Food–Microbiome Interaction: Implications for Health and Disease
Posted August 10, 2016
There is a strong link between diet and health, and research has elucidated the important role of diet in the health of the gut microbiota, a link that may be as important as the one between diet and metabolism. Gut microbiome dysbiosis (dysregulation) has been linked to a gastrointestinal, metabolic, autoimmune and neurological disorders; thus the microbiome could be a target for therapeutic intervention.
On May 10–12, 2016, the Academy's Microbiome Discussion Group and the Quadram Institute convened a conference at the Royal Society in London, UK, titled Food–Microbiome Interaction: Implications for Health and Disease. The conference covered topics including the links between food, the microbiome, and healthy living; the microbiome in development; microbiome interactions outside the gut; and the therapeutic potential of targeting the microbiome. There was a strong clinical focus, highlighting translational opportunities and new perspectives on established therapies. This was the third of three symposia on the causal relationships between microbiota and disease.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations available from:
M. Andrea Azcarate-Peril, PhD (University of North Carolina Chapel Hill)
Laurence Ashley Blackshaw, PhD (Queen Mary University of London, UK)
Thomas Borody, MD, PhD (Center for Digestive Diseases, Australia)
Jan Claesen, PhD (University of California, San Francisco)
Marcus Claesson, MSc, PhD (University College Cork, Ireland)
Lawrence David, PhD (Duke University)
Jean-Michel Faurie, PhD (Nutricia DANONE Research)
B. Brett Finlay, PhD (University of British Columbia, Canada)
Denise Kelly, PhD (Seventure Partners)
Omry Koren, PhD (Bar-Ilan University, Israel)
Britt Koskella, PhD (University of California, Berkeley)
Trevor David Lawley, PhD (Wellcome Trust Sanger Institute, UK)
Richard Mithen, PhD (Quadram Institute; Institute of Food Research, UK)
Karen Scott, PhD (Rowett Institute of Nutrition and Health)
Melanie Welham PhD (BBSRC, UK)
This eBriefing is part of a series on the causal relationships between microbiota and disease, also including:
Advances in Human Microbiome Science: Intestinal Diseases
Advances in Human Microbiome Science: Gut–Brain Interaction
How to cite this eBriefing
The New York Academy of Sciences. Food–Microbiome Interaction: Implications for Health and Disease. Academy eBriefings. 2016. Available at: www.nyas.org/FoodMicrobiome-eB
- 00:011. Introduction
- 03:192. A paradigm shift; Metagenomic sequencing; Experiment examples
- 10:173. Sporulation methodology and implementation; A working model; Pan-microbe database
- 16:034. Genomic blueprint of human microbiome
- 22:195. Extrinsic reservoirs of bacteria and AMR; Acknowledgements and conclusio
- 00:011. Introduction and overview
- 05:212. Bypass surgery; Targeting entroendocrine cells; Nutrient sensing in the gut wall
- 11:503. How the nutrient capsule works; Further research and studies
- 18:504. Synergism in nutrient sensing; Specific delivery of stimuli; Clinical trial
- 23:285. Conclusions and acknowledgement
- 00:011. Introduction and overview
- 02:122. Bacterial production of natural products; Genomic revelations; Identification
- 05:173. In silico approaches; Global analysis; Cloning study
- 10:064. Structural studies; Molecular mechansims
- 15:555. Genomics-driven approach; Future directions; Acknowledgements and conclusio
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European life-sciences focused venture capital fund running the Health for Life program to invest in early-stage translational research targeting the microbiome.
Algorithm for predicting biosynthetic gene clusters in microbial genomes.
Clinical trial of fecal microbiota transplantation in ulcerative colitis.
Finlay B, Arrieta M-C. 2016. Let Them Eat Dirt: Saving Our Children from an Oversanitized World. Algonquin Books, Chapel Hill, NC.
Bradshaw RA, Stahl PD eds. 2015. Encyclopedia of Cell Biology. Academic Press.
John Bienenstock, CM, FRCPC, FRSC
Jeffrey Gordon, MD
M. Andrea Azcarate-Peril, PhD
Guido Joost Bakker, MD
Laurence Ashley Blackshaw, PhD
Richard Blumberg, PhD
Thomas Borody, MD, PhD, FRACP
Jan Claesen, PhD
Simon Carding, PhD
Marcus Claesson, MSc, PhD
Lawrence David, PhD
Sonya Dougal, PhD
The New York Academy of Sciences
Jean-Michel Faurie, PhD
B. Brett Finlay, PhD
Maria Gloria Dominguez-Bello, PhD
Lindsay Hall, PhD
Ailsa Hart, MRCP, PhD
Nathalie Juge, PhD
Trevor David Lawley, PhD
Denise Kelly, PhD
Omry Koren, PhD
Britt Koskella, PhD
Richard Mithen, PhD
Karen Scott, PhD
Melanie Welham, PhD
Clare Sansom holds a PhD in biophysics from the University of Bristol, United Kingdom. She previously held postdoctoral positions in bioinformatics at the National Cancer Institute, USA and the Universities of Aston and Leeds, UK; she now teaches bioinformatics and medicinal chemistry at the MSc level and works as a freelance science writer and editor. She enjoys writing about basic and applied biomedical research for a diverse audience of students, scientists, and clinicians.
