Volume 209 - Issue 7
The gut microbiota: cause and cure of gut diseases
Authors: Lauren S White, Johan Van den Bogaerde and Michael Kamm
Med J Aust 2018; 209 (7): 312-317. || doi: 10.5694/mja17.01067
Published online: 1 October 2018
Published online: 1 October 2018
The gut microbiota is a key cause, and potential cure, of modern gut disorders including inflammatory bowel disease, liver diseases, metabolic syndrome and obesity
Summary
- The gastrointestinal microbiota is emerging as a central factor in the pathogenesis of a range of gastrointestinal and hepatic disorders. Epidemiological studies, and experimental studies in animals and humans, have highlighted a likely causative role of this microbial community in the modern global epidemics of inflammatory bowel disease, non-alcoholic fatty liver disease, non-alcoholic steato-hepatitis, obesity and metabolic syndrome.
- New techniques for microbial culture and gene sequencing are enabling the identification of specific pathogens and protective organisms in these conditions.
- Factors that change the microbiota are being defined: dietary pattern, specific foods, food additives in processed food and drinks, such as emulsifiers and non-sugar sweeteners, and antibiotics. Microbiota changes in early life appear critical to the later development of a range of inflammatory disorders.
- For many of these conditions, the treatment paradigm will change, at least in part, from immune suppression and drug therapy to treatments that reshape the microbiota or restore its integrity. These treatments include dietary changes, specific microbial manipulation and faecal microbiota transplantation.
- A dialogue is needed regarding population strategies that target disease prevention. This will include how food is produced, what additives it contains, and how it is processed. Widespread use of antibiotics, from agricultural and veterinary to medicinal settings, needs more attention.
- At the individual level, microbial profiles may be able to predict who is at risk of disease when subjected to particular environmental influences, and what microbial restoration is needed to minimise risk.
The gut microbiota is recognised increasingly to be of central importance to our wellbeing, disease pathogenesis, and our ability to treat many common conditions. This microbial community inhabiting the human gastrointestinal tract comprises a vast ecosystem of bacteria, viruses, fungi and archaebacteria,1 living within a chemical environment of nutrients, proteins and transmitters.
The differentiation between extrinsic pathogens and commensal organisms, the latter previously believed to be harmless, is changing. Commensals can cause disease when gut homoeostasis changes. Key examples are Helicobacter pylori in the genesis of gastro-duodenal ulcer disease and cancer, and the transformation of Clostridium difficile into a toxin-producing dominant organism when antibiotics change the enteric microbial balance.
Most gut bacteria have not been amenable to traditional culture, although this is changing with new techniques.2 The 3 million bacterial genes present in our gut vastly outnumber the human genome.3,4 Recent metagenomic analysis has provided insights into the composition of this community and its relationship to disease processes. Combining novel culture techniques with 16S rRNA analysis and shotgun sequencing may allow up to 95% of gut organisms with a concentration above 0.1% to be characterised.5
This review considers how the gut microbiota might be central to a range of gut-related diseases,6-8 such as inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steato-hepatitis (NASH), obesity and diabetes; how it is shaped by environmental factors; and its modification to prevent and treat these disorders.
References were sourced after searching English language publications in PubMed for gastrointestinal microbiota, and selected for inclusion on the basis of relevance and new insights.
This review does not consider gastrointestinal cancers, functional gut disorders, or areas of medicine outside gastroenterology, although the gut microbiota may play a role in these conditions.
Recent advances in understanding the main features of microbiota
Studies of the bacterial 16S rDNA genes tell us “who’s there”, while functional metagenomics answers the question “what are they doing?”1
Seventy per cent of colonic bacteria belong to the main phyla Bacteriodetes, Firmicutes, Actinobacteria and Proteobacteria1,9 Progressing caudally along the gut, the microbial population increases in quantity and diversity and transitions from predominantly aerobes to anaerobes.6 Changes in microbial populations at the mucosal level may be more important for gut diseases which involve microbial–epithelial–immune interactions,6 such as IBD, while disorders related to food processing and harvesting, such as obesity and diabetes, may relate to altered luminal populations.
