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A symbiotic relationship occurs between two organisms where at least one benefits from the association with the other. There are four symbiotic relationships relevant to the HG microbiome and the human host. The two most common are:
Mutualism (+/+). Both organisms benefit. Many of the widespread gut bacteria probably fall into this category. A mutualistic microorganism is beneficial to the human host or to another microbe, which in turn may benefit the host. In return, the organism reaps the benefits of a structured environment that offers protection, nutrients and an opportunity to multiply.
Strictly speaking, symbiosis describes a binary relationship; however, the gut ecology is more complicated and involves microbial communities working together as metabolically cohesive consortia to break down indigestible food resources (PascualGarcia2020). For a case study on a ternary example of mutualism, see the Triumvirate mutualism below.
Commensalism (+/0). One organism benefits, while the other is unharmed. One can imagine that many gut microbe interactions would fall into this category. Vibrio cholerae is a dangerous human pathogen that is parasitic toward the human host. However, the pathogen relies on mucosal bacteria, such as Bacteroides thetaiotaomicron or Akkermansia muciniphila, to provide nutrients from the degradation of mucin. V. cholerae doesn't compete with or attack the mucin foragers, and the nutrients scavenged by the former have no metabolic cost to the latter, either.
Less common symbiotic interactions are:
Parasitism (+/-). One organism benefits from another at the latters expense, but is rarely fatal. This differs from amensalism in that the resource in the case of parasitism is (or is part of) the other organism. Obligate (endo)parasitic bacteria of humans are rare in the gut (e.g., Chlamydia trachomatis). However, numerous important pathogenic bacteria, such as Salmonella enterica, Campylobacter jejuni and Aeromonas caviae, have nutrient-acquiring strategies that result in disease. Invasive pathogens would therefore be described as parasites, while opportunistic pathogens might be called potential parasites. Some pathogens, although non-invasive, can release substances that the host finds toxic (e.g. botulinum neurotoxins) and probably wouldn't be considered parasitic (Henkel2010). A healthy microbiome greatly reduces the frequency and severity of parasitic organisms in the gut.
Predation (+/-). One organism (predator) kills and consumes all or part of the other organism (prey). Bacteriophages and predatory bacteria (e.g., Bdellovibrio bacteriovorus) are organisms that predate bacteria. While phages in particular can have a massive effect on the microbiome ecology and community structure, predation is not a common strategy amongst gut microorganisms.
Amensalism (antagonism) (0/-). One organism negatively impacts another for little or no gain, while the other is unable to defend or retaliate against the antagonist. an extreme form of amensalism is competition, where both organisms are competing for the same resource and the least adapted loses out. This type of competition is, at best, a zero-sum strategy (i.e., 0/-), but can be a harmful strategy for both (-/-).
Although this is considered a non-symbiotic relationship, the bottom-up selective pressure through competition between gut microbes occupying the same niche may create metabolic functional redundancy, which could ultimately benefit the human host in the event of the loss of a key metabolic function (Lozupone2008, Ley2006). Similarly, a species that excludes a competitor ultimately benefits from reduced competition.
A note on Pathogenicity. A mutualist, commensal, antagonist or parasite may become pathogenic toward its human host. While few bacteria are outright human pathogens, quite a number are opportunistic pathogens and become pathogenic under certain conditions. This will be dealt with further in the section on Health, but suffice to say some bacteria can develop characteristics whereby the interaction between it and the host results in a disease state. For example, about a dozen widespread mutualists are described by BAuA as being "opportunistic in immunocompromised patients", including Alistipes shahii, Bacteroides stercoris, Bifidobacterium adolescentis, Bifidobacterium breve, Coprococcus comes, Enterocloster bolteae, Lactobacillus acidophilus, Lactococcus lactis subsp. lactis, Limosilactobacillus fermentum, Parabacteroides merdae, Phocaeicola vulgatus, and Veillonella atypica.
