ReviewMetabolism

Therapeutic Modulation of Microbiota-Host Metabolic Interactions

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Science Translational Medicine  06 Jun 2012:
Vol. 4, Issue 137, pp. 137rv6
DOI: 10.1126/scitranslmed.3004244

Abstract

The complex metabolic relationships between the host and its microbiota change throughout life and vary extensively between individuals, affecting disease risk factors and therapeutic responses through drug metabolism. Elucidating the biochemical mechanisms underlying this human supraorganism symbiosis is yielding new therapeutic insights to improve human health, treat disease, and potentially modify human disease risk factors. Therapeutic options include targeting drugs to microbial genes or co-regulated host pathways and modifying the gut microbiota through diet, probiotic and prebiotic interventions, bariatric surgery, fecal transplants, or ecological engineering. The age-associated co-development of the host and its microbiota provides a series of windows for therapeutic intervention from early life through old age.

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Introduction

There is lifelong metabolic communication between the gut microbiota and the mammalian host that develops and changes with time. There are many channels of chemical information exchange operating between various microbial players and pathways in multiple host tissue compartments [see Review by Nicholson et al. (1)]. These channels operate in a similar way to hormonal communication in that specific substances are released under certain physiological conditions that have targeted actions elsewhere in the body. In the case of the gut microbiota and the host, there are a number of metabolic axes about which host and microbe interact (for example, metabolites of bile acids produced by microbial enzyme action bind to host nuclear receptors, linking microbes with cholesterol and steroid synthesis in the host) (1).

As a deeper understanding of the multiple channels and mechanisms of the metabolic (and linked immunological) axes of host-microbiota interactions emerges, so do new opportunities to exploit such knowledge for human health benefits through therapeutic targeting of these microbe-host co-regulated pathways (1, 2). Attempts to modulate the microbiota by controlling diet and using probiotics and prebiotics are well established (3), although underlying biochemical mechanisms are often lacking. Systems biology approaches are illuminating transgenomic cross-talk between the host genome (and signaling pathways) and the genomes (and metabolic products) of the microbiota and, in particular, how diet and the microbiota together influence host systemic biochemistry in animal models and humans (48). However, there are other modalities for microbiota and microbiome manipulation (Fig. 1) that could yield new therapies for treating a variety of common diseases caused by abnormalities of the gut microbiota and gut dysbiosis (where potentially hostile microbes proliferate at the expense of normal commensal and symbiont microbes) (1). Such modalities include highly selective uses of targeted antibiotics (9) to remove or attenuate unwanted bacterial species, which may include nonpathogenic organisms that influence the many microbial niches of the gut. There are also more subtle approaches that address the concept of the “druggable microbial genome” (2) where selective microbial activities are manipulated for host benefit without killing the bacteria themselves. This approach would capitalize on knowledge of specific aspects of co-regulated signaling pathways in man and microbe, and drugs would be targeted specifically at microbial genes operating in key host-microbe metabolic and signaling pathways (1, 2) (Fig. 2). Microbial products, such as secondary metabolites that have drug-like activity, can also be harnessed for therapeutic purposes. Because molecular understanding of microbial action advances and new tools in synthetic biology become available, it is also possible to envisage ecological engineering of the microbial genome (microbiome) with modifications to genetic activities of individual organisms or even microbial communities to benefit the host (Fig. 1) [see Review by Lemon et al. (9)]. However, these types of interventions are still distant in terms of both our theoretical understanding and practical implementation. The complex co-development of the gut microbiota leads to different types of potential interventions at different stages of a host’s life span (1, 5). Early interventions (before, say, 3 years old) would be aimed at creating a long-term stable and “healthy” microbiota associated with disease prevention both in childhood and in adult life. Interventions later in life would be more geared to treating specific conditions, such as inflammatory bowel disease (1), but could also influence the longer-term health of the elderly as the microbiota changes in old age (Fig. 1).