Quadram Institute and Institute of Food Research, UK
Hippocrates suggested over two millennia ago that "all disease begins in the gut," and indeed modern science has elucidated the important role gut microbes play in health and disease. The gut microbiome is the densest and most complex in the human body; it changes considerably throughout life and as a result of diet and disease.
This Microbiome Discussion Group conference was co-hosted with a UK-based food and health research institute, the Quadram Institute, which is so new that it does not yet have a building but is scheduled to open fully in 2018. The institute will combine interdisciplinary expertise from four institutes currently based at the Norwich Research Park: the Institute of Food Research (IFR); the John Innes Centre, which focuses on plant and microbial science; the genome analysis center TGAC; and Norfolk and Norwich University Hospital. One clinical service—gastrointestinal endoscopy—will move from the hospital to the institute when it opens.
A keynote lecture by Richard Mithen, head of the Food & Health Institute Strategic Programme at the IFR who gave the talk on behalf of its director, Ian Charles, introduced the new institute and its research themes: the gut and microbiome, food innovation, food safety, and healthy aging. Its broad goals will involve integrating research in relevant disciplines together and with its clinical and industrial applications. The gut and its microbes affect almost all metabolism and are involved in diseases with enormous human and economic costs worldwide.
Mithen suggested that the new institute has opened opportunities in a "new era for food and health research." He concluded by setting the scene for the four main sessions of the conference: food, health and the microbiome; the microbiome in development; microbiome interactions outside the gut; and translational opportunities. Speakers in the first session discussed the effect of diet on the microbiome throughout life and how microbial populations can change rapidly in response to food. They also discussed the mechanisms of microbe interaction with the mucus layer lining the GI tract and described microbial changes in inflammatory bowel disease (IBD). IBD is among the top indications for the emerging microbiome-targeted therapies presented by the second keynote speaker, Denise Kelly, from a venture capital company called Seventure Partners.
The so-called hygiene hypothesis links the recent increase in autoimmune disease to a lack of exposure to microbes in early life. Several speakers in the second and third sessions showed how this effect can be mediated through the gut microbiome, and showed how breastfeeding and avoiding unnecessary antibiotics in infancy promote the development of a healthy mix of microbiota. The final keynote speaker, John Bienenstock, from McMaster University in Canada, described ways in which gut microbes and their metabolites interact with the immune and nervous systems, providing detailed, mechanistic evidence for links between microbiome dysfunction and diseases such as depression.
The microbiome can be targeted therapeutically by conventional, small-molecule drugs, and products of bacterial metabolism can also be mined for drug development leads. Some innovative therapies use the microbes themselves as a therapeutic product, either given by mouth as probiotics or transplanted from the feces of a healthy volunteer, and novel clinical applications of these products were discussed throughout the meeting.In his closing remarks, Mithen stressed the long history of innovations that target the microbiome, for example with fecal transplants, going back to ancient Chinese medicine, as well as the gaps in knowledge that still exist. He quoted Isaac Newton, once President of the Royal Society, who described himself as a boy playing on the seashore while "the great ocean of truth lay all undiscovered before me." The more we learn about diet and the microbiome, the more we understand how little we have learned. Many open questions remain, and the Quadram Institute is poised to tackle them.
Karen P. Scott
Rowett Institute of Nutrition and Health, University of Aberdeen, UK
Institute of Food Research, UK
University College Cork, Ireland
The human gut microbiome changes throughout life, following age-associated changes in diet.
Bacteria that digest mucus thrive in the human gut, and some of these express a sialidase enzyme with an unusual mechanism of action.
Diet-associated changes in microbial diversity occur rapidly.
The variable microbiomes of patients with IBD differ from those of healthy individuals, and differences between them may help define patient subgroups for specific therapies.
Your microbiome is what you eat
Karen Scott of the Rowett Institute of Nutrition and Health at the University of Aberdeen began the first session by introducing the link between diet and the microbiome. The gastrointestinal (GI) tract is the organ most heavily colonized by microbes, and the density of microbes in it increases from the mouth to the colon. Many factors affect the composition of the gut microbiome, which varies from birth to old age, and diet is one of the most—if not the most—important of these. Diet tends to become more varied as a child grows and is introduced to different food groups; it then becomes more restricted late in life, often because of poor food choices, illness, and frailty. There is some evidence that a Western diet leads to less diverse and less healthy microbiota.
Studies of the gut microbes of young babies have given conflicting results. Scott showed that their results depend strongly on the methodology used, and that standard methodologies underestimate the proportion and diversity of the bifidobacteria, which ferment milk oligosaccharides. Next-generation sequencing methods such as 16S rRNA pyrosequencing can identify these bacteria and follow post-weaning microbial diversification precisely.