The gut microbiota involvement in growth and maturation starts in utero. Bacteria have been detected in the placenta of healthy mothers. The individual microbiome relates to mode of delivery, breastfeeding, illness, diet and antibiotics in childhood.10 The first years of life, especially the first year after cessation of breastfeeding,11 shape the microbial fingerprint. By the age of 3 years it resembles that of adults.10 It then remains stable but can change with diet, antibiotics, illness and age.12
The gut microbiota protects against pathogenic organisms through immune and metabolic processes.6,10 For example, the pathogenic emergence of C. difficile after antibiotics appears to relate to elimination of the competitive C. scindens,13 bile acid changes that enhance C difficile spore germination,14 and increased levels of succinate which enhance C. difficile proliferation.15
Chemical production by the microbiota — metabolomics — reveals one aspect of microbial functional activity.1 In addition to local effects, small-molecule microbial metabolites can cross the epithelium and play a systemic role, creating a microbial endocrine “organ”.10
Gut microbiota and the changing disease landscape
The prevalence of IBD, metabolic syndrome, NAFLD, NASH and obesity have all increased markedly over the past 50 years in Western populations16-18 and 25 years in Asian populations.19 The gut microbiota appears to play a role in the pathogenesis of these conditions.20
IBDs are modern diseases,19,21 previously rare in developing countries but now representing a substantial health care burden.22
More than 200 genetic changes have been associated with the development of IBD but each confers only a slightly increased risk, and they are often present in non-affected individuals. Many of these genes relate to host antimicrobial defence mechanisms, but differ between Caucasian, Asian and Afro-Caribbean populations.23
The gut microbiota is the antigenic drive in IBD.16 Environmental factors that have an impact on the microbiota most likely cause these epidemiological changes.16 In China, for example, the past 25 years have witnessed the end of China’s isolation, with increased exposure to Western microbiota through Chinese travelling abroad and Westerners visiting China. The staple Chinese diet has changed from home-grown to food intensively farmed and transported, and the incorporation of processed Western foods with a range of additives. Antibiotic exposure is now ubiquitous in the food chain and water supply, prescribed in Western-style medicine, and sold over the counter. These environmental factors have paralleled the shift from rural to urban habitation. In Asia, traditional protective factors for IBD — such as breastfeeding, rural habitation and contact with domestic animals — have diminished, whereas permissive factors such as exposure to Westerners and Western diets have increased.19
Environmental exposure to factors that influence the microbiome at a young age is a precursor to developing IBD later. Asian adults who migrate from countries of low prevalence to countries of high prevalence do not have an increased risk of developing IBD, but their children experience the IBD incidence of their new country of residence.24,25
The recent increasing incidence of obesity, metabolic syndrome, NAFLD and NASH in the West and developing countries likely relates to similar environmental changes. Specific environmental factors influencing an individual’s particular microbiota and genetic factors are likely to determine which disorder is expressed in a particular person.26
Microbiota in disease pathogenesis
Whether microbial differences between disease and health are cause or effect is addressed by intervention and experimental studies. For example, bacterial diversity is reduced in active ulcerative colitis compared with health, is increased by faecal microbiota transplantation (FMT) in all subjects, but increases to a greater degree in patients in whom FMT induces remission.27 Prospective longitudinal studies are identifying specific bacteria predictive of disease course, and which may have pathophysiological significance. For example, the presence of Proteus species at the time of Crohn's disease resection is associated with early disease recurrence, while the presence of Faecalibacterium prauznitzii is protective against recurrence.28 The persistence of Fusobacterium is associated with lack of response to FMT in ulcerative colitis.29
Inflammatory bowel disease
The mucosa-associated microbiota in IBD30 is less diverse, has decreased abundance of Firmicutes and Bacterioidetes, and increased abundance of Proteobacteria and Actinobacteria.31 At the species level in Crohn's disease, the “protective” F. prauznitzii, and butyrate-producing Roseburia, are reduced, while Escherichia coli populations are increased.31 However, these cross-sectional observational differences do not establish causality.