Fig. 1

Therapeutic modulation of the gut microbiota: from the cradle to the grave. The changing relationship between the gut microbiota and the human host throughout life offers a series of time windows for therapeutic intervention. During infancy and early childhood, a healthy gut microbiota helps to avoid dysbiosis that can lead to disease later in life. In adulthood, corrective strategies to deal with emergent dysbiosis and associated diseases such as inflammatory bowel disease, obesity, and type 2 diabetes include modulating the microbiota using probiotics and prebiotics, antibiotics, bariatric surgery, or by “drugging the microbiome.” Drugs targeted to microbial enzymes could also be used to boost the efficacy and reduce the toxicity of therapeutics. For extreme cases of gut-related disease, fecal transplantation or helminth therapy may prove beneficial. In the future, it may be possible to prevent or treat abnormalities of the gut microbiota using modified organisms engineered through genetic or synthetic biology approaches.

Fig. 2

Axes of host-gut microbiota metabolic interactions. A host-microbe metabolic axis can be defined as a multidirectional interactive chemical communication highway between specific host cellular pathways and a series of microbial species, sub-ecologies, and activities. Examples of such axes include bile acid production, where bile acids metabolized by gut microbes, especially lactobacilli, bind to host nuclear receptors involved in a variety of cellular processes. The endocannabinoid system is modulated by microbially generated molecules such as lipopolysaccharide that alter gut permeability and signaling to the brain. The aromatic acid axis links metabolically active molecules such as cresols and amines (which are vasopressors) generated by colon microbes like clostridia to the host’s ability to sulfate drugs such as acetaminophen. Short-chain fatty acids such as n-butyrate (formed from gut fermentation of complex carbohydrates in the proximal colon) provide an energy source for colon microbes but are also pharmacologically active, inducing angiogenesis in the gut mucosa. A diverse range of neurochemically active species (neurotransmitter axis) are produced by gut microbes ranging from γ-aminobutyrate to hydrogen sulfide and other gasotransmitters, which modulate ion transport and the enteric nervous system locally in the gut (87). The microbial-specific conversion of dietary choline to trimethylamine can also generate potentially toxic species that have been associated with atherogenesis and nonalcoholic fatty liver disease in mice. Collectively, these notional host-microbe metabolic axes provide potential targets for therapeutic intervention at different stages in life.

The evolution of drug-metabolizing enzymes has not been driven by recent drug exposure, but rather by exposure of humans throughout history to plant toxins in the diet and microbial toxins and the need to detoxify and eliminate them [see Perspective by Turnbaugh (10)] (2, 11). Indeed, there are multiple mechanisms of microbiota-host-drug interactions, and these can be modulated to enhance drug therapy (for example, minimization of toxicity or enhancement of efficacy). In the future, we can envisage how such modulation could be exploited for personalized healthcare (11, 12). In this Review, we examine strategies for interventions at multiple levels of biomolecular organization and host-microbiome “command and control” to optimize health, prevent disease, and develop new therapeutics (Fig. 1). Many of these interventions will not be practical without in-depth knowledge of the connections in the host-microbiota metabolic axes (1). The depth of association of gut microbiota abnormalities with increasingly common diseases such as inflammatory bowel disease, obesity, and diabetes makes the implementation of microbiome-based therapies an almost inevitable component of future personalized and precision medicine (13).

Drug-Microbiota-Host Interactions and Human Health

Because animals have evolved with specific gut microbes and interdependent dietary tolerances, so they have evolved tailored detoxification systems to deal with gut-derived toxins and xenobiotics (other compounds of nonmammalian origin that enter the gut with the diet or are produced by the microbiota) (14). These detoxification systems include the cytochrome P450 enzymes of the host gut, liver, and other organs that regulate phase 1 drug metabolism reactions (oxidation, reduction, hydroxylation, etc.), which render foreign compounds more polar and hence more easily eliminated in the urine (13). So-called phase 2 drug metabolism reactions are also used extensively to modify gut microbial products. These involve conjugation of endogenous metabolites or ions to foreign compounds through reactions catalyzed by host enzyme transfer systems that typically increase the polarity of foreign molecules, thus boosting their urinary excretion. These enzyme transfer systems include sulfotransferases that transfer sulfate to phenolic compounds and other hydroxylated species to form O-ether sulfates. For example, host sulfotransferases transfer sulfate to hydroxyl groups of phenolic compounds, such as 4-cresol (which is made from putrefaction of tyrosine in the colon by microbes) that is then phase 2–conjugated to form 4-cresyl sulfate, an abundant urinary microbial metabolite (14, 15). Other major phase 2 conjugations use host uridine diphosphate–glucuronosyltransferase enzymes that transfer d-glucuronic acid to phenols and aromatic amines to form phenolic O-ether glucuronides or N-glucuronides, or to benzoic and phenylacetic acids to form O-ester glucuronides. Benzoate and phenylacetate can also be metabolically activated by host mitochondrial coenzyme A with subsequent enzymatic conjugation via amino acid transferases with glycine and glutamine to form hippurate and phenylacetylglutamine, respectively, two of the most abundant gut microbial co-metabolites in man (16). The generation of benzoic and phenylacetic acids in the gut by microbial action may play an important role in preventing excess systemic accumulation of the neuroactive amino acids glycine and glutamate (glutamate being the neuroactive deamination product of glutamine) (17).

