The gut microbiome in disease
The gut microbiome has been associated with diseases from inflammatory bowel disease to cancer through proposed pathways, though whether its disturbance causes disease or follows from it is unclear. Its promise is easily overstated in public discourse, and reporting it responsibly means presenting the evidence with its limits.
The interactome
The gut microbiome is one of many players in the interactome, the complex interconnected biological network within the human body. The interactome consists of the metabolome, the gut–organ axes, environment, genetics and epigenetics. It is a biological community that functions on the basis of an interactive network of human genes, epigenetic modulation, environmental features and the microbiome. A metabolome is the comprehensive collection of metabolites in a system such as a body, cell or organ. Epigenetic changes modify gene expression by acetylation or methylation of DNA in the absence of changes such as insertions, deletions or duplications to the DNA sequence. Xenobiotics are chemicals, such as industrial pollutants, drugs, fertilisers or pesticides, that are not naturally found within a biological system and are metabolised by microbes. A circadian cycle is a 24-hour cycle that governs the metabolic, physical, behavioural and mental signalling networks within the body.
How dysbiosis leads to disease
A disruption to any part of the interactome could alter the crosstalk within it and result in disease. Disease results from a disruption in the biochemical network within an organ system, and research now indicates that diseases occur when associations between the biochemical networks of different organ systems, including the gut, are disrupted. Diseases manifest when the microbial diversity of the gut microbiota shifts, a shift called dysbiosis. Dysbiosis results from infections, stress, antibiotics and other medications, age, exposure to xenobiotics, seasonal changes, circadian rhythms, an unhealthy diet, industrialisation, environmental changes and triggers, exposure to pets, use of chemical disinfectants, type of birth, epigenetic modulations, pathogenic microbes, and metabolites released from an unhealthy diet, among other factors. Drastic disturbances to the gut microbial balance are linked to inflammatory bowel disease, obesity, type 1 diabetes, asthma, autism spectrum disorder and allergies.
In healthy people there is a bidirectional crosstalk between the gut microbiota, the immune system and the intestinal mucosal surface, and in a disease state this crosstalk is affected. Gut dysbiosis causes inflammation and immune reactions. Dysbiosis favours the proliferation of pathogenic gut bacteria, which results in inflammation that triggers an immune response. Inflammation increases the permeability of the intestinal epithelial membrane, which allows pathogenic gut microbes and metabolites to translocate through the membrane and travel through the systemic circulation and the respective gut–organ axes to target organs. The circulating pathogenic gut microbes and their metabolites can activate or enable epigenetic modifications, and individually or jointly these factors can affect human disease.
Gut dysbiosis along with an unhealthy diet and gene sequence changes can disturb the body's usual homeostatic balance, which is linked to disease. Interconnected pathways are potentially associated with human diseases such as inflammatory bowel disease, obesity, Parkinson disease, COVID-19, type 2 diabetes, cancer, asthma and autism. The pathways are:
- Epigenetic modulation, caused by environmental change, age, an unhealthy diet, mutations and metabolic disturbance, whose effect is an increase in acetylation and methylation of DNA that unbalances cell proliferation and apoptosis.
- Dysbiosis, caused by an unhealthy diet, age, antibiotics, environmental pollution, internal pH changes, type of birth and social determinants, whose effects are inflammation, a leaky gut epithelium and immune dysregulation.
- Metabolites, caused by an unhealthy diet (high in fat and low in fibre, with alcohol consumption, pesticides in food and processed food) that an increased number of pathogenic bacteria metabolise, whose effects are fewer of the beneficial bacteria that produce anti-inflammatory short-chain fatty acids, polyphenols and vitamins, and more inflammatory markers.
- Genetic changes, sporadic or hereditary, such as mutations, deletions, insertions and amplifications.
- Disrupted gut–organ axes.
Association and cause
It is unclear whether gut dysbiosis causes diseases or is caused by them. Microbiome researchers set out to confirm the association of gut dysbiosis with many chronic diseases, but a decade later it is becoming increasingly difficult to link gut dysbiosis conclusively with specific diseases, because of the vast heterogeneity of the human microbiome.