The mechanisms by which organisms such as F. prauznitzii protect against Crohn's disease may provide direction for the development of specific new therapies. An anti-inflammatory protein produced by F. prauznitzii has been identified.32
Specific microbial associations with disease phenotypes are emerging. In children with newly diagnosed Crohn's disease, Ruminococcus has been associated with subsequent stricturing disease and Veillonella has been associated with penetrating disease.33
Diet has a profound impact on the microbial profile.34,35 The impact on short chain fatty acid production may be particularly important in shaping disease expression. A decrease in Firmicutes-driven butyrogenesis36 in Crohn's disease may contribute to disease activity.
The success of FMT in treating ulcerative colitis suggests that the gut microbiota drives inflammation in ulcerative colitis.27 Specific bacteria have been associated with both treatment failure and success.29
While most attention has focused on bacteria in the gut, the virome (viruses) and mycobiome (fungi) in IBD6,37,38 remain relatively underexplored.
Microbiota role in obesity and the metabolic syndrome
The gut microbiota appears to be directly implicated in the dramatic global increase in metabolic syndrome prevalence,39,40 manifesting as obesity, hypertension, glucose intolerance and dyslipidaemia.41 The blood glucose level is a key pathophysiological factor; maintaining blood glucose levels within a narrow range prevents the development of the metabolic syndrome.42
The gut microbiota is involved in energy harvesting. FMT from lean or obese humans to germ-free mice causes mice to develop the phenotype of their human faecal donor.43
Patients with type 2 diabetes have a microbial profile similar to that of obese patients.44 Microbial profiling can predict a type 2 diabetes mellitus — permissive metabolism and disease behaviour.44
Microbiota in liver disease
NAFLD, the hepatic manifestation of the metabolic syndrome, affects a quarter of the global population, and is the most common liver abnormality in Western and some Asian countries (Box 1).45 A microbial compositional shift towards energy harvesting and production of volatile organic compounds, including ethanol, is associated with obesity-related NAFLD.18 However, these microbial changes are also observed in non-obese individuals with NAFLD.46 Germ-free mice exposed to the microbiome of mice with NAFLD develop obesity and NAFLD.47
Bile salts are likely involved in this microbiota-related liver pathology. They act as signalling molecules that regulate hepatic glucose and lipid metabolism and inflammation,48 and modulate the intestinal microbiota via their detergent effects on bacterial cell membranes.49
A proportion of patients with NAFLD develop inflammation (NASH), and a proportion of these progress to liver fibrosis. NASH is now the most common indication for liver transplant in the Western world. NASH with advanced fibrosis is associated with a faecal microbiome-derived metagenomic signature50 and increased endotoxaemia.51
The gut microbiota may also play a role in the variable susceptibility to alcoholic liver disease. The microbiota differs between patients with severe alcoholic hepatitis and those who maintain normal hepatic function despite similar alcohol intake.7 Transfer of microbiota from each cohort to germ-free mice reproduces their donor phenotype. Further, amelioration of hepatitis occurred after FMT from patients without hepatitis and with a high alcohol intake to mice in which hepatitis had been induced by FMT from patients with hepatitis and a high alcohol intake.7
In summary, the human gut microbiota and its metabolites affect mucosal immune homoeostasis, as evidenced in IBD. Both mucosal and remote effects, mediated by metabolites or non-mucosal immunity, may be involved in the inflammation associated with insulin resistance, obesity, NAFLD, NASH and alcoholic liver disease.
What causes microbiota differences?
Diversity of the microbiome in adults is related to socio-economic status, diet, age, geography, drugs and other environmental substances.
Microbial composition differs geographically and between vegans, vegetarians and omnivores.52,53 Vegans, vegetarians and omnivores demonstrate a positive correlation between short chain fatty acid production, fibre-degrading bacteria and levels of fruit, vegetable and legume intake.54 Dietary manipulation leads to an increase in bile-tolerant organisms and decreased Firmicutes, a pro-inflammatory microbiota phenotype.55 Western diets, and diets in Western and non-Western lower socio-economic populations, are both associated with a more inflammatory microbiota phenotype.56-58
Strong evidence is emerging that a key link between dietary changes and the susceptibility to modern gut diseases is the introduction of processed foods and their dietary additives.
