■■■口 Prospects& Overviews J. Alcock et al Microbial genes outnumber human genes by 100 to 1 in the casei in participants whose mood was initially in the lowest intestinal microbiome, leading some to propose that it is a tertile [ 21] microbial organ"that performs important functions for the There are many other examples of microbes affecting their host, such as nutrient harvesting and immune develop- hosts'mood and behavior, mostly from animal studies(Fig. 1). ment [11]. However, as with any complex and intimate Butyrate a short chain fatty acid largely produced by the interaction, there is a mixture of common and divergent microbiota, has been shown to have profound central nervous interests with opportunities for mutual benefit [11] and system effects on mood and behavior in mice[22]. Microbiota manipulation [12]. Fitness interests of gut microbes are also transfer to germ free mice leads to timid behavior when fed often not aligned, because members of the microbiota feces from mice with anxiety-like behavior. When germ-free compete with one another over habitat and nutrients. This mice from an anxious strain were fed with a fecal pellet from a means that highly diverse populations of gut microbes may be control mouse, the inoculated mice exhibited behavior that ≤o≤o0 nore likely to expend energy and resources in competition, was more exploratory, and more like their fecal donors [23 .In compared to a less diverse microbial population. A less diverse addition, a probiotic formulation with Lactobacillus helveticus microbial population is likely to have species within it that Ro052 and Bifidobacterium longum Ro175 alleviated psycho- have large population sizes and more resources available for logical distress [24]. This effect can be altered by diet and host manipulation. Moreover, the larger a particular microbial inflammation (25 If one feeds Lactobacillus rhamnosus B-1) population is, the more power it would have to manipulate to mice, not only does it reduce their stress- induced he host through higher levels of factor production or other corticosterone hormone levels, but it also makes them more strategies (see below) and large scale coordination of these dogged: L rhamnosus B-1)fed mice swim longer than the activities (e.g, through quorum sensing). Therefore, we control fed mice when put in a glass cylinder filled with 15cm hypothesize that lower diversity in gut microbiome should of water and no means of escape[26]. This effect disappeared be associated with more unhealthy eating behavior and when the experimenters severed the vagus nerve, suggesting a greater obesity (i. e, decreased host fitnes role for the vagus nerve in microbial manipulation of host behavior. In contrast, severing the vagus nerve had no effect on swimming behavior of control mice that were not fed Evidence indicates many potential L. rhamnosus (B-1)[26]. In a widely cited example of mechanisms of manipulation microbes affecting behavior, Toxoplasma gondii suppresses rats, normal fear of cat smells often to the detriment of the There is a selective influence of diet on rats, but to the benefit of the microbes that are ingested into microbiota their new feline host. T. gondii infected rats are reported to become sexually aroused by cat urine [271, a propensity that Individual members of the microbiota, and consortia of those promotes transmission of T gondii at the expense of the fitness microbes, have been shown to be highly dependent on the of the rat. nutrient composition of the diet. Prevotella grows best on carbohydrates; dietary fiber provides a competitive advantage to Bifidobacteria [131, and Bacteroidetes has a substrate Microbes can induce dysphoria that changes preference for certain fats [14]. Some specialist microbes, e.g. feeding behavior ucin degrading bacteria such as Akkermansia mucinophila thrive on secreted carbohydrates provided by host cells. Other Although certain Lactobacillus appear to reduce anxiety butyrate producing microbes, e.g. Roseburia spp, fare better colonization of the gut with the pathogen Campylobacter when they are delivered polysaccharide growth substrates in jejuni increased anxiety-like behavior in mice[28, raising the he diet. Specialist microbes that digest seaweed have been possibility that microbe- induced dysphoria might also affect isolated from humans in Japan [15. African children raised human behavior. Recent studies have linked the inconsolable on sorghum have unique microbes that digest cellulose [16]. crying of infant colic with changes in gut microbiota including Many other examples exist [17 Even microbes with a reduced overall diversity, increased density of Proteobacteria generalist strategy tend to do better on some combinations and decreased numbers of Bacteroidetes compared to of nutrients than others, and competition will determine controls [29]. Colic has been reported to result in increased which microbes survive[18, 19 energy delivery to infants, sometimes resulting in accelerated weight gain [ 30]. If infant crying has a signaling function that increases parental attention and feeding [31, 32 colic may Microbes can manipulate host behavior increase the resource delivery to the gut and hence microbial access to nutrients There is circumstantial evidence for a connection between One potential mechanism by which dysphoria can cravings and the composition of gut microbiota. Individuals influence eating involves bacterial virulence gene expression who are " chocolate desiring" have different microbial and host pain perception. This mode of manipulation is metabolites in their urine than " chocolate indifferent" plausible because production of virulence toxins often is individuals, despite eating identical diets [20]. There is also triggered by a low concentration of growth-limiting nutrients. evidence for effects of microbes on mood. A double-blind, Detection of simple sugars and other nutrients regulates randomized placebo controlled trial found that mood was virulence and growth for a variety of human-associated significantly improved by drinking probiotic Lactobacillus microbes [33-37 These commensals directly injure the Bioessays 36: 940-949, 2014 The Authors Bioessays published by WILEY Periodicals, Inc. 941Microbial genes