Original Contribution

Am J Gastroenterol Suppl (2012) 1:41–46; doi:10.1038/ajgsup.2012.8

Manipulation of the Gut Microbiota as a Novel Treatment Strategy for Gastrointestinal Disorders

Amy E Foxx-Orenstein DO1 and William D Chey MD2

  1. 1Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
  2. 2Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA

Correspondence: Amy E. Foxx-Orenstein, DO, FACG, FACP, Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA. E-mail: foxx-orenstein.amy@mayo.edu

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Abstract

The gut microbiota play a role throughout the human lifecycle, not only in harvesting energy from otherwise indigestible components of the diet, but also in directing submucosal angiogenesis and the establishment of the intestinal mucosal barrier during development as well as modulating the host immune system throughout life. The composition of the gut microbiota reflects two-way interactions between the gut microbiota and the host that promote mutual cooperation and functional stability of this complex ecosystem. Dysregulation of this balance as a result of diet, antibiotic use, or other exogenous factors has been shown to lead to disease, either directly—as in the case of antibiotic-associated diarrhea—or indirectly, as might occur in patients predisposed to visceral hypersensitivity who are fed a highly fermentable, poorly absorbed diet. Manipulation of the gut flora through dietary modification, antibiotics, probiotics, and other routes represents a promising therapeutic avenue in patients with disorders caused or exacerbated by imbalances in the gastrointestinal microbiota.

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INTRODUCTION

In adult humans, up to 100 trillion bacteria, representing between 500 and 1,000 different species, coexist within the gastrointestinal (GI) tract. The composition of the gut microbiota varies widely among individuals as a result of natural selection at both the microbial and host levels; although the eubacteria predominate in the GI tract of all healthy individuals, archaea and eukaryotes also participate in competitive and syntrophic relationships in the gut.

It has been suggested by several authors that the gut microbiota have a metabolic activity equivalent to a virtual organ (1,2) and, as might be expected, it has been shown to have profound influence on health and disease. In human development, the gut microbiota have been shown to direct the maturation of the intestinal mucosa. The microbiota also influence digestive enzyme activity, muscle wall thickness, and various immunologic parameters (1). It is increasingly recognized that there is a two-way interaction between bacteria and gut motor function; this interaction is supported by the presence of small bowel intestinal overgrowth in a proportion of patients with irritable bowel syndrome (IBS). Germ-free mice are protected against obesity; transfer of gut microbes from conventionally raised animals results in dramatic increases in body fat content and insulin resistance (3,4). The composition of the gut microbiota has been shown to differ in lean and obese animals (5) and humans (6), and the relative composition of the gut microbiota during early life has been shown to predict becoming overweight or obese (7).

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HUMAN COLONIZATION

At birth, the human GI tract is sterile; subsequently, it is colonized in succession by facultative Gram-positive cocci, enterobacteria, and lactobacilli that later give way to more strictly anaerobic species and—in breast-fed infants—a microbiota dominated by bifidobacteria. By age 2 years, the species diversity and population profile stabilizes and is essentially equivalent to that of adults.

A number of factors contribute to gut microbiota composition in early infancy (8). In one study, fecal samples from over 1,000 infants were taken at 1 month of age and assessed for the presence of various bacterial species by quantitative real-time PCR assays. Compared with infants delivered vaginally, reduced numbers of bifidobacteria and Bacteroides were observed in infants delivered by cesarean section; these infants were also more often colonized with Clostridium difficile compared with vaginally born infants. Similarly, hospitalization and prematurity were associated with higher prevalence and counts of C. difficile. Notably, antibiotic use by the infant was associated with decreased numbers of bifidobacteria and Bacteroides. Thus, full-term infants born vaginally who were breast fed were colonized by potentially “beneficial” microbiota (e.g., bifidobacteria) and were less likely to be colonized by C. difficile and Escherichia coli.

The gut microbiota are modulated by early-life nutrition. Intestinal flora in infants stabilizes at ~4 weeks after birth until the introduction of solid foods (9). During weaning, the microbiota of breast-fed infants—but not formula-fed infants—undergo dramatic changes. Although formula-fed infants develop a complex gut ecosystem consisting of facultative anaerobes, Bacteroides, and clostridia, breast-fed infants appear to develop a less diverse microbiota that are dominated by bifidobacteria. Several factors may account for the reduced diversity of the intestinal microbiota in breast-fed infants, including the presence of antimicrobial factors in human milk (such as lysozyme) and a reduced buffering capacity of human milk relative to infant formula that allows luminal contents to be more easily acidified, and this, in turn, may have an inhibitory effect on the growth of clostridia, Bacteroides, and other anaerobes.