Turning to the adult microbiome, Scott described changes that arise from altering the amount or type of carbohydrates in the diet. Community living elderly people have been found to have more diverse microbiomes compared to care-home residents of a similar age. Yet diet is more important than place of residence: elderly individuals in the community who habitually eat the monotonous, high-fat diet that is common in care homes have microbiomes that are similar to those of the care-home residents.
The inside of the gut wall is lined with a thick layer of mucus that separates gut bacteria from host cells; it is formed from highly glycosylated proteins known as mucins, which form an important food for the gut bacteria. Mucin glycosylation varies along the GI tract and is altered in many diseases. Nathalie Juge from the Institute of Food Research described the complex interactions between the microbiome and the mucus layer.
Anaerobic bacteria in the genus Ruminococcus, particularly Ruminococcus gnavus, are very common in the human gut. R. gnavus strains that can degrade mucins encode an unusual sialidase enzyme that breaks down the sialic acid component of mucin. Juge's group collaborated with David Owen and Garry Taylor at the University of St. Andrews, UK, to solve the three-dimensional structure of this enzyme and thus determine its mechanism of action. The enzyme is similar in structure to other sialidases but its mechanism is unusual: it transports the product of the sialidase reaction into its cells, depriving other bacteria of potential nutrients in what has been termed a selfish model of glycan utilization. Since the discovery of this protein, similar sialidases have been discovered in other gut bacteria. The proportion of sialidase-expressing Ruminococci in the gut is particularly high in patients with irritable bowel disease.
Shaped by diet
Lawrence David of Duke University presented a systems approach to measuring, modeling, and controlling the gut microbiota through diet. In one study, researchers collected fecal and saliva samples while recording lifestyle factors that affect the microbiome, including diet, from two healthy adult men every day for a year. The results of fecal 16S rRNA sequencing of the microbial samples show that life events, such as illnesses and trips abroad, were linked to rapid and significant shifts in the composition of the microbiomes, and small changes in certain species were linked to different types of food.
Another study in 11 healthy volunteers compared the effects of two types of diet on the composition of the microbiome. Each volunteer consumed a high-fiber diet based on fruit and vegetables and then a low-carbohydrate diet of mostly meat, dairy products, and eggs, eating each diet for five days. Fecal samples were collected during this time, as well as for 4 days before and 6 days after. Interestingly, there was no significant change in bacterial diversity during either diet, but there were significant shifts in microbiome composition, which correlated with the bile acid composition of the feces, in a similar pattern to that seen in mice. Changes in gene expression patterns matched some of the known microbiome differences between herbivores and carnivores.
David noted that studies of this kind have a long history. In 1929, a physician, Clarence Lieb, observed a "simplification of the intestinal flora" in two volunteers—Arctic explorers—who lived for a year on an exclusive diet of meat.
The microbiomics of IBD
Marcus Claesson of University College Cork moved the focus to digestive disease. The inflammatory bowel diseases Crohn's disease (CD) and ulcerative colitis (UC) together affect about 0.8% of people in Europe, causing mucosal ulceration and perforation, along the GI tract in CD and in the colon in UC. There is no disease-modifying treatment, and patients rely on immune suppression and anti-inflammatory drugs to relieve their symptoms.
Patients with these diseases have less diverse microbiomes with more Proteobacteria and fewer Firmicutes species compared to healthy individuals. Most comparative studies, however, have been small and therefore lacking statistical power. Claesson and his team carried out a larger study, sequencing the micobiomes from non-inflamed and inflamed colonic mucosa from 141 patients with IBD (87 UC and 54 CD) and comparing them with 32 samples from healthy controls. Most samples from inflamed mucosa differed more from the control samples than from the samples from non-inflamed mucosa. The diseased samples were split into two groups, with the "healthy-like" group less divergent than the other from the controls. Interestingly, long-term dietary habits obtained using a food frequency questionnaire seemed to have little effect on the colonic microbiome in patients with these diseases.
In a pilot study of gene expression in inflamed colonic tissue, Claesson's team used paired biopsies from a subset of 13 individuals to show that that about 1% of the mRNA in each sample was microbial. The team observed distinct differences in both human and microbial gene transcription between healthy and diseased samples, but the human genes diverged more. A further subset of six samples revealed differences in human gene methylation associated with colonic inflammation. Although larger studies are still needed, microbiome composition, and potentially microbial gene expression, may be added to the factors used to stratify IBD patients and select an appropriate therapy for each subgroup.
The first session ended with a couple of very short data-blitz presentations of selected posters. Michael Goran from the University of North Carolina described how dietary sugar affects the gut microbiome and cognition in mice, and Cristina Torres Fuentes from University College Cork showed that novel probiotic bacteria can modify appetite through directly targeting the ghrelin receptor in the gut.