The phase 2 conjugating enzymes that modify gut microbial products also conjugate drugs that have certain functional groups. The commonly used drug acetaminophen (paracetamol, Tylenol) is extensively sulfated and glucuronidated as are many other drugs that are also metabolized via cytochrome P450–based phase 1 reactions. Thus, the enzymatic basis of drug metabolism is directly linked to this microbial metabolite detoxification process, and so it is unsurprising to find that gut microbial activities affect drug metabolism and toxicity. Pharmacometabonomics is based on the notion that preinterventional metabolic signatures can be used to predict post-interventional outcomes of drug treatments (18). Pharmacometabonomics has shown that the ratio of sulfated to glucuronidated acetaminophen (when given at therapeutic doses) in human urine correlates with the preinterventional excretion of the microbial co-metabolite 4-cresyl sulfate. This implies that the dominant metabolic fate (glucuronidation and sulfation) of the drug acetaminophen depends on gut microbial activity that varies extensively between individuals (19). There are potentially hundreds of drugs that either have hydroxyl groups or form hydroxylated metabolites that require sulfation for detoxification and elimination. Thus, gut microbial activities in the distal colon that produce 4-cresol from tyrosine could affect the metabolism and fate of many drugs. This, in turn, may explain individual variations in certain drug responses that are poorly predicted by pharmacogenomics. This is just one example of a drug-microbial interaction (substrate conjugation competition) that affects drug metabolism and potentially toxicity. There are other gut microbial contributions to host phenotype that can alter the absorption, metabolism, and safety of drugs and that may offer new directions for modulating drug activities [see Perspective by Turnbaugh (10)]. These include (i) competitive metabolic substrate utilization (as described above), (ii) primary metabolism of orally administered drugs by the gut microbiota, (iii) microbial secondary metabolite–mediated enzyme induction, (iv) secondary metabolism of human metabolites, and (v) gut bioavailability (local pH control and ionization state).

Such dependencies of conventional xenobiotic metabolism and toxicity also lead to the possibility of altering function or activities of the gut microbiota deliberately to affect changes in drug activity to improve patient safety. An excellent example is the deliberate modulation of gut microbiota activity to ameliorate toxicity of the anticancer drug CPT-11 that has severe gastrointestinal (GI) side effects. The drug itself is absorbed from the gut and then partially detoxified via phase 2 conjugation in the liver, forming a glucuronide conjugate. The glucuronide conjugate is then secreted into the gut in bile where the drug CPT-11 is regenerated due to the action of the β-glucuronidase enzymes of gut commensal bacteria resulting in GI toxicity due to the free drug. Wallace et al. (20) showed in mice that selective microbial β-glucuronidase inhibitors when given at the same time as CPT-11 prevented deconjugation, hence minimizing the GI toxicity of the drug. This study shows that designing drugs to modulate microbiota activities to reduce the side effects of therapeutics should be possible in patients.

Host genes in concert with the gut microbiota, diet, and environmental stressors determine the metabolic phenotypes of individuals (21, 22). There are specific axes of interaction that couple particular microbial activities to particular host pathways acting principally in the gut, liver, and brain (1). These axes are highly metabolically interconnected, vary in relative activity throughout the human life span as well as in response to diet and life-style, and provide specific targets for therapeutic interventions (Fig. 2).