Data suggest that the composition of the gut microbiota can have multiple effects on gut development in the early postnatal environment (10). For example, the complexity of the intestinal submucosal network of germ-free animals is primitive compared with conventional animals; colonization of adult germ-free animals with Bacteroides thetaiotaomicron “restarts” angiogenesis such that, within 10 days, development of the submucosal network is completed (10). B. thetaiotaomicron also appears to influence the establishment of the intestinal mucosal barrier by inducing the expression of a Paneth cell protein, Ang4, that is bactericidal for several Gram-positive pathogens but has little effect on B. thetaiotaomicron itself (10). Thus, the composition of bacteria in the gut lumen during early postnatal development can directly affect the ultimate composition of the bacterial flora in a given individual. These data also highlight the potential for two-way, beneficial interactions between the host and the gut microbiota.

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KEY FUNCTIONS OF THE MICROBIOTA IN THE ADULT

The gut microbiota perform a number of critical roles in the adult (Figure 1). Perhaps the most readily apparent function of the intestinal microbiota is their role in the metabolism of indigestible dietary components. Anaerobes within the gut ferment endogenous (e.g., epithelial-derived mucus) and exogenous (i.e., dietary) substrates, producing—among other products—short-chain fatty acids, especially acetate, propionate, butyrate, and lactate, which contribute up to half the energy requirement of colonocytes and are also metabolized by host tissues, including the liver, muscle, and brain. This metabolic activity not only provides energy and nutrients for bacterial growth, but also recovers energy for the host. For example, germ-free mice compared with colonized controls have a reduced uptake of glucose in the intestine and require greater caloric intake to sustain normal body weight (4). The byproducts of microbial metabolism also provide up to half of the energy requirement of colonocytes through the fermentation of carbohydrates to organic acids. The colonic microbiota also play roles in vitamin synthesis (e.g., biotin, folate), intestinal motility, enterohepatic cycling of bile acids, and cholesterol metabolism (11). The microbiota are capable of synthesizing many essential vitamins; two of these, folate and biotin, are closely involved with epigenetic regulation of colonic epithelial proliferation (12). A connection between the microbiota and intestinal motility has also been well documented (13). The microbiota may influence gut motor function through a variety of mechanisms, including the release of bacterial substances or end products of bacterial fermentation, the effects of mediators released by gut immune response, or by intestinal neuroendocrine factors (14). Numerous studies support that intestinal microbiota may influence host cholesterol metabolism (15), presenting mechanisms ranging from modification of bile acids that affect enterohepatic circulation and de novo synthesis of bile acids, to cholesterol absorption and inhibition of lipoprotein lipase (3).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Key functions of the gut microbiota.

Full figure and legend (59K)

Beyond their role in harvesting energy for the host, influencing vitamin and cholesterol synthesis, affecting gut motor function, and influencing dietary and bile acid metabolism, the gut microbiota act to modulate the immune system—a key effect that may underlie the therapeutic efficacy of probiotics. For example, commensal bacteria within the gut have been shown to limit signaling through transcription factor nuclear factor-κB, a key regulator of the host inflammatory response to pathogenic bacteria and other stress signals, through a variety of mechanisms (1). Other mechanisms for modulating host immune response include limiting signaling through Toll-like receptor-4 and induction of transforming growth factor-β, nerve growth factor, and mitogen-activated protein kinase and protein kinase B pathways.

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EVOLUTIONARY SIGNIFICANCE OF THE HUMAN MICROBIOTA

Humans and their microbiota have clearly coevolved. Perhaps the best-known example is lactose tolerance. Animal milk has been a key food source for >8,000 years; however, not all adults retain the ability to digest lactose (16). A geographic pattern has been observed for lactose tolerance, which is much more prevalent in milk-dependent societies, such as Northern Europeans. Selective pressures are also evident in the evolution of human amylase, a key enzyme required for starch hydrolysis; populations with high-starch diets tend to have more copies of the salivary amylase genes compared with those with traditionally low-starch diets (17).