Denise Kelly, Keynote Speaker
Seventure Partners, France
Bar-Ilan University, Israel
New York University
Institute of Food Research, UK
Wellcome Trust Sanger Institute, UK
Pregnant women share some features of their microbiomes and metabolism with people with metabolic disorders.
The microbiomes of premature infants are underdeveloped; this is one risk factor for necrotizing enterocolitis, a serious disease that may be treatable with probiotics.
Techniques are being developed to culture previously unculturable microbes and to select and study specific phenotypes from the microbiome.
Companies are developing products targeting the microbiome for commercial and clinical application.
Mom's microbes: pregnancy and the microbiome
Omry Koren from Bar-Ilan University, Israel, began the second session with a discussion of the complex series of changes to the microbiomes of mother and baby that take place during gestation and early infancy. Pregnancy affects every organ of a woman's body, with a series of changes that mimic those accompanying typical weight gain, such as, in late pregnancy, reduced insulin sensitivity. Distinctive changes occur in a woman's mouth, gut, and vaginal microbiomes, and a new microbial niche is formed in the placenta. Pregnant women are metabolically similar to people suffering from metabolic syndrome, and Koren suggested that metabolic changes in normal pregnancy may, like those in metabolic syndrome, be triggered by gut microbiota. This possibility provides an incentive for studying the microbiome in pregnancy.
In a study in Finland, Koren's group recruited 91 pregnant women and analyzed gut microbiome samples obtained during the first and third trimesters. The microbiomes of all the infants were sampled at one month. A subset of the women were also sampled one month after delivery and a subset of children at six months and four years. The microbiomes sampled in the first trimester were generally within the normal range for non-pregnant women, but significant changes were observed in the third trimester: women's gut microbiomes had become more diverse by late pregnancy and the proportions of Proteobacteria and Actinobacteria had increased. This change in the abundance of these species is similar to the inflammatory response observed in irritable bowel disease. The women also had increased inflammatory cytokines in the stool in late pregnancy. Mice transplanted with microbes taken from these stool samples gained weight and developed insulin resistance. Infant microbiomes were very variable and gradually settled down as the children were weaned and introduced to new foods.
Koren concluded by suggesting that the same changes to the gut microbiome can be interpreted in different ways depending on the context, with healthy pregnancy mimicking some aspects of disease. She is beginning to extend this work to study diseases of pregnancy, including preeclampsia.
The early microbiome
Maria Dominguez-Bello from New York University described the complex process by which babies acquire their first gut microbes, through the birth process and then during lactation. Microbial diversity helps infants develop healthy immune system, and both vaginal delivery and breastfeeding help establish a diverse microbiome. Dominguez-Bello described her work correlating details of infant microbiota with delivery method, feeding, and antibiotic exposure, much of which is unpublished. She thus introduced the topic of the pressure of modern urban lifestyles on humans and their microbiomes, which other speakers returned to in more detail in the third session.
Probiotics for preterm infants
Lindsay Hall from the Institute of Food Research described her studies of the microbiomes of preterm infants, which she is beginning to take into the clinic. Preterm birth is defined as birth before 37 weeks' gestation; most preterm infants weigh under 1.5 kg at birth, and their guts and immune systems are not fully developed. Tiny babies are immediately transferred to sterile incubators in a neonatal intensive care unit (NICU), and almost all are prescribed antibiotics. All these characteristics hinder the development of a healthy gut microbiome.
Abnormal gut colonization has been implicated in the development of a severe gastrointestinal disease, necrotizing enterocolitis. This disease affects 5%–15% of infants in intensive care; it is difficult to treat and often fatal. One treatment that has had some success is provision of the missing gut bacteria, including Lactobacillus and Bifidobacterium, as probiotics. Hall has designed a study with Cristina Alcon and Jenny Ketskemety of the Norfolk and Norwich University Hospital to correlate the microbiomes of premature babies given these probiotics with clinical outcomes. This hospital was one of the first in the UK to offer this treatment routinely, and early results are promising. Preliminary data suggest that supplementation with probiotics reduces the incidence of necrotizing enterocolitis and may accelerate the development of the babies' immune systems.
Culturing the unculturable
Trevor Lawley from the Wellcome Trust Sanger Institute near Cambridge, UK, took the focus back to microbiology, which he suggested has been neglected for 'omics technologies. Although we can sequence an enormous number of bacteria, we still know relatively little about them, and we do not have enough complete, annotated microbial genomes to map the new sequences to. The difficulty—if not impossibility—of culturing many species of bacteria, including most of our gut microbiota, in the laboratory has held research back.
It is a mistake to think that sequencing a microbial sample will give us everything we need to know about the composition of microbial ecosystems; culturing and sequencing the same sample will produce different lists of bugs. Lawley has set up a novel workflow for sequencing fecal samples and culturing them in a fatty acid–based medium; most of the bacteria in the samples will grow on these plates, including some that have not yet been named. Others can be made to grow on more specialized media.