Probiotic and Prebiotic Interventions

Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” (Food and Agriculture Organization of the United Nations, 2002). Probiotics must be safe, that is, meet the U.S. Food and Drug Administration standard, should be amenable to industrial processes necessary for commercial production, must remain viable in the food product and during storage, must persist in the GI tract long enough to elicit an effect, and must improve host health (2326). Consumers and healthcare workers are starting to appreciate the clinical importance of our resident gut microbiota and the part that prebiotic and probiotic microbial species can play. Abnormal gut microbial activity has been implicated in a wide variety of diseases from inflammatory bowel disease to atherosclerosis, and manipulation of the microbiota is one approach to improve health and to treat disease (1, 3). Scientific research has focused on how to use probiotic bacterial species such as bifidobacteria and lactobacilli to alter the composition of the indigenous gut microbiota (23). These probiotic bacterial species help to protect the host by directly inhibiting the growth of harmful bacteria, and also benefit host health by reducing cholesterol levels, sustaining immune responses, and synthesizing vitamins such as folate and B12 (2326).

Probiotics have been knowingly ingested by humans for hundreds of years in the form of live yogurt. In contrast, prebiotics—defined as “nondigestible food ingredients that are selectively metabolized by colonic bacteria that have the capacity to improve health”—were developed only in the mid-1990s (3). Prebiotics are dietary ingredients such as nondigestible oligosaccharides that can selectively enhance the activity of beneficial indigenous gut microbes such as lactobacilli and bifidobacteria. Unlike probiotics, prebiotics can be added to food products that will be heated or cooked without destroying their effects. Thus, prebiotic use is directed toward favoring beneficial changes within the indigenous gut microbial milieu. Prebiotics are distinct from most dietary fibers such as pectin, celluloses, and xylan, which are not selectively metabolized in the gut. Criteria for classification as a prebiotic are as follows: (i) must resist gastric acidity, hydrolysis by mammalian enzymes, and GI absorption; (ii) must be readily fermented by the gut microbiota; and (iii) must selectively stimulate the growth and activity of gut microbes associated with health (27). Any dietary component that reaches the colon intact is a potential prebiotic; however, it is the third criterion that is the most difficult to fulfill.

It is only recently that we have been able to sequence and annotate the complete genomes of many gut microbes in any depth (28). Although the broad taxonomic classification of “good bacteria” has been known for some time (the restricted palette of probiotics has been drawn from this), we have not established criteria for what is “normal” in man, let alone what is healthy in man. With increasing premorbidity due to obesity and insulin resistance, what is considered a normal gut microbiota may not necessarily be healthy for many people. From a chemical perspective, much of the interest in the development of prebiotics is aimed at nondigestible oligosaccharides such as fructooligosaccharides, trans-galactooligosaccharides, lactulose, isomaltooligosaccharides, xylooligosaccharides, soyoligosaccharides, and lactosucrose. In Europe, several human volunteer trials have succeeded in defining fructooligosaccharides, trans-galactooligosaccharides, and lactulose as prebiotics as evidenced by their ability to change the gut microbiota composition after a short feeding period (29).

Both probiotics and prebiotics have been investigated for their ability to alter the gut microbiota in a manner that improves human health. Gastroenteritis, inflammatory conditions, atopic reactions, and intestinal cancers (30) are among the diseases that have been targeted (Fig. 1). Recent studies in mice and human twin pairs fed probiotic yogurt containing Lactobacillus rhamnosus and Lactobacillus paracasei have shown that although probiotic microbial species have only a slight impact on the gut microbiota composition (unsurprising given the size of the indigenous microbial population), they can up-regulate expression of host genes involved in carbohydrate metabolism (31). Also, direct measurement of the metabolic effects of probiotics and prebiotics in germ-free mice seeded with the gut microbiota of a human baby (4, 6) indicates that both probiotics and prebiotics induce shifts in urinary and plasma metabolite profiles. These gnotobiotic mice also showed markedly altered plasma lipid and lipoprotein profiles measured by nuclear magnetic resonance (NMR) spectroscopy and multiple metabolic effects in different tissue compartments (4, 6, 32). Such systemic effects suggest that a metabolic amplification of effect is occurring, with the probiotics and prebiotics changing microbe-host signaling properties. This may well be the case given the mismatch between the minor effects of prebiotics and probiotics on species composition and their much larger observed effects on host metabolism. Furthermore, different probiotics and prebiotics and their combinations may not be equivalent because they cause different metabolic effects in the host, suggesting that they are modulating different signaling pathways (4, 6). Even in microbiologically and genetically homogeneous mouse models, a diverse response exists to the same prebiotic-probiotic combination, suggesting that one size may not fit all. Detailed functional assessments of probiotic and prebiotic interventions and the identification of specific microbial-metabolic connections (33) will provide new multivariate metrics (in terms of shifts toward healthy host metabolic phenotypes) that will facilitate the rational design of dietary interventions that are more finely targeted in terms of their health attributes.