Studies have found that migratory patterns from Africa can be traced through the lineage of bacterial species such as Helicobacter pylori (18). Although H. pylori has been linked to the development of gastroduodenal diseases (gastritis, peptic ulcer disease, and gastric cancer) new data suggest that its presence may also be associated with a number of clinical benefits. Some—but not all—H. pylori strains carry a 40-kb region of chromosomal DNA known as the cag pathogenicity island (cag-PAI) (19). The cag-PAI encodes, among other proteins, an effector protein (CagA) as well as proteins involved in translocating CagA into gastric epithelial cells. CagA itself has numerous effects on gastric epithelial cells, including, but not limited to, alterations in cell structure and motility, changes in the structure and function of tight junctions, and disruption of the polarity of epithelial cells (19). Although these effects may contribute to gastroduodenal disease, the absence of CagA+ H. pylori may be linked to disease; in particular, relationships have been identified between the presence of CagA+ H. pylori and gastroesophageal reflux disease, Barrett's esophagus, esophageal adenocarcinoma, and allergy. H. pylori may also influence metabolism through an effect on the production of ghrelin and leptin, two hormones involved in satiety.

The composition of gut flora reflects two-way interactions at both the microbial and host levels. The adaptive immune system has been shown to influence the diversity of the gut microbiota. For example, bacteria-specific IgA responses are observed when germ-free mice are colonized with members of the normal gut microbiota. However, colonization of mice that lack a functional adaptive immune system with one or more species of bacteria is associated with a robust innate immune response compared with immunocompetent mice (20). These data suggest that the adaptive immune response may attenuate the innate immune response to normal gut microbiota. Thus, the mammalian immune system has evolved the capacity to “recognize” certain members of the intestinal bacterial community, promoting a noninflammatory relationship between the gut symbiont and the host.

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MANIPULATING THE GUT FLORA FOR THERAPEUTIC BENEFIT

The data presented above clearly indicate that the gut microbiota play a critical role in human health. Even species widely believed to be pathogenic are increasingly being shown to confer benefits to the host. Thus, manipulation of the gut flora for therapeutic benefit (or incidentally as the result of treatment for other diseases) has the capacity to be a double-edged sword. A general summary of commonly available approaches to modifying the gut flora is shown in Table 1.


The gut microbiota may contribute to the onset and maintenance of IBS. Perhaps the clearest demonstration of the relationship between the GI flora and IBS comes from studies indicating that the risk for IBS is increased dramatically among patients who have previously experienced an episode of infectious gastroenteritis. Among patients with acute bacterial gastroenteritis, there is a sevenfold increase in risk for IBS (21). Recent literature has also documented an increased risk of IBS following viral and parasitic gastroenteritis, suggesting that any type of infection that can lead to changes in gut ecology and immune function can lead to IBS symptoms (22,23,24). In fact, mucosal biopsies from these patients demonstrate immunologically mediated alterations including increased lymphocytes, increased inflammatory mediators, and increased small bowel permeability (25). Furthermore, small intestinal bacterial overgrowth has been reported to occur in between 20 and 80% of patients with IBS (26,27).

The gut microbiota of patients with IBS may be different from controls. Although it is important to acknowledge the considerable overlap in fecal microbiota recovered from IBS patients and healthy controls, recent studies do suggest some differences. One study that evaluated stool samples from patients with a broad range of IBS symptoms—diarrhea, constipation, and alternating bowel habits—identified reduced amounts of Lactobacillus spp. in samples of patients with diarrhea-predominant IBS. In contrast, constipation-predominant IBS patients had increased Veillonella spp. (28). Differences were also observed in the Clostridium coccoides subgroup and Bifidobacterium catenulatum group. No indication for a relationship between IBS and either H. pylori or C. difficile was seen (28).