outnumber human genes by 100 to 1 in the intestinal microbiome, leading some to propose that it is a “microbial organ” that performs important functions for the host, such as nutrient harvesting and immune develop￾ment [11]. However, as with any complex and intimate interaction, there is a mixture of common and divergent interests with opportunities for mutual benefit [11] and manipulation [12]. Fitness interests of gut microbes are also often not aligned, because members of the microbiota compete with one another over habitat and nutrients. This means that highly diverse populations of gut microbes may be more likely to expend energy and resources in competition, compared to a less diverse microbial population. A less diverse microbial population is likely to have species within it that have large population sizes and more resources available for host manipulation. Moreover, the larger a particular microbial population is, the more power it would have to manipulate the host through higher levels of factor production or other strategies (see below) and large scale coordination of these activities (e.g., through quorum sensing). Therefore, we hypothesize that lower diversity in gut microbiome should be associated with more unhealthy eating behavior and greater obesity (i.e., decreased host fitness). Evidence indicates many potential mechanisms of manipulation There is a selective influence of diet on microbiota Individual members of the microbiota, and consortia of those microbes, have been shown to be highly dependent on the nutrient composition of the diet. Prevotella grows best on carbohydrates; dietary fiber provides a competitive advantage to Bifidobacteria [13], and Bacteroidetes has a substrate preference for certain fats [14]. Some specialist microbes, e.g. mucin degrading bacteria such as Akkermansia mucinophila, thrive on secreted carbohydrates provided by host cells. Other butyrate producing microbes, e.g. Roseburia spp., fare better when they are delivered polysaccharide growth substrates in the diet. Specialist microbes that digest seaweed have been isolated from humans in Japan [15]. African children raised on sorghum have unique microbes that digest cellulose [16]. Many other examples exist [17]. Even microbes with a generalist strategy tend to do better on some combinations of nutrients than others, and competition will determine which microbes survive [18, 19]. Microbes can manipulate host behavior There is circumstantial evidence for a connection between cravings and the composition of gut microbiota. Individuals who are “chocolate desiring” have different microbial metabolites in their urine than “chocolate indifferent” individuals, despite eating identical diets [20]. There is also evidence for effects of microbes on mood. A double-blind, randomized, placebo controlled trial found that mood was significantly improved by drinking probiotic Lactobacillus casei in participants whose mood was initially in the lowest tertile [21]. There are many other examples of microbes affecting their hosts’ mood and behavior, mostly from animal studies (Fig. 1). Butyrate, a short chain fatty acid largely produced by the microbiota, has been shown to have profound central nervous system effects on mood and behavior in mice [22]. Microbiota transfer to germ free mice leads to timid behavior when fed feces from mice with anxiety-like behavior. When germ-free mice from an anxious strain were fed with a fecal pellet from a control mouse, the inoculated mice exhibited behavior that was more exploratory, and more like their fecal donors [23]. In addition, a probiotic formulation with Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 alleviated psycho￾logical distress [24]. This effect can be altered by diet and inflammation [25]. If one feeds Lactobacillus rhamnosus (JB-1) to mice, not only does it reduce their stress-induced corticosterone hormone levels, but it also makes them more dogged: L. rhamnosus (JB-1) fed mice swim longer than the control fed mice when put in a glass cylinder filled with 15 cm of water and no means of escape [26]. This effect disappeared when the experimenters severed the vagus nerve, suggesting a role for the vagus nerve in microbial manipulation of host behavior. In contrast, severing the vagus nerve had no effect on swimming behavior of control mice that were not fed L. rhamnosus (JB-1) [26]. In a widely cited example of microbes affecting behavior, Toxoplasma gondii suppresses rats’ normal fear of cat smells, often to the detriment of the rats, but to the benefit of the microbes that are ingested into their new feline host. T. gondii infected rats are reported to become sexually aroused by cat urine [27], a propensity that promotes transmission of T. gondii at the expense of the fitness of the rat. Microbes can induce dysphoria that changes feeding behavior Although certain Lactobacillus appear to reduce anxiety, colonization of the gut with the pathogen Campylobacter jejuni increased anxiety-like behavior in mice [28], raising the possibility that microbe-induced dysphoria might also affect human behavior. Recent studies have linked the inconsolable crying of infant colic with changes in gut microbiota including reduced overall diversity, increased density of Proteobacteria and decreased numbers of Bacteroidetes compared to controls [29]. Colic has been reported to result in increased energy delivery to infants, sometimes resulting in accelerated weight gain [30]. If infant crying has a signaling function that increases parental attention and feeding [31, 32], colic may increase the resource delivery to the gut and hence microbial access to nutrients. One potential mechanism by which dysphoria can influence eating involves bacterial virulence gene expression and host pain perception. This mode of manipulation is plausible because production of virulence toxins often is triggered by a low concentration of growth-limiting nutrients. Detection of simple sugars and other nutrients regulates virulence and growth for a variety of human-associated microbes [33–37]. These commensals directly injure the ....Prospects & Overviews J. Alcock et al. Bioessays 36: 940–949,
2014 The Authors. Bioessays published by WILEY Periodicals, Inc. 941 Review essays