This workflow can be altered to pick up bacteria with a specific phenotype. Spore formers like Clostridium difficile, for example, are resistant to ethanol, and treating plates with ethanol will select these bacteria. The population of spore-forming bacteria in the feces of healthy individuals is variable. Lawley's group has identified a signature of 66 genes that can be used to predict which of the bacteria in a sample will form spores, and about 60% of those in an average healthy gut fall into this category. Spore-forming bacteria are adapted for transmission between hosts, and it is possible that bacteria passing between family members may be partly responsible for shared metabolic traits. The group has recently released a database of human gut microbiota, including viruses, archaea, and fungi as well as bacteria; the sequences will be deposited in public repositories.
Commercializing the microbiome
Denise Kelly from Seventure Partners, based in Paris, ended the second session and the first day with a keynote lecture on opportunities to commercialize microbiome-focused technologies. Seventure is a European venture capital company that invests in innovative companies in digital technologies and the life sciences. Within its life sciences portfolio, it has established the Health for Life fund focusing on nutrition and the microbiome in health and disease.
Kelly illustrated the growth of the sector by showing graphs of near-exponential growth in publications on the human microbiome and by listing start-up companies in the area. She enumerated the advances in technology that have made this growth possible, particularly in sequencing and computational biology, but also in microbiology, as described by Lawley. Data from large patient cohorts, which produce statistically significant results, are becoming tractable, and there is a growing interest in nonbacterial members of the microbiota, including viruses.
Many recent studies have highlighted the diversity in the human microbiota—between individuals, between body sites in the same individual, and throughout the life span. Techniques being developed to analyze this diversity include ConStrains, an open-source algorithm to map the dynamics of the microbial community against phenotypic data. Methods are also being developed for comparing disease-affected and healthy metagenomes using phylogeny.
Several biotech companies are developing microbiome-focused drugs and other interventions to promote health and longevity and to prevent or treat disease. A reduction in the complexity or stability of the gut microbiome can be correlated with many infectious, metabolic, and inflammatory diseases, some of which are still intractable. There are opportunities for companies with an interest in the gut microbiome to work in pharmaceuticals, diagnostics, nutrition, and population health, and also in animal health. The managers of the Health for Life capital fund are seeking to invest in companies working in all these areas and targeting diverse areas, including oncology and neurodegenerative conditions, as well as more traditional areas—inflammatory, autoimmune, metabolic, and childhood disease. Kelly ended her talk by listing companies that have recently benefited from such investment. One company is developing a novel microbiome-based solution for appetite regulation, which could have applications in both obesity and anorexia.
John Bienenstock, Keynote Speaker
McMaster University, Canada
Institute of Food Research, UK
Queen Mary University of London, UK
University of North Carolina at Chapel Hill
University of British Columbia, Canada
The gut microbiome influences the host immune, endocrine, and nervous systems through many complex interactions.
These interactions can take place without direct contact between the microbes and the gut, mediated by secreted small molecules or extruded vesicles.
Nutrients secreted by gut bacteria can be used to stimulate the secretion of satiety hormones, with applications for appetite control.
Prebiotics that stimulate lactose-digesting bacteria may have a role in treating lactose intolerance.
The composition of the gut microbiome in early infancy affects susceptibility to inflammatory and autoimmune disorders including, asthma and IBD.
Interactions in the microbiome-gut-brain axis
John Bienenstock of McMaster University began the third session with a keynote address that introduced the session theme—the ways in which the "forgotten organ," the gut microbiome, interacts with the body as a whole. Our immune, endocrine, and nervous systems communicate constantly with each other and with the microbiome (fungi and viruses as well as bacteria), with the nervous system responding to microbial changes. These interactions are frequently studied using germ-free (GF) mice or other rodents that are bred and kept free from all microbes; the responses of these rodents to stimuli differ between the sexes in unexpected ways.
Bienestock surveyed a wide range of experiments that, taken together, strongly suggest that the gut microbiome affects the immune system and the enteric and afferent nervous systems, and that metabolic products of the microbiome—short-chain fatty acids (SCFAs) and other metabolites—interact with the nervous system. For example, the SCFA salt of sodium butyrate has been shown both to inhibit the potassium channel IKCa, increasing immune responses, and to act as a potent antidepressant. Many of the effects of live bacteria on the nervous system are also mediated through cation channels.
Physiological responses to stress are controlled by complex interactions between three endocrine glands, collectively termed the hypothalamic–pituitary–adrenal (HPA) axis. Both HPA axis signaling and stress responses are enhanced in germ-free mice and reduced when the mice are fed a diet including normal gut microbes; changes in gene expression in the brains of the colonized mice mimicked the effect of an antidepressant. Interestingly, transplanting feces between mice with anxious and non-anxious phenotypes can reverse these behaviors. Ingestion or injection of microbes also reduces visceral pain responses in mice, with the effect of this intervention dependent on both the type of bacteria and the site of injection.
