Abstract
All mucosal surfaces of the human body are home to vast, complex communities of microbial organisms. These multitudes of non-pathological microbes are otherwise known as the human ‘microbiome’. It is only in recent years with developments in genome coding, that we are beginning to comprehend the significance of the microbiome on host physiology and disease. These microbes, once considered malevolent, have now become high profile in the media. The phrases ‘gut health’ and ‘microbiome’ are referred to across a range of industries and social media. This surge in interest may signal the potential for exciting developments and novel therapies. However, with such burgeoning public interest come new areas of debate, misinformation, and unanswered questions. This article provides an overview of: what the microbiome is, its function, its impact on disease and areas of ongoing research. This may enable clinicians to give evidence-based information to patients presenting with questions in practice.
Clinical case scenario 1.
A 15-month-old infant, with no significant past medical history, is brought into the surgery by his mother. She reports the child had a fever yesterday and a painful right ear for 2 days. There has been no exudate from the ear.
The child is apyrexial, alert and all observations are within normal parameters. You are happy that the child is systemically well. On examination of the ear there is mild inflammation of the right tympanic membrane.
You diagnose otitis media and recommend a symptom management approach and explain it will likely self-resolve. The mother asks, ‘Does the baby not need antibiotics?’ She asks if he can ‘Just have some anyway, as what harm could they do?’
Antibiotics should not routinely be prescribed for otitis media. The emphasis should be on symptomatic management. You explain to the mother that antibiotics for uncomplicated otitis media have been shown to make no difference to the course of the illness. Many cases are caused by viruses and not bacteria.
You explain that recurrent antibiotic exposure in early childhood has been associated with poorer health outcomes later in life (increased asthma, allergies and inflammatory bowel disease). And that use of antibiotics in infancy has been shown to delay development of the ‘gut microbiome’, the community of ‘good bacteria’ in the gut that is an influencing factor in many areas of health and disease.
What is the microbiome?
The human microbiome is a hugely complex community of cells; it is made up mostly of bacteria, but includes fungi and viruses. Most of the microbiome resides in the gut. It is estimated there are up to 100 trillion of these cells in each individual human host. These microbes have a genetic make-up far more dynamic and extensive than the human genome itself. The Human Microbiome Project has described 3 300 000 unique protein-encoding genes from samples of the human microbiome, whereas the entirety of the human genome has only 23 000 genes (Qin et al., 2010). This catalogue of microbial cells and their genome is referred to as the microbiome.
The gut microbiome is studied by sequencing bacterial genomes using DNA found in stool samples. These samples can be compared to a growing database of microbiome samples. This enables taxonomy of cell types and mapping of the microbiome. It does not, however, describe the functionality of the bacteria themselves.
Composition of this microbial genomic landscape is in a constant state of flux compared with the relatively stable human genome. Each person’s microbiome is thus totally unique, an ever-changing microbial fingerprint.
An individual’s microbiome begins early in life, and the most important changes to its composition occur during infancy. The core components of the adult microbiome are formed by 3 years of age. Multiple factors affect the infants developing microbiome and are summarised in Fig. 1. These include mode of birth, mother’s diet, type of feed and use of antibiotics (Robertson et al., 2019). It is worthy of note that although there is less microbiome diversity seen in babies born by Caesarean section than those born vaginally, ‘vaginal seeding’ (the practice of exposing babies born by Caesarean section to their mother’s vaginal fluids in the hope of building their gut microbiome and immunity) is not to be recommended. Haahr et al. (2018), in the British Journal of Obstetrics and Gynaecology, concluded that vaginal seeding could not be recommended due to associated risks. Instead, they encourage healthcare professionals to encourage safe methods that are known to promote the healthy colonisation of a baby’s gastrointestinal bacteria, such as early skin-to-skin contact and breastfeeding.
Factors that influence the microbiome.
The adult gut microbiome is established by colonisation in infancy and inherited genetics. It is modified thereafter by multiple environmental factors. The most robust evidence for environmental alteration throughout adulthood is related to diet (David et al., 2014). This makes diet a clear target for therapeutically altering the gut microbiome, but also makes studies of the microbiome difficult to interpret without taking account of different diets and controlling for different diets.
