Bacterial Pathogenesis. Brenda A. Wilson
host-microbe interactions that stimulate multiple endocrine, neurocrine, and immunologic signals to the brain and vice versa. These bidirectional interactions have been dubbed the microbiota-gut-brain axis. Recent studies have shown that modulating the gut microbiota impacts emotional behavior, including anxiety, depression, and pain, supporting the therapeutic potential of appropriate probiotics, prebiotics, and diet as interventions for psychiatric and neuroimmune disorders.
The colon is an anoxic environment, so it is not surprising that the numerically predominant colonic bacteria are obligate anaerobes. The numerically predominant anaerobes include the phyla Bacteroidetes (Gram-negative Bacteroides species), Firmicutes (Gram-positive bacteria, including Lactobacillus and Clostridium species), and Actinobacteria (Corynebacterium and Mycobacterium species). Facultative bacteria such as E. coli and Enterococcus species are also present in lower numbers. Bacteroides species are the ones that are thought to play a major role in fermenting the dietary polysaccharides that our bodies cannot digest. Sequence analyses of the gut bacterial communities have shown that obese individuals have fewer Bacteroidetes (5%) and more Firmicutes (85%) than lean individuals (25% Bacteroidetes, 75% Firmicutes). Understanding colonic fermentation, together with 16S rRNA gene analyses of the microbiota of the colons of obese humans or mice compared to those of nonobese individuals, has fueled the notion that obesity might be caused in part by the composition of the colonic microbiota (Box 5-2), which could be treated through manipulation of the microbial contents of the gut.
Box 5-2.
We Are What We Eat, or Rather What Our Microbiota Eats
Conventional wisdom has it that obesity is a result of genetics, lack of exercise, or a poor diet. But what if your intestinal bacterial population also contributes? An early study that used 16S rRNA gene profiling found that the microbiota of obese mice and humans differed from that of lean mice and humans. Moreover, when germfree mice (mice lacking any intestinal bacteria) were colonized with an “obese microbiota,” those mice gained more fat than germfree mice colonized with a “lean microbiota.” The main difference was the ratio of the two numerically predominant bacteria, the Bacteroidetes (Bacteroides species) and the Firmicutes (Gram-positive obligate anaerobes), in which a higher proportion of Bacteroidetes was associated with leanness.
The hypothesis that the composition of the colonic microbiota is associated with obesity is, as you might imagine, quite controversial, especially among those committed to theories that give precedence to exercise or diet. Also, association of obesity with a more active colonic fermentation seems to run counter to the belief that high-fiber diets would be associated with increased colonic fermentation due to the fact that fiber is primarily composed of polysaccharides that are fermentable by colonic bacteria. The efficiency of the fermentation may be a factor. If so, the prediction from the obesity studies would be that the Firmicutes are more efficient fermenters than the Bacteroidetes. Since virtually nothing is known about the Gram-positive anaerobes and their carbon sources, this is difficult to assess. Another possibility is that some fermenters take a lower energy toll in the form of stimulating mucosal cell turnover.
A good feature of the hypothesis regarding a connection between obesity and the microbiota composition is that it may prompt more studies of the metabolic activities of Gram-positive anaerobes. Moreover, it illustrates the fact that the 16S rRNA gene approach, and even the metagenomics approach, may be a good start for addressing these questions, but that work on better understanding bacterial physiology will be critical.
The idea that we might be able to combat obesity by manipulating our microbiota has received some strong experimental support. To study the impact of microbiota composition on obesity, germfree mice were inoculated with microbiota from obese or lean human twins fed a low-fat, high-fiber diet. As illustrated in panel A of the figure mice that received a microbiota from the obese twin (red) became obese, while mice that received a microbiota from the lean twin (blue) did not become obese. When the two groups of mice were housed together and fed a low-fat, high-fiber diet (as illustrated in panel B of the figure), transmission of microbes (mostly Bacteroides species) from the mice with a lean-promoting microbiota occurred to the mice with an obesity-promoting microbiota, such that none of the mice became obese. On the other hand, when the two groups were fed a high-fat, low-fiber diet, no transmission occurred and the mice with an obesity-promoting microbiota became obese.
Sources:
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. 2006. An obesity-associated gut microbiota with increased capacity for energy harvest. Nature 444:1027–1031.
Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, Gordon JI. 2013. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341:1079.
The products of fermentation (acetate, CO2, and H2) are also used as carbon and energy sources by minor populations of methanogenic archaea. These methane producers convert H2 and CO2 to methane, which is absorbed, though not used, by the human body and is expelled in breath and flatus. About one-fifth of people tested have enough methane produced in their colons to be easily detectable in their breath by gas-liquid chromatography. Sulfate-reducing bacteria also reside in the colon, using H2 to help convert sulfate to HS. The main source of the sulfate that they reduce is not clear, but some of it probably comes as a byproduct of fermentation of human-produced sulfated glycoproteins and sulfated polysaccharides, such as mucopolysaccharides and mucin. Sulfides produced by the sulfate reducers are responsible in part for the odor of feces and are thought to contribute as a risk factor for colon cancer.
In judging the energy balance, it is worth realizing that intestinal microbes also take a toll from us; they stimulate the immune system and the turnover of intestinal mucosal cells. The constant sloughing of intestinal mucosal cells is a very effective defense that prevents bacteria that have attached to the mucosal cells from staying in the site long enough to invade. Similarly, the intestinal immune system is an important defense. But these activities require an output of proteins and energy by the human body. On balance, however, the energy balance seems to go in our favor, unless you count the effort we put into cultivating and obtaining the foods we eat that ultimately feed the colonic bacteria.
Many colonic bacteria, such as Bacteroides species and numerically minor populations like E. coli, Enterococcus, and some Clostridium species, are capable of causing serious infections if they escape from the colon as a result of surgery or some other trauma and get into the bloodstream and tissues. How could obligate anaerobes like Bacteroides cause infection in the human body, which would seem to be an aerobic environment that could kill them? Bacteroides prefer to lodge in regions of prior tissue damage. Disruption of the blood supply to such areas causes them to become anoxic, and thus fertile ground for an anaerobic infection. Moreover, blood itself is actually a hypoxic environment that is low in free oxygen. These normal colonic inhabitants are increasingly becoming resistant to many antibiotics.
Bacteria in the intestine interact with each other metabolically in the sense that methanogens and sulfate reducers use the end products of the polysaccharide fermenters, but they also interact with each other genetically by exchanging DNA. There is an old idea called the reservoir hypothesis that frames this interaction in terms of the transfer of antibiotic resistance and virulence genes (more on this in chapter 7). Briefly, colonic bacteria exchange DNA with each other. They may also exchange DNA with swallowed bacteria that are present only transiently in the colon as they pass through and are expelled into the environment. In this view, colonic bacteria act as reservoirs of antibiotic resistance and virulence genes in the sense that they are present in high numbers in an area in which other bacteria are transiently present for 24–48 hours, which is more than enough time for DNA transfers to occur. Only recently has it been possible to test this hypothesis by using molecular sequencing methods to follow the host-to-host transmission and movement of particular genes through and within the human colon. In fact, evidence