In many cases, physiological effects of gut bacteria outside the GI system can be replicated using bacterial components. Both bacterial cell wall polysaccharides and microvesicles extruded from bacterial cells have been shown to affect rodent immune and nervous systems in similar ways to live bacteria. Exposure to just a single bacterial protein, GroEL—which is expressed at high levels in microvesicles and is homologous to a mammalian stress response protein—can mimic the immune but not the neuronal effects of live bacteria.
In concluding his presentation, Bienenstick emphasized the complexity of interactions in the so-called microbiome–gut–brain axis, which involves the immune and nervous systems, as well as its potential clinical implications, much of which are still unknown.
Vesicles in cross-kingdom dialogue
Simon Carding from Norwich Medical School and the Institute of Food Research addressed one important way communication between gut bacteria and their mammalian hosts takes place: via extracellular outer membrane vesicles (OMVs) extruded by the bacterial cells. The mucus barrier described earlier in the day by Juge prevents much, if any, direct contact between bacteria and host epithelial cells, except in disease. Commensal Gram negative bacteria including Bacteroides thetaiotaomicron (Bt) extrude spherical vesicles up to 300nm in diameter from their outer membranes. These nanoparticles, which are rich in protein components of both membranes, are important for forming microfilms and colonizing niches in the host, and can transfer macromolecules into the host's intestinal epithelial cells.
Carding described OMVs as good Samaritans with functions that benefit their host organisms and, less usefully for humans, neighboring bacteria. Bt vesicles contain enzymes that play a role in human digestion, such as phosphatases not found in humans that help break down phytate, a component of plant seeds. Vesicles from some other species contain antigens that offer protection against IBD. The Bt vesicles extract a beta-lactamase that can protect other species against beta-lactam antibiotics. This work has potential therapeutic value: several groups are attempting to engineer Bacteroides thetaiotaomicron to generate stable vesicles to deliver vaccine antigens to the GI tract.
An alternative to gastric bypass?
Ashley Blackshaw from the Blizard Institute at Queen Mary University of London described how modulating the activity of enteroendocrine cells in the gut may provide a means to non-surgically treat obesity. These cells produce the satiety hormones peptide YY and GLP-1, but this response to food intake is reduced in obese people, who have "persistent numb guts." This dysfunction is not altered by normal dieting but it is greatly increased after gastric bypass surgery, which results in food being shunted directly into the lower GI tract.
Enteroendocrine cell walls contain receptors that sense the presence of nutrients, activating the pathway that leads to the release of satiety hormones. Blackshaw suggested that it should be possible to fool this system by priming the lower GI tract of obese individuals to over-respond to the presence of nutrients, reducing the need for surgery. Receptors that respond to nutrients, including amino acids and the SCFAs, produced by gut bacteria appear to act in synergy. A preliminary clinical trial of appetite control is looking at the effects when obese volunteers ingest capsules containing multiple nutrients.
The gut microbiome in lactose intolerance
About 75% of the global population is lactose intolerant; that is, they lose all or some of their ability to digest the milk sugar lactose in the small intestine after early childhood. Andrea Azcarate-Peril from the University of North Carolina at Chapel Hill explained the role of the gut microbiome in lactose digestion, and described the therapeutic options targeting these mechanisms. In 1908, the Russian immunologist Élie Metchnikoff suggested that it might be possible to replace harmful gut microbes by beneficial ones. We now know that prebiotics—substances that useful bacteria feed on but that humans cannot digest—can have similar effects. In particular, prebiotic galacto-oligosaccharides, which are similar to lactose, can produce changes in the microbiota that improve lactose digestion.
Azcarate-Peril presented results from a recent clinical trial of such an oligosaccharide, RP-G28, in lactose-intolerant volunteers. The subjects were asked to avoid dairy products for 35 days while receiving daily doses of either RP-G28 or a placebo. After they began consuming lactose, about 90% of the subjects who received RP-G28 were found to have gained some tolerance. Ingesting RP-G28 led to changes in the gut microbiome composition in all subjects, but these differed between responders and non-responders. In the case of the responders, these changes included an increase in lactose-digesting bifidobacteria: "a bifidogenic effect," Azcarate-Peril said.
Early-life immune response to microbiota
Inflammatory bowel diseases are among the many chronic diseases that are increasing in prevalence, and this trend is particularly marked in the first decade of life. Richard Blumberg of Harvard Medical School studies these diseases in the context of the immune response of natural killer T cells (NKT cells), which rapidly recognize lipid antigens. The MHC molecule, CD1d, that presents lipids for this reaction is highly expressed in gut epithelia, and its secretion is important in regulating the microbiota. Blumberg's group has recently shown in mouse models that the presence of commensal microbiota in early infancy is essential for the development of a normal colonic NKT cell population. During this "window of opportunity" in early life, interaction with gut microbes can stimulate the immune system. This finding implies that both antibiotic treatment and a near-sterile early environment in babyhood (the latter as described in the hygiene hypothesis) may contribute to defects in the immune system and susceptibility to immune-mediated diseases such as IBD later in life.