An ulcerative colitis-like colitis can be induced in animals by carrageenan gum, a thickener and stabiliser, at concentrations used in common food products.59
Emulsifiers are emerging as potent pro-inflammatory modifiers of the microbiota. These detergent-like molecules are present in a wide range of common processed foods, homogenising their composition and preventing separation of fat-soluble and water-soluble ingredients. They radically alter bacterial–mucous–epithelial interactions. In mouse models, emulsifiers, in concentrations normally found in processed foods, alter the microbiota towards a pro-inflammatory composition, inducing low grade inflammation, obesity, NAFLD and metabolic syndrome (Box 2).60,61 Pro-inflammatory microbiota leads to erosion of the protective mucous layer lining the gut, increased gut permeability, and microbial epithelial adherence and translocation.60 FMT from emulsifier-fed mice results in the same process in germ-free mice, demonstrating that these changes are microbiota dependent.
Non-caloric artificial sweeteners (saccharin, sucralose or aspartame) are also concerning. Among the most widely used food additives globally, they were originally introduced to reduce caloric intake.62 A wide range of processed foods, including breakfast cereals, and “diet” or “sugar-free” products, contain these substances. Most non-caloric artificial sweeteners pass through the gut without being absorbed or metabolised, ultimately reaching the colonic microbiota.63 The ingestion of non-caloric artificial sweeteners, at levels corresponding to the equivalent daily intake in humans, drives glucose intolerance in lean and obese mice independent of caloric intake or energy expenditure. This glucose intolerance is mediated by alteration of gut microbiota,64 and is transferrable by FMT from non-caloric artificial sweetener-fed mice to germ-free mice.64
The presence of metabolic syndrome appears to be related to non-caloric artificial sweetener intake even when corrected for body mass index.64 In a small study, typical non-caloric artificial sweetener intake resulted in impaired glycaemic responses in four of seven individuals, with associated microbiota compositional changes. FMT from these subjects to germ-free mice resulted in similar impaired glycaemic control to the donors.64
Antibiotics are another potent cause of microbiota alterations, potentially associated with “modern” diseases. Exposure to antibiotics is ubiquitous in developed and developing countries. Urine analysis in Shanghai school children detected a wide range of antibiotics and a relationship between antibiotic presence and obesity.65
In a nationwide study of 577 627 Danish children born between 1995 and 2003, the relative risk for those who had received antibiotics for developing IBD was 1.9; for Crohn's disease, 3.4; and for Crohn's disease after receiving seven or more courses of antibiotics, 7.3.66
In a UK study of more than a million subjects, antibiotic exposure in childhood was associated with an increased risk of subsequently developing IBD, proportional to the number of courses of antibiotics.67
A causal relationship also appears to exist between antibiotic exposure and the subsequent development of obesity, insulin resistance and NAFLD (Box 3).39,68-70 The development of NAFLD and insulin resistance in mice receiving a high fat diet is increased when combined with low dose antibiotics.69 Antibiotic exposure in children has also been associated with the development of obesity later in childhood, independent of covariates such as socio-economic status, maternal and sibling obesity.68,71
Microbiota manipulation as a treatment
The elimination of H. pylori, originally considered a harmless commensal organism, changed the natural history of peptic ulcer disease.72,73
FMT has been shown to be the most effective therapy for recurrent C. difficile infection.74
Four controlled trials have evaluated FMT as a treatment for active ulcerative colitis, three of which have shown a consistent beneficial effect (Box 4).27,75-77 FMT will enter the therapeutic armamentarium for this condition, shifting the treatment paradigm from chemical therapy and immune suppression to changing the antigenic drive. FMT involves no assumption about which part of the microbiota is responsible for driving disease, instead changing the entire microbial and chemical luminal environment.