Function of the microbiome
The gut microbiome acts not only in anaerobic breakdown of digestion products, but also endogenous creation of compounds by the microorganisms themselves. We are only beginning to understand how these compounds interact with the host and its environment. There are numerous functions of the human microbiome which are briefly summarised in Fig. 2 and explained in more detail below.
Functions of the microbiome.
Immune function and production of short chain fatty acids
Research is still in its infancy, but it is understood that multiple microbial metabolites appear to have influence on immune cells. Complex carbohydrates are broken down to short chain fatty acids (SCFAs) by microbes in the gut. The most common of these SCFAs are acetates, propionates, and butyrates. These have been shown to act on multiple enzymatic processes that influence the function of immune cells. We know SCFAs are the key to maintaining the mucosal protection by promoting the intestinal epithelial cell’s production of mucin genes; they also tend to promote anti-inflammatory cell function (Rooks and Garrett, 2016). The cell components and receptors of the microbes can also act in signalling cascades influencing immune responses. All these mechanisms show that the gut microbiome and immune system are involved in a complex cross connection to ensure survival in a microbial-dominated world. This suggests alteration in the individual’s microbiome could lead to immune dysregulation or down-regulation. For this reason, it seems likely that the gut microbiome has a strong relationship with inflammatory conditions.
Microbiome and metabolism
Metabolic disorders are fast becoming one of the largest health challenges worldwide. We now know many metabolic disorders are associated with alterations in the composition and function of the gut microbiome.
Studies have shown that individuals with lower microbial gene diversity have higher levels of adiposity, insulin resistance and dyslipidaemia than those with richer bacterial populations (Le Chatelier et al., 2013). Specific microbiota-derived metabolites such as SCFA (also bile acids and branch chain amino acids) have been strongly linked to the pathogenesis of metabolic disorders, such as obesity and insulin resistance (Agus et al., 2021). This raises the possibility that these metabolites could be used as a biochemical marker for early diagnosis of metabolic disorders, and that modulating the microbiome could provide novel therapy for metabolic pathologies in the future.
Microbiome and the gut–brain axis
The bi-directional signalling between microbiome, gut and brain is complex, involving the central and enteric nervous system along with the circulatory system. This link with the central nervous system (CNS) suggests that the microbiome could affect neurological development and function. Animal studies show that the gut microbiota and its metabolites can influence stress responses, anxiety levels, pain, feeding and socio-neurological development (Bercik et al., 2011; Mayer et al., 2015). The mechanisms for this are only just beginning to be understood. Circulating SFCAs have an effect on the blood– brain barrier, and thus, which metabolites (many undesirable) can enter the CNS. Furthermore, the microbiome’s action on the immune system can influence cytokines that cross the blood– brain barrier and could have an effect on neurological behaviour.
There is increasing interest in the effect of probiotics on cognition, mood, and brain function. A functional MRI (fMRI) study (Tillisch et al., 2013) that assessed participants’ responses to emotional tasks showed significant differences between those taking probiotic supplements compared with the control group. Another randomised control trial looking at Alzheimer’s disease patients demonstrated an improvement in the mini mental state exam after taking probiotics (Akbari et al., 2015).
The gut microbiome influences the stress response and is implicated in anxiety, mood, and cognition. However, the specific causative mechanisms for this influence remain unclear.
A word on ‘dysbiosis’
Dysbiosis is a term used to describe a shift away from the healthy state of the gut microbiome; usually relating to a loss in microbes or microbial diversity. Although there is no consensus on exactly what a ‘healthy’ gut microbiome looks like, a trend is emerging in the gut ‘dysbiosis’ of patients with specific diseases.
This raises many questions about the role of the microbiome in disease pathology.
Role of the microbiome in disease
There is research into the links between the microbiome and disease in every speciality from psychiatry to orthopaedics. We will consider a few of the pathologies commonly linked with the microbiome in clinical practice.
Inflammatory bowel disease
Research has shown congruent microbiome disruptions in both Crohn’s disease and ulcerative colitis characterised by a reduction of commensal bacteria.