Asthma and the microbiome
Brett Finlay of the University of British Columbia also focused on the hygiene hypothesis, this time in the context of asthma. This disease, like IBD, is increasing in incidence, and it is mainly concentrated in western countries: asthma prevalence is highest in Scotland, at over 18%. Finlay explored the correlation between early life experiences, including mode of delivery and antibiotic exposure, and asthma prevalence and severity. He showed using a mouse model that an antibiotic-induced shift in the population of gut microbes leads to an enhanced susceptibility to allergic asthma. The researchers think this effect is mediated through an interaction with regulatory T cells (Treg): numbers of Treg cells were decreased in the guts but not in the lungs of mice treated with antibiotics.
Turning to human subjects, Finlay described a study of childhood asthma in which feces from 319 children in a Canadian longitudinal cohort study, CHILD, were analyzed at 3 months and 1 year. Babies do not develop asthma, but 223 infants in the study had atopy and/or wheeze symptoms, which are highly predictive for childhood asthma. Stool sample analysis at 3 months revealed the presence of microbial genera that correlated with both resistance and susceptibility to asthma. Four genera were significantly decreased in samples from the highest-risk infants. There were, however, no significant differences in samples taken from the same babies at 1 year. Finlay's group has shown that these bacterial early biomarkers of asthma can reduce airway inflammation when injected into germ-free mice. He concluded his talk, and the session, by stressing that gut microbiome development is one factor in the crucial first hundred days of life that can influence the later health of an individual, for good or ill.
University of California, San Francisco
Center for Digestive Diseases, Australia
Imperial College London, UK
University of California, Berkeley
Nutricia DANONE Research, France
Academic Medical Center, Amsterdam, The Netherlands
Gut microbes are a rich source of metabolites that may have important therapeutic applications.
Transplantation of fecal microbes from healthy donors is an effective therapy for Clostridium difficile infection and may have many other applications, such as in IBD, which can also be treated with probiotics.
Coevolution with bacteriophages may be studied in the commensal bacteria of long-lived eukaryotic hosts such as trees.
Variation in the production of short-chain fatty acids by microbes in the mammalian colon can be modeled accurately in vitro and in vivo.
The gut microbiome, which is unique to each individual, is a potential target for treating insulin resistance and diabetes.
Mining the microbiota for drug candidates
Jan Claesen from the University of California San Francisco started the final session by turning the idea of the microbiome as a drug target on its head, exploring it instead as a source of therapeutic small molecules. In some therapeutic areas, including cancer, the majority of drugs to enter the clinic in the last 30 years have been, or have been derived from, natural products. Many of these were found in microbes, particularly soil microbes: the human microbiome is a rich potential source for such compounds.
Two complementary methods are used to identify new natural products in microbes: one starts with the phenotype, and the other identifies clusters of genes that code for biosynthetic proteins. Using software tools AntiSMASH and ClusterFinder, Claesen's group has identified a large family of gene clusters with two subfamilies, prevalent in both pathogens and symbiotic bacteria. The protein products of these gene clusters synthesize a class of lipids known as aryl polyenes (APEs), which act as "reactive oxygen sponges" to protect the bacteria from oxidative stress. Work is underway to characterize the molecular mechanisms of these and other metabolites of gut microbes, and to search for therapeutic applications.
The promise of poop
Thomas Borody from the Centre for Digestive Diseases in New South Wales, Australia, introduced one of the dominant themes of this session: fecal microbial transplantation (FMT) as therapy. This procedure involves transplant of stool microbiota from a healthy donor into a patient, with the aim of correcting imbalances in the patient's microbiome. FMT has a long history: In 1958, in the first documented instance of this treatment in the modern era, four patients with then-termed colitis—a condition now believed to have been C. difficile infection—were cured with fecal enemas. This infection is now the most common indication for fecal transplantation.
Many patients with recurrent C. difficile infections lack some of the Bacteroidetes and Firmicutes species that are present in healthy gut microbiota. Infusion of filtered stool material into the colon of infected individuals generates stable colonies of these microbes in the GI tract, with a cure rate of over 90%. Cures have also been noted in some other digestive and autoimmune diseases, particularly inflammatory bowel diseases, and these applications are now being tested in large clinical trials. Borody is lead investigator on a current phase II trial, FOCUS, investigating the use of an intensive regimen of multiple fecal transplants in treating resistant ulcerative colitis.
The microbiome in inflammatory bowel disease
Ailsa Hart from Imperial College London went on to discuss the gut microbiome as a therapeutic target in IBD. Crohn's disease and ulcerative colitis are known to be driven by both genetics and changes in the gut flora; the best evidence for the latter effect comes from animal models. Patients with these conditions have less-diverse gut microbiota than healthy individuals, with a marked reduction in Firmicutes in Crohn's disease. Studies have also found increases in bacterial genera linked to ulcer formation and colorectal cancer progression. A similar pattern is seen in patients with so-called pouchitis, which is the name given to inflammation of the artificial rectum created in patients undergoing colectomy.