The Host and Its Microbiota During Aging

With a global impact on GI tract physiology, aging together with an associated decline in immune system function and increase in chronic inflammation affects gut microbiota homeostasis, leading to changes in intestinal function and microbiota composition. Changes in the composition of the symbiotic microbiota with age may result in altered fermentation (carbohydrate breakdown) and putrefaction (protein breakdown) in the colon and a greater susceptibility to disease. Disease- or age-related physiological changes in the GI tract, as well as modifications in life-style, diet, and immune system function, inevitably alter the metabolic pathways and small molecules involved in host-microbiota co-metabolism in the gut (1). There is now interest in tailoring probiotic and prebiotic preparations, diets, drugs, and even microbial engineering to populations of different ages and health status. The gut microbiota continues to change over life from infancy to old age (Fig. 1). During the first year of life, the infant’s gut ecosystem is colonized principally by opportunistic microorganisms to which the baby is exposed (34). Aerobes such as staphylococci, streptococci, and Escherichia coli are usually the earliest colonizers followed within days to weeks by strict anaerobes such as clostridia, bifidobacteria, ruminococci, and bacteroides. The microbiota of breast-fed infants is largely dominated by Bifidobacterium spp. An adult-like gut microbial profile with a remarkable diversity develops gradually after weaning, driven by a solid diet and development of the gut mucosa itself.

It has been suggested that administration of probiotics, prebiotics, or synbiotics (a mixture of prebiotics and one or more probiotic strains) could counteract age-related gut microbial changes in humans (3537). A clinical trial with 6-week-old healthy, full-term infants (38) showed that addition of a probiotic Bifidobacterium animalis subspecies lactis to infant formula increased intestinal immunity and reduced inflammation of the gut mucosa. Improved immune responses, such as increased production of immunoglobulin A antibodies against rotavirus and poliovirus after immunization, have been reported in Cesarean-delivered, non–breast-fed infants. Prebiotic supplementation with galactooligosaccharides and fructooligosaccharides (39) was well tolerated by formula-fed infants and showed beneficial effects including an increased abundance and proportion of bifidobacteria and reduced pH of feces.

Autistic children have an unusual gut microbial composition (40, 41) with a higher abundance of clostridia and altered urinary metabolic profiles with increases in phenylacetylglutamine, hippurate, and 4-cresyl sulfate compared to unaffected siblings or healthy children (42). 4-Cresyl sulfate appears to be elevated in the urine of severely autistic children (43), which may partly explain the poor ability of these children to sulfate drugs such as paracetamol (acetaminophen) (44), although the biological implications of these findings remain to be elucidated.

In the elderly, the microbiota exhibits a lower microbial diversity and a lower abundance of bifidobacteria, an increase in opportunistic environmental facultative aerobes such as Staphylococcus, Streptococcus, and Enterobacteriaceae, and an increase in anaerobes such as Clostridium groups and Bacteroides spp. (35). Increased antibiotic use in older people results in an altered gut microbiota, although the metabolic implications of this are ill-defined (36). A recent study showed that the fecal microbiota of the majority of an elderly cohort (>65 years) is dominated by a greater proportion of Bacteroides spp. and Clostridium groups compared to that of younger adults. A cohort of centenarians (>100 years old) in Northern Italy who were homogeneous regarding life-style and diet showed a gut microbial signature very different from that of their younger (<70 years old) counterparts. The gut microbiota of these centenarians is compromised by an altered Firmicutes population and by enrichment of facultative anaerobes, notably pathogenic organisms associated with increased inflammation. There was more than a 10-fold increase in the anaerobe Eubacterium limosum and its relatives in the centenarians compared to that in the younger cohort (37). E. limosum is seen as a beneficial species because it generates acetate, which can be used by the host as an energy source. Supplementation of the diet of an elderly cohort with probiotic Bifidobacterium strains increased the numbers of these health-promoting bacteria in the colon (45). Ingestion of prebiotic trans-galactooligosaccharides, as well as synbiotic preparations, boosted the number of bifidobacteria in elderly individuals (46).