Prebiotics

Diet has considerable influence on the composition of the microbiota. Prebiotics are a category of nutritional compounds grouped, not so much by structural similarities as by ability to promote the growth of commensal (probiotic) gut bacteria, especially, but not exclusively, lactobacilli and bifidobacteria. Fructooligosaccharides, bran, and inulin are among the most recognized prebiotic compounds. The data suggest that indirect manipulation of the GI flora through dietary modification, among other potential mechanisms, may provide clinical benefits for selected GI symptoms. Malabsorption of fructose, a simple monosaccharide found in many foods, has been linked to the development of GI symptoms in a subset of individuals. Although the prevalence of fructose malabsorption is similar in IBS patients and healthy individuals, the consequences may differ in these two patient populations. In one study conducted by Shepherd et al. (29), nearly 30% of IBS patients were unable to tolerate a large load of fructose or fructans, whereas this relationship was not observed in non-IBS patients with or without fructose malabsorption. The potential importance of fermentation of poorly absorbed substrates to the development of GI symptoms has been the focus of multiple recent studies. FODMAPs (fermentable oligosaccharides (e.g., fructans), disaccharides (e.g., lactose), monosaccharides (e.g., fructose), and polyols (e.g., sorbitol)) are highly fermentable, poorly absorbed substances that have been shown to influence IBS symptoms; restriction of foods that contain FODMAPs has been explored as a potential therapeutic intervention (30). The rationale is that FODMAPs contribute to symptoms in IBS through a combination of mechanisms (31). FODMAPs may induce GI symptoms in patients with pre-existing visceral hypersensitivity or abnormal motility responses by causing luminal distension as a consequence of bacterial fermentation and the resultant production of osmotically active byproducts and gases such as hydrogen and methane (32). In a study conducted by Ong et al. (32) in IBS and healthy patients, subjects were randomized to diets that were either low (9g/day) or high (50g/day) in FODMAPs for 2 days; assessments were made using breath sampling on day 2 of each diet. Notably, the area under the curve for breath hydrogen was significantly higher during the high-FODMAP diet than during the low-FODMAP diet for both healthy volunteers (P<0.0001) and patients with IBS (P<0.0001). In addition, GI symptoms and lethargy were seen in IBS patients but not in healthy volunteers who received the high-FODMAP diet. In animal models, rats fed fructooligosaccharides developed injury of the colonic epithelium and increased intestinal permeability; moreover, FODMAP-fed rats developed more severe colitis when experimentally infected with Salmonella spp. (33).

FODMAPs also appear to have prebiotic effects, selectively inducing proliferation of certain bacterial strains, including Bifidobacterium spp. (34). For years, products such as fiber and lactulose—which also exert prebiotic effects—have been widely prescribed in the treatment of constipation. These data provide a link between diet, the intestinal microbiota, and GI function in health and disease.

Antibiotics

Conceptually, antibiotics represent the simplest and most direct approach to manipulate the gut microbiota for potential therapeutic benefit. In IBS, results for nonabsorbable antibiotics have been positive. For example, an early study that evaluated the effects of neomycin on IBS symptoms as well as the results of lactulose breath testing found that neomycin resulted in a 35.0% improvement in a composite score measuring abdominal pain, diarrhea, and constipation vs. 11.4% for placebo (P<0.05) (27).

More recent studies have focused on the nonabsorbable antibiotic rifaximin (approved in the United States for traveler's diarrhea and the risk of overt hepatic encephalopathy recurrence but not for IBS) (35). In two recent studies, patients were randomized to treatment with rifaximin 550mg or placebo 3 times daily for 2 weeks in a 12-week trial. More rifaximin than placebo patients achieved adequate relief of global IBS symptoms for ≥2 of the first 4 weeks after treatment (40.7% vs. 31.7%, P<0.001). Rifaximin was also superior for adequate relief of IBS-related bloating (40.2% vs. 30.3%, P<0.001). The results from the phase III trials were recently validated in a meta-analysis that contained data from five randomized, placebo-controlled trials evaluating the efficacy of rifaximin in the treatment of IBS (36).

The relationship between disruption of the normal GI microbiota with antibiotic therapy and the development of C. difficile infection is but one example of the potential risks of dramatically manipulating the gut microenvironment. C. difficile infection accounts for between 26 and 50% of cases of antibiotic-associated diarrhea, and patients are at risk for recurrent disease; in long-term care facilities, there is a 10% risk of being colonized if hospitalized for ≥2 days (37). As C. difficile colitis has been linked to disruption of normal colonic microbiota, reconstitution of bacterial populations may be a potential therapeutic avenue for selected GI disorders. This approach was examined in a small study conducted by Rohlke et al. (37) in which 19 patients with confirmed recurrent C. difficile infection were treated by infusing donor stool through a colonoscope. Of these, 18 responded to a single fecal transplantation treatment, 1 responded after a second treatment, and all maintained prolonged remission for 6 months to 5 years. Reinfection was detected in only three patients, all of whom tested positive for C. difficile after treatment with antibiotics for unrelated infections.