Many refinements of FMT therapy will now emerge. Faecal filtrate which excludes whole bacteria was successful in curing C. difficile infection in a small group of patients, raising the possibility that full FMT may not be required for this indication.78
In FMT for ulcerative colitis, pooled donor stool provides greater microbial diversity than single stool infusions,77,79 although it is unknown if this is therapeutically important. Ruminococcus gnavus in donor stool is associated with failed FMT,80 while Fusobacterium in the recipient is associated with a lower chance of achieving remission.27 One-year follow-up of sustained remission after FMT in ulcerative colitis demonstrated ongoing high levels of butyrate producers and relapse associated with higher abundance of Proteobacteria and Bacteroidetes.80 The optimal intensity and frequency of treatment, the value of maintenance therapy, and the identification of “good” donors and patients likely to respond have yet to be defined.27,75 Mixtures of key bacteria are the logical next step in this kind of therapy.
FMT has not been evaluated sufficiently in other diseases to confirm benefit. A single trial in obesity demonstrated promising results with FMT from lean to obese humans, lowering triglyceride levels and increasing insulin sensitivity.81 FMT resulted in an increase in faecal butyrate concentration and the abundance of the butyrate producer Roseburia intestinalis.81
Dietary therapy may also profoundly affect the microbiota. Enteral formulated liquid nutrition diets, with food exclusion, induce remission in Crohn's disease, an effect thought to be mediated by microbial change.82 Wholefood anti-inflammatory diets exclude food items that are postulated to degrade the mucus layer, increase intestinal permeability or induce microbial changes, and include wholefoods such as certain fruits and vegetables, resistant starch and certain animal proteins.82 An anti-inflammatory diet combined with liquid formulated enteral nutrition has shown promising results for induction of clinical remission in Crohn's disease,82 and controlled trials are currently in progress.
Dietary manipulation in other inflammatory-driven diseases, including obesity, NAFLD and diabetes, is currently a focus of research. Personalised nutrition based on an individual’s gut microbiota, anthropometric data, dietary habits, blood glucose monitoring and physical activity has demonstrated improved post-prandial glucose control.42
Probiotics (live bacteria thought to confer health benefits) have not shown benefit in the majority of inflammatory-driven conditions.40,83,84 There is some evidence for benefit in pouchitis,85 and in ulcerative colitis maintenance.86
Conclusion
The microbiota is central to the development of a wide range of gut and liver diseases in Western and non-Western populations. Although the precise causative microbial changes for most or all of these emerging diseases have not yet been fully defined, data are rapidly emerging. Changes in the microbiota result in altered gut barrier and metabolic functions, resulting in systemic inflammation and dissemination of bacterial products.
The nature of food production and the widespread use of antibiotics in agricultural, veterinary and medicinal settings are now public health issues. At an individual level, microbial profiles may be able to predict who is at risk of disease when subjected to particular environmental influences, and what microbial restoration is needed to minimise risk. Microbial manipulation is an effective therapy, likely to have broadening indications.26
Box 1 – Liver histology (haematoxylin–eosin stain), showing normal liver (A) and non-alcoholic fatty liver disease (B)
Box 2 – Bioluminescence imaging showing the effect of emulsifiers on mouse gut microbiota and resulting destruction of the protective mucous layer
A: Normal thick mucous layer (green) between epithelium below (purple and blue) and luminal content above. B and C: Emulsifiers (carboxymethyl cellulose [B] and P-80 [C]) given to mice in the same concentrations found in human food cause changes in the gut microbiota (red), resulting in destruction of the protective gut mucus layer. Luminal contents reach the epithelium, causing epithelial inflammation. Mice subjected to emulsifiers developed obesity and non-alcoholic fatty liver disease, in contrast to their unexposed counterparts.60 Reprinted with permission from Chassaing B, Koren O, Goodrich JK, et al Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 2015; 519: 92–96.
Box 3 – Effect of penicillin on obesity in mice, mediated via changes in the microbiota70
FMT = faecal microbiota transplantation.
Competing interests
No relevant disclosures.
Acknowledgements
We acknowledge the support for this work from the Helmsley Charitable Trust.
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Provenance: Not commissioned; externally peer reviewed.