Candidatus savagella

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1. Classification

Also known as Segmented Filamentous Bacteria (SFB)

a. Higher order taxa

Domain: Bacteria Phylum: Firmicutes Class: Clostridia Order: Clostridiales Family: Clostridiaceae Species: candidatus savagella

2. Description and significance

Candidatus savagella, also known as Segmented Filamentous Bacteria (SFB), is a well-studied member of the gut microbiota in mammals, fish, and birds [1]. SFB belongs to the genus Clostridia, which are known to be Gram-positive and spore forming rod-shaped anaerobes [2]. SFB are near obligate symbionts as they lack the metabolic capabilities to survive without the nutrients made accessible by host metabolism [4]. Research has shown clear genetic distinction between SFB variants of different host organisms. Current research focuses on SFB’s role in immune system activation. SFB are unique in that they have been connected to T helper cell activation and immune responses in humans [7]. SFB have also been shown to protect male mice from colorectal cancer [6].

3. Genome structure

SFB are associated with the family Clostridiaceae but diverged early in evolution from the family [1]. SFB has a small genome that encodes a single circular chromosome with a low Guanine-Cytosine (GC) content [1,4,7]. About 78% of protein-coding genes are like other Clostridia or Firmicutes, but 8.6% of proteins have no orthologues. SFB has four clusters of SFB-specific proteins that are not found in other bacteria and further distinguishes SFB from the Clostridiaceae family. Cluster one and three are proteins that are part of the surface structures that are relevant to environment adaptation. Yet, little is known about clusters two and four [1]. These SFB-specific proteins have variations in DNA sequence that may be relevant to host selectivity [1]. SFB lack genes responsible for synthesis of nutrients such as vitamins, amino acids, nucleotides, and cofactors. Therefore, SFB are between obligate and facultative symbionts [1,4]. SFB have several genes involved in the transport of small molecules and ions across the cell membrane and have various extracellular proteases that assist in degrading host and dietary proteins. SFB have an anaerobic metabolism and require vitamins, cofactors, and amino acids from the environment to maintain their cellular processes [1,4]. Like other bacteria, SFB have high numbers of genes that code for cell cycle control, cell differentiation, cell shape, the release of holdfasts and spores from filament and the elimination of cytoplasmic proteins [1]. Moreover, SFB are subject to foreign invading DNA through horizontal gene transfer [1,4]. Yet, SFB has an important protein responsible for membrane remodeling, endocytosis, and cell morphology and the making of holdfast cells required for making a strong host-microbe interaction [1,4]. SFB also has genes that encode for flagella [1,4].

4. Cell structure

SFB are spore-forming, Gram-positive, filamentous bacteria that have a septate and a segment within the body [4]. SFB have flagella that allow the bacteria to be momentarily motile in their early stages of maturation [1,4]. The flagellin proteins have mucin-degrading enzymes that help SFB move within the mucus layers of the intestinal epithelial cells, respond to chemotactic signals, facilitate adhesion to surfaces and trigger immune responses, including the secretion of Immunoglobulin A (IgA) and the coordination of mature T-cell responses [1,4].

5. Metabolic processes

SFB’s have a very limited range of metabolic capabilities compared to other Clostridia-related bacteria [2]. SFB are obligate anaerobes; they do not contain genetic coding sequences for the tricarboxylic acid cycle nor respiratory chain-related proteins [9]. While it may be possible to get SFB to be somewhat aerotolerant, given the intestinal epithelial environment they are found in, SFB’s contain a complete set of enzymes for the glycolytic pathway to convert glucose to pyruvate, and pyruvate into acetate, ethanol, or lactate, but not butyrate and butanol, similar to other Clostridium-related bacteria [9, 10]. Therefore, they are fermenters.

SFBs almost completely lack any de novo biosynthesis pathways for amino acids, vitamins/cofactors, and nucleotides, and therefore likely gain these compounds from extracellular environments. 103 genes of SFB are devoted to transport functions of these compounds, versus the 20 genes for only amino acid synthesis and 14 for vitamin and cofactor synthesis [9].

6. Ecology

SFB is present and native to the gut of mammals, fish, humans, and birds. They are found mainly in the end of the ileum near the lymphoid follicles which are involved in the lymphatic system [3]. Since SFBs demonstrate strict specificity to its host animal, SFBs adapt their optimal growth conditions to the environment of the animal gut biome they are indigenous to [11]. Therefore, its geographic range is unconfirmed at the moment as it can be found in the guts of a varied range of mammals differing in many ecological regions [9, 11]. SFBs are currently unculturable; however, SFBs prefer to be attached to the epithelial lymphoid tissue covering the Peyer’s patches of the ileum [12]. As obligate anaerobes that lack the ability to biosynthesize many nutrients for survival, SFBs depend on their extracellular intestinal epithelial environment to gain these nutrients from their host cells [9].

7. Pathology

Although this isn't the case of all Clostridia-related bacteria, SFB is non-pathogenic to animals the intestinal environment. It is known to stimulate the mucosal immune system: studies have shown that mice that are monoassociated with SFBs had significantly higher duodenal immunoglobulin A (IgA) plasma cells and immunoglobulin-secreting cells (Ig-SC) compared to mice of normal intestinal flora and germ-free mice [2, 13].

