Commensal Microbes: The Frenemy Within

        As part of their symbiotic association with humans, intestinal bacteria sometimes need and sometimes lend a helping hand. In this Select, we examine how commensal microorganisms or the inflammation they produce cause undesirable outcomes, such as the development of type 2 diabetes or cancer. In addition, we see how commensal bacteria can receive assistance in colonization from resident phages and send messages to the host via outer membrane vesicles.

        Inflammation Fuels Genotoxic Gut Bacteria

        Inflammation is a risk factor for colorectal cancer, but it has been unclear whether manipulation of the host immune system by commensal microbiota plays a role in the inflammation leading to colorectal cancer. To examine this further, Arthur et al. (2012) colonized germ-free wild-type or colitis-susceptible interleukin-10 (IL-10)-deficient animals with pathogen-free commensal organisms treated with and without the colon-specific carcinogen azoxymethane (AOM). Mice lacking IL-10 develop colitis, and the majority develop cancer; microbiome analysis showed that IL-10-deficient mice have a reduced number of bacterial species. AOM treatment does not seem to affect the microbiota, suggesting that this difference in richness is due to changes in inflammation from IL-10 deficiency and not from cancer. In particular, Proteobacteria populations expand in Il10 knockout mice with greater populations of Enterobacteriaceae, of which Escherichia coli is a member. When gut microbiota consists only of either E. coli or Enterococcus faecalis (another human commensal), only mice colonized with E. coli develop invasive mucinous adenocarcinoma, although both bacteria induce severe colitis, suggesting an E. coli-specific factor may aid the development of colorectal cancer. Bioinformatic analysis of strains associated with colitis and colorectal cancer suggested the importance of the polyketide synthase (pks) pathogenicity island, which appears to induce DNA damage as evidenced by the increased number of cells arrested at the G2/M checkpoint. When treated with AOM and colonized with E. coli without pks, IL-10-deficient mice show reduced tumor burden and decreased invasion without changes in inflammation, suggesting pks may accelerate tumor formation. Host inflammation could give genotoxic bacteria, such as pks-producing E. coli, the foothold they need to expand within the gut. Although E. coli containing pks is found in patients with intestinal inflammation and colorectal cancer, it will be important to further explore the contribution of this pathogenicity island to colorectal cancer development in humans.
        Arthur, J.C., et al. (2012). Science 338, 120–123.
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        Histology of IL-10 knockout mice intestines monocolonized with E. coli containing and lacking pks. Photo courtesy of Christian Jobin.

        Microbial Prognosticators of Diabetes

        Understanding the role of gut microbiota in dysbiosis is of considerable interest because it could open avenues toward both preventive measures and treatments. In a recent report, Qin et al. (2012) provide a thorough assessment of the gut microbiota associated with diabetes in a metagenome-wide association study (MGWAS) of 345 fecal samples from diabetic Chinese patients and nondiabetic controls. Their data extends previous studies with 16S ribosomal RNA and whole-genome shotgun sequencing to determine the relative proportions of bacterial species in the gut of diabetic patients and identify metagenomic linkage groups (MLGs) composed of physically linked genetic material. Type 2 diabetes associates with 47 MLGs, and 17 of these MLGs could be assigned to known bacterial species. Opportunistic pathogens and mucin-degrading species are enriched in patients with type 2 diabetes, and butyrate-producing organisms are enriched in controls. Microbes that are more prevalent in the context of type 2 diabetes are functionally enriched for membrane transport, whereas the species more prevalent in controls are enriched in cell motility and the metabolism of vitamins and cofactors. A type 2 diabetes index created using 50 of these gene markers accurately predicts type 2 diabetes in 33 individuals based on the presence of these genes in their gut microbiota. Those with the highest index were diabetic, and this index could be used more broadly to help predict who might be at risk for developing type 2 diabetes. This work furthers the idea that particular types of gut microbes, such as butyrate-producing organisms, may be protective against disease, whereas opportunistic pathogens, such as E. coli, could be associated with, or provide a helping hand, to chronic diseases.
        Qin, J., et al. (2012). Nature 490, 55–60.
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        MGWAS identified gut microbial markers for classifying type 2 diabetes. Image courtesy of Dongqian Shen and Qiang Feng.

        A Prophage Lends a Hand to Commensals

        To thrive within the crowded confines of the human intestine, commensals must be able to establish and maintain a foothold. Duerkop et al. (2012) find that the production of the composite phage φV1/7 by Enterococcus faecalis, a commensal organism of the human intestine, aids this strain in its competition with other E. faecalis strains by lysing nearby competitors. Compared with strains lacking this phage, growth of E. faecalis is enhanced by φV1/7 production both in the gastrointestinal tract of germ-free mice and in vitro. Free amino acids, which are found in millimolar concentrations in the intestine, may help induce φV1/7 prophages in the intestine, given that E. faecalis produces φV1/7 in culture in response to amino acid availability. This work furthers our understanding of the interplay between prophages and host biology, in this case giving E. faecalis a helping hand during colonization, and provides a glimpse of how E. faecalis can carve out a niche. Going forward, it will be important to identify the specific trigger that induces φV1/7 production in the intestine and to understand whether φV1/7 plays a role in allowing other bacterial species to compete effectively in the intestine.
        Duerkop, B.A., et al. (2012). Proc. Natl. Acad. Sci. USA 109, 17621–17626.
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        Transmission electron micrograph of a φV1/7 particle. Arrows indicate the capsid and tail. Image courtesy of Breck Duerkop and Sohini Mukherjee.

        Care Packages from Com-mensals to Hosts

        In addition to establishing a niche for themselves during colonization of the host gut, commensal bacteria must suppress the immune system to avoid clearance and elimination. A capsular polysaccharide (PSA) from Bacteroides fragilis has previously been shown to suppress intestinal immunity, perhaps for the benefit of both the microbe and host, but the way in which PSA was delivered to immune cells was unclear. Bacteria have several needle-like secretion systems that require close contact between the bacterium and host cell, but they can also release outer membrane vesicles (OMVs) from the bacterial membrane as a kind of long-distance delivery system. Shen et al. (2012) show that PSA from B. fragilis is packaged within OMVs and orally treating mice with OMVs protects against experimental colitis, an experimental model for inflammatory bowel disease that is characterized by inflammation of the intestine. Furthermore, PSA in OMVs is sensed by Toll-like receptor 2 (TLR-2) on dendritic cells, leading to tolerogenic dendritic cells and anti-inflammatory responses. Growth arrest and DNA-damage-inducible protein (Gadd45α) is required for OMVs to induce expression of the anti-inflammatory cytokine IL-10. In the context of experimental colitis, OMVs can restore colon length and reduce inflammation, so long as Gadd45α signaling is functional. This study leaves open the question of whether other anti-inflammatory roles of PSA exist outside the gut—B. fragilis can prevent and treat experimental autoimmune encephalomyelitis, a model of multiple sclerosis—or whether PSA could be more broadly used in treating inflammation. Certainly, the unique delivery mechanism that helps B. fragilis modulate its environment bears further examination as we ask what else might be sent express mail in the communication between commensals and their hosts.
        Shen, Y., et al. (2012). Cell Host Microbe 12, 509–520.
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        Electron micrograph of OMVs being released from B. fragilis. Photo courtesy of Yue Shen.
        Gail Teitzel
        Editor, Trends in Microbiology