Disrupted Microbe-Immune Interactions, Metabolic Disease, and Potential Targets

A major challenge for effectively modulating the gut microbiota is the need for new host and microbial markers and mediators of nutritional status that characterize the integrity of the gut mucosal barrier and mucosal immunity. We are beginning to understand how host signaling pathways are regulated by microbial-host co-metabolites and how these metabolites, which shuttle information between eukaryotic and prokaryotic cells, modulate adaptive and innate immunity in the host. The worldwide epidemic of diabetes, obesity, and metabolic disease has been linked to disruption of both the innate (47) and the adaptive (4850) immune systems. It has been suggested that excessive production of the cytokines tumor necrosis factor–α, interleukin-6 (IL-6), and IL-1 by immune cells may contribute to insulin resistance and hyperglycemia, eventually resulting in diabetes (5153). Deletion of genes encoding cytokines (53) and chemokines (54) or their corresponding receptors (55), or immune modulation through anti–T lymphocyte antibodies (50), could be used to attenuate the impact of a fat-enriched diet on the development of metabolic disease. In mice fed a high-fat diet, CD8+ effector T cells have been reported to infiltrate adipose tissue with a decrease in CD4+ helper T (TH) cells and regulatory T (Treg) cells (56). This study also showed through loss- and gain-of-function experiments and adoptive T cell transfer that Treg cells modulate the inflammatory state of adipose tissue, prompting the question of the origin of the antigens stimulating this immune response (56). The recent discovery that the phylotypic ecology of the intestinal microbiota is markedly altered in response to a fat-enriched diet in rodents (57) and in obese individuals (58) or in patients with type 2 diabetes (59) may help to answer this question. The marked improvement in metabolic characteristics in humans after Roux-en-Y gastric bypass (bariatric) surgery used to treat obesity (or, as is increasingly the case, type 2 diabetes) has been associated with major and stable changes in the gut microbiota with increases in γ-Proteobacteria (60). Similar observations have been made in rodents after bariatric surgery and microbial metabolic analysis using 454 pyrosequencing and high-resolution NMR spectroscopic and mass spectrometric measurements of urine and plasma metabolites (61). These studies also revealed overgrowth of γ-Proteobacteria especially Enterobacter hormaechei and extensive disruption of microbiota-host metabolic axes exemplified by marked shifts in bile acid metabolism after Roux-en-Y gastric bypass surgery (61). A variety of other microbially generated compounds are altered after bariatric surgery including increases in 4-cresol, several vasoactive amines, γ-aminobutyrate, acetate, and propionate (from fermentation). The microbial products modulated by bariatric surgery represent changes in nearly all of the metabolic axes shown in Fig. 2, suggesting that the microbiota is an essential part of the “gearbox” that connects the physical effects of bariatric surgery to the resulting beneficial effects, although determination of the exact role of these pathways awaits further study in man.