Diseases associated with the gut microbiome
Metabolic syndrome
Metabolic syndrome encompasses non-alcoholic fatty liver disease (NAFLD), diabetes, obesity, hypertension and cardiovascular disease. Antibiotic use in infants appears to be associated with the risk of developing these diseases in later life. Obesity in metabolic syndrome results in part from gut dysbiosis from a high-fat, sugar-concentrated and low-fibre Western diet, genetics, a sedentary lifestyle, maternal gestational diabetes and the circadian cycle. In patients with type 2 diabetes, gut dysbiosis is associated with a Western diet, obesity, persistent inflammation and an increase in the concentration of branched-chain amino acids in the serum.
Studies have found that high plasma trimethylamine N-oxide (TMAO) levels are associated with a risk of cardiovascular disease, although their findings are inconsistent. TMAO, a microbial metabolite, is the byproduct of a low-fibre, meat-oriented Western diet.
In NAFLD, gut dysbiosis or fat accumulation in the liver inflames the liver and the other organs of the gut–liver axis. Inflammation increases intestinal wall permeability, which allows pathogenic microbes and their metabolites to reach the liver through the portal vein or the systemic circulation.
Inflammatory bowel disease
Inflammatory bowel disease (IBD) is an umbrella term for the group comprising indeterminate colitis, ulcerative colitis and Crohn disease. Research has convincingly shown microbial perturbations in the gut in people with IBD, although it is not clear whether gut dysbiosis is a cause or an effect of IBD. IBD has been associated with gut dysbiosis, inflammation of the intestinal mucosa, lesions in the gastrointestinal tract, genetics, environmental influences and immune system perturbations.
Malnutrition
Inadequate nutrition or overnutrition causes malnutrition, and dietary supplements alone rarely correct it. However, research has shown that a diet of peanuts, bananas and chickpeas may modify the gut microbiomes of malnourished children by encouraging the growth of age-specific bacteria.
Mental and neurological disorders
Gut microbes have been postulated to influence emotions, processing capabilities and even behaviour. Research now shows associations between gut dysbiosis and mental disorders such as anxiety, epilepsy, autism, depression, sleep irregularities, Parkinson disease and Alzheimer disease. The gut microbiota communicates with the brain through the gut–brain axis. Intestinal microbiota translocate across the permeable intestinal wall and migrate to the brain, where toxic metabolites, inflammation and oxidative stress damage the integrity of the blood–brain barrier.
Skin diseases
Dysbiosis in the gut–skin axis is associated with psoriasis, acne vulgaris, alopecia areata and atopic dermatitis, among others. Diet, genetic susceptibility and hygiene influence the bidirectional communication within the gut–skin axis.
Asthma
The risk of developing asthma has been attributed to a Western lifestyle, the mode of birth (such as caesarean section), industrialisation and the use of antibiotics. Although genetics may be involved, environmental changes that reduce gut microbial diversity increase the susceptibility to airway inflammation. Changes in the gut microbiome are reversible and dynamic. Replenishing the gut microbiome with health-promoting bacterial strains helps to reduce airway inflammation.
COVID-19
The SARS-CoV-2 virus infects the gastrointestinal and respiratory tracts, and the infection is associated with inflamed lungs and colon damage. Faecal sampling studies have shown reduced gut microbial diversity, fewer of the commensal species that maintain intestinal equilibrium and regulate host immunity, more bacteraemia-associated bacteria and other distinct differences in patients infected with SARS-CoV-2 compared with healthy individuals.
Cancer
The role of the gut microbiome in colorectal cancer and gastrointestinal cancer has been documented. Genotoxins secreted by Escherichia coli (colibactin) and Morganella morganii (indolimine) act in distinct ways to damage DNA and cause genomic instability that gives rise to benign and metastatic tumours. Pathogenic bacteria such as Fusobacterium nucleatum, Bacteroides fragilis and Shigella flexneri inhibit the immune response to tumours and potentially contribute to carcinogenesis.