Modification of the gut microbiome to return it to a healthy condition is now a common strategy for the treatment of several inflammatory bowel conditions. Interestingly, these modifications include both antibiotics—for postoperative disease, for pouchitis, and in children—and probiotics, but not prebiotics. Probiotics are used successfully to maintain disease remission and to treat mild IBD. Trials of fecal transplantation have been successful, with many induced remissions and no severe side effects, although there is little long-term follow-up data. Many questions remain, however, such as how to select donors: stool from some donors has been found to be particularly effective.
Bacteria-phage coevolution on a long-lived host
Any community of microbes living within a eukaryotic host will itself be infected by bacteriophages, and when that host is long-lived—as is a human—the bacteria and phages will experience coevolution. Britt Koskella of University of California, Berkeley described her studies of a model bacteria–phage system on a different type of long-lived host: the horse chestnut tree. The leaves of these trees are often affected by a bacterial canker, and these bacteria are infected with lytic phages that are easily spotted when the bacteria are cultured.
Koskella sampled bacteria and phages obtained from four leaves from each of eight neighboring trees, finding, interestingly, that the phages were less well adapted to bacteria from a tree other than their host, even if the species of bacteria was identical. Moving between leaves from a single tree made no difference. Then, to test for coevolution, she infected bacteria with phages that had been taken from the same tree at different time points. The bacteria were most resistant to phages collected earlier in the growing season and least resistant to those collected later (so-called future phages). This adaptation is again specific to the individual host tree. It appears that phage populations are complex and dynamic, and that they are able to shape the phenotype of the host bacteria.
Models of microbial SCFA production
Returning to the mammalian gut microbiome, Jean-Michel Faurie from Danone Nutricia Research described in vitro and in vivo models of the production of short-chain fatty acids (SCFA) by the gut microbiome. These acids, particularly acetate, propionate and butyrate, are major end products of microbial fermentation in the colon. They can have important health benefits, but their production is dependent on both the microbiome and the diet; thus, they form an important link between diet and health. However, it is difficult to study what is going on inside a human colon, so models of the system in test tubes and in rodents must play a key role.
SHIME (Simulation of the Human Intestinal Microbial Ecosystem) is an in vitro fermenter model with five vessels, representing the stomach, the intestine, and three regions of the colon. Stool samples obtained from human donors were placed in the vessels, the microbes were fed starch and fermented milk products, and the fatty acid products were measured. The in vivo model involved inoculating male and female germ-free mice with donor stool samples, feeding them the same range of products and, again, sampling the fatty acids produced. Although there were some significant differences in fatty acid production between the models and between male and female rats, the most important factor determining the composition of the SCFA produced was the donor.
A novel therapeutic target: the gut microbiome
The final talk was given by Guido Bakker from the University of Amsterdam, who discussed the idea of the gut microbiome as a target of therapies for obesity, insulin resistance, and type 2 diabetes. Diabetes is one of the fastest-growing diseases, with over 400 million cases worldwide, and its increasing prevalence is closely correlated with an increase in obesity. In many obese people, insulin sensitivity decreases over time leading to progressive beta-cell failure, an increase in plasma insulin levels, and eventually, overt diabetes.
There is much evidence to link an individual's gut microbiome to his or her propensity to become obese. Early life events favoring the development of a healthy gut microbiome, such as vaginal delivery and breast feeding, tend to offer some protection against obesity. And although diet is self-evidently linked directly to weight control, it can also affect the microbiota, as David had explained earlier in the meeting. Some studies have suggested a link between antibiotic exposure in early childhood and an increase in BMI. Fecal transplants from lean, healthy donors have been shown to increase insulin sensitivity, and the same effect has been noted in a mouse model after probiotic treatment with Eubacterium hallii, a component of the healthy gut microbiome. The microbiome may well become the next therapeutic target for the personalized treatment of type 2 diabetes.
Can it be helpful to offer dietary advice based on the effect of foodstuffs on the composition of the gut microbiota at either the individual or the population level, and are there any ethical considerations?
What is the most effective combination of microbial analysis and sequencing methods for identifying and characterizing the microbes present in a sample?
How practicable and ethical is it to expect patients or volunteers to contribute to long-term clinical studies by, for example, keeping detailed food diaries and/or collecting stool samples?
What is the most appropriate way of targeting the microbiome in treating inflammatory bowel disease?
Are there potential clinical applications of the observed metabolic and microbial similarities between pregnancy and metabolic syndrome?
What further interactions between the gut microbiome and organs and systems outside the gut remain to be characterized?
How universal is the 'hygiene hypothesis'?
What are the most appropriate applications of fecal microbial transplantation other than Clostridium difficile infection?
How can fecal transplant donors best be identified?
What types of microbiome dysfunction and associated disease can be effectively targeted by what types of small-molecule drugs?