The microbe antigenic repertoire can help to shape the immune system (62) and adapt the intestinal mucosa to the arrival of new commensals and symbionts. Bacterial antigens such as lipopolysaccharides trigger the innate immune system through Toll-like receptors such as TLR4 (63). Female mice lacking TLR2 were protected from the adverse effects of a high-fat diet. They showed greater glucose tolerance, insulin sensitivity, and insulin secretion after 20 weeks on a high-fat diet compared to wild-type mice fed the same diet (64). In the case of TLR5, this receptor may protect against metabolic syndrome (that is, the opposite effect to TLR2 and TLR4) because mice genetically engineered to lack TLR5 exhibit hyperphagia and develop hallmark features of inflammation-mediated metabolic syndrome (65). The metabolic phenotype is also “transmissible” because transplantation of the microbiota from TLR5-deficient mice to germ-free wild-type mice resulted in obesity and reduced insulin sensitivity in the recipient animals. These findings also demonstrate that modulation of the immune system may affect host metabolism by altering the gut microbiota (Fig. 2) (1). The impact of the host immune system on the gut microbiota has been shown in mice lacking Nod-like receptors NLRP3 and NLRP6, which control activation of the inflammasome (66, 67). Bacterial DNA fragments have been detected in the blood of obese mice, and it has been suggested that they could be used to predict diabetes (68, 69). In contrast to the increased ratio of Firmicutes to Bacteroidetes observed in the intestine of obese mice (58), the blood of obese mice has DNA fragments of Proteobacteria (68), facultative anaerobes that can survive in the presence of oxygen. How these bacterial DNA fragments reach the blood is unclear, although loosening of the tight junctions between gut epithelial cells (57, 70) as well as colocalization of bacteria with intestinal dendritic cells (69) have been reported. A reduction in mRNAs encoding zonula occludens-1 and occludin proteins that compose tight junctions has been associated with metabolic disease induced by a high-fat diet (57, 71). This mechanism correlates with changes to the gut microbiota independent of the genetic background of the mice or the diet they are fed (70). Antibiotic treatments (72), as well as prebiotics improve intestinal permeability in mice through a mechanism that requires the secretion of glucagon-like peptide 2 (71). On the other hand, a transcellular mechanism may be responsible for the continuous surveillance of changes in the gut microbiota that could alter immune system function through changes in the intestinal antigenic repertoire. In obesity and type 2 diabetes, initial evidence suggests that mucosal dysbiosis in the ileum (69) could disrupt immune tolerance (73).

Dendritic cells expressing CX3CR1 that are able to access the gut lumen may be able to clear bacteria. In metabolic disease, the clearance of intestinal bacteria from the mucosa may be incomplete because bacteria have been reported to reach the mesenteric lymph nodes that are connected to adipose tissue (69). This mechanism involves NOD1 (the nucleotide-binding oligomerization-containing domain protein 1), which promotes metabolic disease induced by a high-fat diet, but does not involve NOD2, which conversely protects against diabetes and obesity (74). Such bacterial translocation generates a state of “metabolic infection,” as also shown in streptozotocin-induced diabetic mice where bacteria that normally reside in the gut, lung, and skin were reported in the liver, spleen, kidneys, and mesenteric lymph nodes (75). The notion is emerging that these mislocalized bacteria might induce inflammation in, for example, adipose tissue, resulting in an influx of cells from the adaptive immune system. This would create a complex milieu containing adipokines, chemokines, and their receptors (MCP-1, CCL7, CCL8/CCR2, CXCL14/CXCR2) and other molecules such as C3, factor B, adipsin, and angiopoietin-like protein 2 (76). Translocation of bacteria from intestinal or oral origin has also been described in atherosclerotic plaques where Proteobacteria rather than Firmicutes predominate (77). These bacteria belong to our commensal microbiota, which has “educated” the immune system from birth and is thus seen by the immune system as “self.” A change in the intestinal microbiota repertoire induced by recent changes in Western nutrition would constitute a rupture in this immune tolerance that has evolved over millennia, potentially leading to an increase in inflammation and metabolic disease. One way to prevent and treat metabolic disease may be to restore the microbiota-host immune relationship [see Review by Blumberg and Powrie (78)].