Microorganisms associated with each disease
| Disease | Reduced | Increased |
|---|---|---|
| Type 2 diabetes | Faecalibacteria, Bacteroides, Akkermansia, Bifidobacteria | |
| Obesity | Bacteroides, Akkermansia | |
| Atopic asthma | Akkermansia, Lachnospira, Faecalibacterium | |
| Autism spectrum disorder | Bacteria: Corynebacterium, lactobacilli, Collinsella. Fungus: Candida | |
| COVID-19 | Faecalibacterium prausnitzii, Roseburia, Lachnospiraceae, Eubacteria | Bacteria: Actinomyces viscosus, Clostridium hathewayi, Bacteroides nordii, Enterococcus, Enterobacteriaceae. Fungi: Aspergillus flavus, Candida albicans, C. auris |
| Depression | Bifidobacteria | Streptococcus, Klebsiella |
| NAFLD | F. prausnitzii | Enterobacteriaceae, E. coli |
| Cancer | Helicobacter pylori, F. nucleatum, B. fragilis, S. flexneri, E. coli |
Hype and misinformation
Popular discourse can be influenced by misinformation. Enthusiasm for gut microbiome research has propelled a flurry of books, articles and videos on the medicinal properties of foods, diets and food-related therapies. The promise (beneficial effects) and peril (harmful effects) of manipulating the gut microbiome have often been exaggerated and misinterpreted. The social media landscape is a vast, fertile ground for the dissemination of information. On sites such as YouTube and TikTok, videos generate interest and find viewership. Many of these videos advocate home remedies while quoting purported beneficial effects of the gut's bacterial constituents on health, which they claim are based on data from research studies. Social influencers and celebrities seek to promote gut microbiome-inspired therapies as part of the wellness industry.
The lay public has limited awareness of the role the gut microbiome plays in gut health within the human body. Microbiome hype is carried by popular health articles and social media, including YouTube videos by celebrities promising instant cures from diseases. The gut microbiome is represented in the public domain through opposing concepts. For example, personalised nutrition companies confidently project gut microbiome therapies as a panacea for good health, yet their disclaimers state that the results obtained with their technology should not be considered in place of a medical expert's opinion.
Government websites and research articles are dense in information and not reader-friendly for the lay public, who are not inclined to absorb information from them, especially when social media provides it in attractive formats. Amid all the hype, gut microbiome-linked health information needs to be approached with caution.
Communicating the gut microbiome to the public
As communicators of scientific data, medical writers play a vital role in educating the public on the merits and limitations of gut microbiome therapeutics. Social media pundits and science communicators are extremely important in monitoring the quality and integrity of discourse on the impact of the gut microbiome on human health. With the ever-growing influence of social media, the lay reader must learn how to critically appraise the health information it propagates.
Medical writers should proceed cautiously when promoting the health benefits of the gut microbiome. They should also have an obligation to counter social media's exaggerated claims of the gut microbiome as a panacea of health by reporting evidence-based information. The gut microbiome is not a panacea for all health issues but part of a large network of interconnected operating systems within the human body.
The gut microbiome should be presented as a unique ecosystem of microbial communities that is indelibly interwoven within the cellular organisation of each individual and evolves from the combined influence of the environment, diet, medications, social determinants and industrialisation. Association data should be interpreted to show that a complex interactome is at work in a disease. During disease, the biochemical network of the gut microbiome should also be considered affected, along with that of the affected organ.
Medical writers, in their role as educators, should understand the current information landscape and use popular channels of public information to communicate effective and credible information to the lay public. Science writers, medical communicators and health experts have a responsibility toward the public to interpret and disseminate evidence-based information on the impact of the gut microbiome on human health and well-being, including popular health trends such as the use of pro-, pre- or postbiotics, so that the public can make educated decisions about using them. In this way, medical writers, health writers and communicators can influence the discourse of scientific information in the public domain, and the lay public will in turn learn to recognise and trust the information from reliable science communicators and websites. This will improve the influence of credible science in the public domain.
Plain-language patient education materials and videos by trusted sources, such as scientists and health professionals, could help to educate the public on the advantages and disadvantages of manipulating the gut microbiome, and so prevent the spread of misinformation. Companies should explain the effects of the gut microbiome on human health so that consumers can make an informed decision on accessing personalised gut microbiome treatment for a given disease.
A future of personalised treatment can be foreseen in which disease is always assessed simultaneously by a cohort of physicians specialised in fields related to the interactome that includes the gut microbiome. When data from large randomised controlled studies are positive and consistent on the benefits of the gut microbiome as treatment, the lay public can use this information with confidence.