Probiotics

Exogenous supplementation or replacement of the intestinal and colonic microbiota with probiotics has long been used in patients with GI symptoms. Probiotics have been developed from a number of sources, including yogurt starter cultures, a World War I soldier (Escherichia coli Nissle 1917), and infant stool (Bifidobacterium infantis) (38). The data on the efficacy of probiotics in the management of IBS are limited, and few high-quality comparative studies are available. A systematic review of various probiotic formulations identified 16 randomized controlled trials, the majority of which had suboptimal study designs, heterogeneous study populations, and utilized a variety of nonvalidated outcome measures. This systematic review also reported that none of the studies provided quantifiable tolerability and adverse event data; for these reasons, the authors did not feel that it was appropriate to perform a meta-analysis. Their systematic review identified two high-quality, randomized, placebo-controlled trials, both of which reported clinical benefits for IBS with B. infantis 35624 (39).

In another meta-analysis of the efficacy of probiotics for IBS, in trials that reported outcomes as a dichotomous outcome, probiotics provided statistically significant benefits for IBS symptoms (relative risk of symptoms persisting in probiotic group=0.71; 95% confidence interval 0.57–0.87) (40). Among trials that reported outcomes as a continuous variable, probiotics also had a statistically significant effect on improving IBS symptoms. Of these trials, 4 (N=200) found no effect of Lactobacillus, 9 (N=772) identified significant benefits with combination formulations, and 2 (N=379) found a trend toward benefit for Bifidobacterium.

In addition to their potential role in the treatment of patients with IBS, probiotics are effective in the prevention and treatment of diarrhea. These indications—as well as other potential indications for probiotics—are discussed extensively elsewhere in this supplement.

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CONCLUSIONS

It is clear that the GI microbiota play a significant role in human health, and conversely, dysregulation or imbalance of the microbiota may lead to both GI effects and extraintestinal disease. An abundance of data point toward a role for the bacterial microbiota in the pathogenesis and maintenance of IBS; data also suggest that the microbiota play a role in energy balance and provide protection against other disease states.

This has led to suggestions that the intestinal microbiota are an attractive target for modulation in a variety of disease states. Indeed, evidence suggests that treatment with antibiotics, probiotics, or dietary modification—all of which would be expected to significantly alter the relative proportions of the bacterial species in the gut—is associated with improvements in the symptoms of a number of GI disorders such as IBS. Moreover, as reviewed in detail elsewhere in this supplement, modification of the GI microbiota may have profound metabolic consequences. Whatever the method used, modification of the gut microbiota is not without risks, as experience with antibiotic-associated C. difficile infection has shown.

Although techniques for assessing the composition of the intestinal microbiota are evolving, limitations remain in our ability to readily examine the intestinal microbial environment in situ. Research will guide identification of factors and dietary components that shape the microbiota and their interaction with the host. Improved understanding of how genes respond to bacterial signals that affect human physiology will open doors to the development of new treatment paradigms (41). Carefully targeted antibiotics have the potential to remove or suppress select components of the human microbiome; probiotics and prebiotics might be used to encourage the proliferation of beneficial microbes to maximize sustainable changes in the microbiome. Combination approaches may come to provide synergistic and effective treatments for specific disorders. Although it is evident that vast potential exists for manipulating the GI microbiota for therapeutic effect, it is evident that more research is needed to rationally target microbe-directed therapies according to disease state.

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Conflict of interest

Guarantor of the article: Mark Pimentel, MD, FRCP(C).

Specific author contributions: Dr Foxx-Orenstein and Dr Chey jointly initiated the study concept and design, analyzed and interpreted data, drafted the manuscript, and critically revised and approved the final manuscript.

Financial support: Amy E. Foxx-Orenstein has received industry grant support from AstraZeneca. An independent medical educational grant from Salix Pharmaceuticals was provided to support the development of this supplement. The grantors did not review the manuscript before publication, nor did they provide input into the content of the supplement.

Potential competing interests: William D. Chey has received consulting fees from Albireo, Astra-Zeneca, Ironwood, Prometheus, SK, SmartPill, Salix Pharmaceuticals, Takeda, and XenoPort. Amy E. Foxx-Orenstein has received consulting fees from Salix Pharmaceuticals, Takeda, and Ironwood; she has received lecture fees from AccredEd.

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Acknowledgments

We thank John Ferguson for editorial assistance in preparing the manuscript for publication.