small intestine by disruption of gut flora in the absence of retinoic acid
J Immunol
The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria
Proc Natl Acad Sci U S A
Mono-association of mice with non-cultivable, intestinal, segmented, filamentous bacteria
Arch Microbiol
Segmented filamentous bacteria are indigenous intestinal bacteria that activate intraepithelial lymphocytes and induce MHC class II molecules and fucosyl asialo GM1 glycolipids on the small intestinal epithelial cells in the ex-germ-free mouse
Microbiol Immunol
Apathogenic, intestinal, segmented, filamentous bacteria stimulate the mucosal immune system of mice
Infect Immun
Increase in the population of duodenal immunoglobulin A plasmocytes in axenic mice associated with different living or dead bacterial strains of intestinal origin
Infect Immun
Immunohistochemical observations on lymphoid tissues from conventional and germ-free mice
Lab Invest
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