The distal gut of adults is dominated by Firmicutes and Bacteroidetes, so a reasonable question to ask would be: Do the members of these phyla compete, cooperate or ignore one another? Mahowald and coworkers (Mahowald2009) have proposed a representative metabolic model involving a Clostridium Cluster XIVa member (Eubacterium rectale), a keystone Bacteroides species (B. thetaiotaomicron) and the human host (Figure 1). The researchers created this 'minimal human gut microbiome' by colonising gnotobiotic (germ-free) mice with these bacteria and then examining their genetic makeup, proteomic disposition and respective responses to biochemical tests to determine the types of interspecies interactions at play.
It appears that B. thetaiotaomicron responds to the presence of the E. rectale by upregulating a variety of polysaccharide-hydrolysing proteins, and communicating with the host to produce more mucin glycoproteins to serve as a sustainable nutrient source. E. rectale, which cannot forage on the intact mucin, relies on the monosaccharides and amino acids produced when B. thetaiotaomicron initiates mucin degradation. In turn, E. rectale responds by increasing transporter proteins for these nutrients and downregulates its own glycan hydrolases (GHs). E. rectale produces butyrate from acetate, and this key short chain fatty acid is actively taken up by the enterocytes as a primary source of energy.
Figure 1. Important metabolic interactions between Bacteroides thetaiotaomicron, Eubacterium rectale and the host. Pts, phosphotransferase systems; Gpd, glycerol 3-phosphate dehydrogenase; Pck, phosphoenolpyruvate carboxykinase; Por, pyruvate:ferredoxin oxidoreductase; Hyd, hydrogenase; Rnf, NADH: ferredoxin oxidoreductase complex; Fdred, reduced ferredoxin; Fdox, oxidized ferredoxin; Pta, phosphate acetyltransferase; Bcd, butyryl-CoA dehydrogenase; Etf, electron transport flavoproteins; Cat, butyryl CoA: acetate CoA transferase; Mct1, monocarboxylate transporter 1. Image derived from Mahowald2009.
A similar experiment using either probiotics Bifidobacterium longum or Lacticaseibacillus casei in combination with B. thetaiotaomicron produced a similar result: an increase in the diversity of polysaccharides targeted for hydrolysis by B. thetaiotaomicron in response to the presence of the other organism (Sonnenburg2006). For example, B. thetaiotaomicron upregulated fucosidase, mannosidase, xylosidase and pectin lyase GH enzymes in response to the presence of B. longum, while the latter responded by downregulating its own β-mannosidases.
Are these really examples of 3-way metabolic mutualism? B. thetaiotaomicron clearly has a mutualistic relationship with the host by providing propionate, acetate and monosaccharides from otherwise inaccessible dietary glycans in exchange for a constant nutrient source of peptidoglycans provided by the host, while the other microbe produces nutrients utilised by the host (e.g., butyrate in the case of E. rectale; acetate and lactate from B. longum; lactate from L. casei) but relies on B. thetaiotaomicron for its nutrients, while appearing to offer nothing in return. A simplistic conclusion regarding the metabolic interactions between these organism might be as summarised below (Figure 2).
Figure 2. A symbiosis schematic representing apparent metabolic interactions between Bacteroides thetaiotaomicron, Eubacterium rectale and the host. Overall, there is a mutualism that benefits all three organisms.
So, if B. thetaiotaomicron can exist happily by itself, foraging on mucin and the sporadic appearance of dietary glycans, why does it respond to the presence of other would-be symbionts? Furthermore, why would the human host tolerate a mucin consumer if thats all it did? Afterall, it takes much more energy to generate mucin than would be returned in the form of microbial byproducts. It would appear as though there is more to the collective relationship than just metabolic inputs and outputs. These factors could include immune system modulation, exclusion of pathogens or support for other members of the metabolic consortium that might produce other important secondary metabolites, such as cobalamin, folate, biotin and riboflavin.
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