Engineering the Microbiota: A Challenge for the Future

Engineering the microbiota to favor human health is a formidable challenge that will require exquisite knowledge of co-metabolic regulation and ecological properties of the gut microbiota. For instance, engineering bacteria has shown potential for altering microbial metabolic pathways to enhance biofuel production in fermentation systems. The same strategy could in principle be used to correct abnormalities in metabolic or signaling pathways involved in disease pathogenesis. Nicaise et al. have shown that a metabolic condition, hyperammonemia, which occurs constitutively or due to liver failure, can be treated successfully in mice by administration of Lactobacillus plantarum (79). A wild-type L. plantarum strain and two strains that were genetically engineered to consume ammonia or to lack the ammonia transporter were used in this study. The ammonia-consuming strain lowered blood and fecal ammonia with improved survival of the mice with hyperammonemia compared with the wild-type L. plantarum strain. Similarly, Jones et al. (80) demonstrated that L. plantarum 80 (pCBH1)–overexpressing bile salt hydrolase, when given to mice in a microencapsulated form, efficiently degraded and removed glycodeoxycholic acid and taurodeoxycholic acid, suggesting that it may prove useful for lowering blood cholesterol. There are likely to be more applications for engineered intestinal microbial strains including the direct consumption of toxic chemicals in the gut. The advantage of these interventions over other gut microbiota modulation strategies is that they can be directed specifically at a toxic molecule or metabolic pathway rather than the entire microbiota. However, even subtle changes in the microbiota and bacterial physiology can exert marked changes in its ability to modulate the host immune system. A mechanistic understanding of such host-microbiota interactions can potentially lead to new interventions through synthetic biology. For example, a genetically engineered defect in techoic acid biosynthesis in L. plantarum converted a proinflammatory response in mice to the wild-type microbe to an anti-inflammatory response including increased IL-10 production (81). Yan et al. have described how protein p40 derived from L. rhamnosus reduced epithelial cell apoptosis and suppressed inflammation in mouse models of inflammatory bowel disease by activating the receptor for epithelial growth factor (82). These findings exemplify how an understanding of the molecular basis of these microbiota-host interactions could lead to the development of new therapeutic strategies for treating a variety of disorders.

The involvement of the gut microbiota in diverse aspects of disease presents a multitude of opportunities for intervention (Fig. 1) (for example, treating obesity and metabolic syndrome with bariatric surgery or modulating the gut microbiota by altering macronutrients in the diet or by administering prebiotics and probiotics) (83). For other diseases, more radical means of altering the gut microbiota have been attempted including fecal transplantation from healthy donors (84) to treat infection with antibiotic-resistant Clostridium difficile (84). Other strategies include direct ecological manipulation of the gut microbiota using microbe-microbe interactions through introduction of similar but nonpathogenic bacterial strains and the use of helminths to treat asthma, Crohn’s disease, and ulcerative colitis (85). Treatment with helminth parasites such as Trichuris trichiura, Trichuris suis, or Necator americanus works on the principle that the parasite induces a TH2 cell–based immunoregulatory response that dampens the TH1 response in the host with a reduction in inflammation and improved gut mucosal barrier function. Animal models have shown marked perturbation of microbial metabolites after infection by parasites, indicating a delicate equilibrium between the host, its resident microbiota, and acquired parasites (86), further emphasizing the metabolically complex nature of the mammalian symbiotic supraorganism.

Future Challenges

Understanding and then deliberately modulating microbiota-host metabolic and immune interactions to improve human health is one of the greatest challenges of 21st century medicine. In addition to the technical complexity of the field, which involves state-of-the art deep genome sequencing, advanced chemical technologies and bioinformatics, and computational integration of astonishing amounts of supraorganism systems data, there is the discovery process of finding potential interventional or therapeutic targets, axes, and pathways within all of this complexity. Advances in systems and computational biology will surely enable us to measure and model many aspects of the dynamic interactions between the human host and its resident gut microbiota. The benefits of harnessing this knowledge for disease management and the modification of disease risk have great potential and will help to underpin future developments in personalized healthcare and stratified medicine and ultimately in determining public health priorities.

References and Notes

  1. Acknowledgments: We acknowledge funding from the following: Imperial College Healthcare Trust Biomedical Research Centre, Bill and Melinda Gates Foundation, U.K. Medical Research Council, The Wellcome Trust, and Fondation Merrieux (J.K.N., E.H., and J.K.); U.K. Biotechnology and Biological Sciences Research Council, Tate + Lyle, Procter and Gamble, Ganeden, Clasado (G.R.G.); Swedish Medical Research Council, COMBINE, EU-project TORNADO, Karolinska Institutet Inflammation Consortium, The Millennium Foundation Singapore, The National Cancer Centre Singapore, and Nanyang Technical University (S.P.); Agence Nationale de la Recherche and European Framework Program FP7 (R.B.); U.S. National Institutes of Health grant # R01AA020212 (W.J.).
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