8. Current Research

Until recently, SFB was classified as a subspecies of Candidatus arthromitus [8]. Current research focuses on the presence of segmented filamentous bacteria (SFB) in the gut microbiota of humans and the role it plays in the host immune system. Advancements in the use of metagenomics have allowed for new discoveries in microbe-mediated host interactions and the dynamic roles that unculturable bacteria play in human health. SFB has recently been implicated in mediating the maturation of postnatal immune functions [14]. Specifically, its ability to coordinate T helper type I (Th1) cell, T helper type 17 (Th17) cell, and regulatory T cell (Treg) responses [14]. The colonization of SFB has been shown to be age-dependent in humans, with the majority taking place within the first two years of life [15]. 16S rRNA sequence comparisons across different organisms, such as chickens, humans and mice show hosts express their own unique, predominant SFB sequence [15]. This demonstrates that SFB exhibits diverse host-specificity, especially that of young humans. This present understanding of SFB suggests that its presence in infant microbiota may be key to developing a functioning immune system before adulthood [14, 15].

9. References

[1] [Pamp, S. J., Harrington, E. D., Quake, S. R., Relman, D. A., & Blainey, P. C. (2012). Single-cell sequencing provides clues about the host interactions of segmented filamentous bacteria (SFB). Genome Research, 22(6), 1107–1119. https://doi.org/10.1101/gr.131482.111]

[2] [Clostridium. (2010). In MicrobeWiki. https://microbewiki.kenyon.edu/index.php?title=Clostridium&oldid=54377]

[3] [Jonsson, H. (2013). Segmented filamentous bacteria in human ileostomy samples after high-fiber intake. FEMS Microbiology Letters, 342(1), 24–29. https://doi.org/10.1111/1574-6968.12103]

[4] [Ericsson, A. C., Hagan, C. E., Davis, D. J., & Franklin, C. L. (2014). Segmented filamentous bacteria: commensal microbes with potential effects on research. Comparative Medicine, 64(2), 90–98]

[5] [Jonsson, H., Hugerth, L.W., Sundh, J. et al. Genome sequence of segmented filamentous bacteria present in the human intestine. Commun Biol 3, 485 (2020). https://doi.org/10.1038/s42003-020-01214-7]

[6] [Wolfe AE, Moskowitz JE, Franklin CL, Wiemken TL, Ericsson AC (2020) Interactions of Segmented Filamentous Bacteria (Candidatus Savagella) and bacterial drivers in colitis-associated colorectal cancer development. PLoS ONE 15(7): e0236595. https://doi.org/10.1371/journal.Pone.0236595]

[7] [Gaboriau-Routhiau, V., Rakotobe, S., Lecuyer, E., Mulder, I., Lan, A., Bridonneau, C., et al. (2009). The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689. doi: 10.1016/j.immuni.2009.08.020]

[8] [Thompson, C. L., Vier, R., Mikaelyan, A., Wienemann, T., & Brune, A. (2012). ‘Candidatus Arthromitus’ revised: Segmented filamentous bacteria in arthropod guts are members of Lachnospiraceae. Environmental Microbiology, 14(6), 1454–1465. https://doi.org/10.1111/j.1462-2920.2012.02731.x]

[9] [Kuwahara, T., Ogura, Y., Oshima, K., Kurokawa, K., Ooka, T., Hirakawa, H., Itoh, T., Nakayama-Imaohji, H., Ichimura, M., Itoh, K., Ishifune, C., Maekawa, Y., Yasutomo, K., Hattori, M., & Hayashi, T. (2011). The Lifestyle of the Segmented Filamentous Bacterium: A Non-Culturable Gut-Associated Immunostimulating Microbe Inferred by Whole-Genome Sequencing. DNA Research, 18(4), 291–303. https://doi.org/10.1093/dnares/dsr022]

[10] [Desvaux, M. (2005). Clostridium cellulolyticum: Model organism of mesophilic cellulolytic clostridia. FEMS Microbiology Reviews, 29(4), 741–764. https://doi.org/10.1016/j.femsre.2004.11.003]

[11] [Umesaki, Y., Okada, Y., Matsumoto, S., Imaoka, A., & Setoyama, H. (1995). 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. Microbiology and Immunology, 39(8), 555–562. https://doi.org/10.1111/j.1348-0421.1995.tb02242.x]

[12] [Klaasen, H. L. B. M., Koopman, J. P., Poelma, F. G. J., & Beynen, A. C. (1992). Intestinal, segmented, filamentous bacteria. FEMS Microbiology Reviews, 8(3–4), 165–179. https://doi.org/10.1111/j.1574-6968.1992.tb04986.x]

[13] [Klaasen, H. L., Van der Heijden, P. J., Stok, W., Poelma, F. G., Koopman, J. P., Van den Brink, M. E., Bakker, M. H., Eling, W. M., & Beynen, A. C. (1993). Apathogenic, intestinal, segmented, filamentous bacteria stimulate the mucosal immune system of mice. Infection and Immunity, 61(1), 303–306. https://doi.org/10.1128/iai.61.1.303-306.1993]

[14] [Gaboriau-Routhiau, V., Rakotobe, S., Lecuyer, E., Mulder, I., Lan, A., Bridonneau, C., et al. (2009). The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689. doi: 10.1016/j.immuni.2009.08.020]

[15] [Yin, Y., Wang, Y., Zhu, L., Liu, W., Liao, N., Jiang, M., et al. (2013). Comparative analysis of the distribution of segmented filamentous bacteria in humans, mice and chickens. ISME J. 7, 615–621. doi: 10.1038/ismej.2012.128]