Irritable bowel syndrome
Roughly 1 in 10 adults in the UK suffers with irritable bowel syndrome (IBS). The symptoms cover a range from constipation to diarrhoea, bloating, and abdominal pain. Despite being one of the most frequently seen gastrointestinal disorders in primary and secondary care, there is very limited understanding of its aetiology, and often few effective treatment options. It is now becoming increasingly evident that there are microbial triggers in its pathophysiology (Pimentel and Lembal, 2020). We know that a pathogen-triggered acute gastroenteritis can precipitate IBS and now studies have observed significant changes in the faecal bacteria of IBS patients compared with a ‘normal host’ (Kassinen et al., 2007). However, no conclusive evidence for a specific microbial pattern in IBS has been identified. It remains unclear if the changes seen are causative, secondary to disease, or a result of modifiable factors such as diet and exercise. Nonetheless, this research opens possible avenues for targeted therapies aiming to treat an underlying cause of IBS.
The theory that the microbiome may be involved in the pathology of IBS has led to a lot of interest both professionally and in the lay community regarding use of probiotics in IBS.
A meta-analysis of multiple randomised control trials (Ford et al., 2018) has demonstrated that probiotics appear to have beneficial effects on global symptoms of IBS or abdominal pain. Although it is not yet possible to prescribe or give specific recommendations on the therapeutic use of probiotics in IBS (due to variation in study design and of strains of bacteria used), use of probiotics has no significant adverse effects on patients.
Clostridium difficile and fecal microbial transplant
Clostridium Difficile (C.Difficile) infection causes severe diarrhoea when bacteria produce exotoxins that lead to inflammation of the mucosal surface and colitis. Increased proliferation of the C.Difficile bacteria has been noted after antibiotic use when the healthy gut bacteria are suppressed. This is an area where the function of the gut microbiome has long been known to be significant. Eiseman et al. (1958) described successful treatment of patients with C.Difficile pseudomembranous colitis using donor faecal enemas. The purpose of the treatment was to restore the healthy bacteria of the gut. Fecal microbial transplant (FMT) has been used successfully in treating C.Difficile since 2015 in the UK. The faecal samples are screened for infection, filtered, and frozen. FMT is administered either via colonoscopy, enema or naso-gastric tube. It should be noted that ‘home FMT’ should be strongly advised against. An online market for purchase of unscreened samples has great potential for harm. Currently FMT is only licensed for patients who have had two recurrences of C.Difficile.
There is ongoing research into the potential use of FMT for other gastrointestinal diseases where disruption of the gut microbiome may be relevant. A recent study looking at FMT in the treatment of hepatic encephalopathy produced some encouraging results (Liu et al., 2021). There is also emerging evidence for use of FMT in Primary Scelrosing Cholangitis. The FARGO trial beginning in 2023 may clarify whether FMT is of benefit in this otherwise untreatable disease.
Modulating the gut microbiome
Diet
A change in diet can cause alteration in the gut microbiome in as little as 24–48 hours.
There is increasing public interest in diet modulation for the treatment of disease. Recent studies looking at the well-known FODMAP diet (Staudacher and Whelan, 2017) and the use of exclusive enteral feeding for severe Crohn’s disease flares (Svolos et al., 2019) suggest these treatments may garner some of their effect through modulation of the gut microbiome. This paves the way for further research into dietary modulation of the microbiome for therapy in the future.
Prebiotics
‘Prebiotic’ is defined as: ‘a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora that confers benefits upon host well-being and health’ (Roberfroid, 2007). Since these substances were named, over 20 years ago, the concept has attracted much interest from both the scientific community and burgeoning ‘wellness’ and food industries.
Prebiotics are non-digestible oligosaccharides (fibres).However, not all dietary carbohydrates will have prebiotic action. They must resist acidic and enzymatic breakdown and absorption, enough to then be selectively fermented by the gut microbiome. This, in turn, then leads changes in gut flora composition and functioning that has benefit to the host. The Roberfroid paper found inulin and oligofructose to be the only substrates to meet all these criteria experimentally. Both of these compounds are increasingly used in new food product development. Prebiotics are available in supplement form, but prebiotic substrates can be found in vegetables such as Jerusalem artichokes, garlic, chicory root and leeks.
Animal models have shown prebiotics act to enhance mucosal integrity and reduce pro-inflammatory cytokines and colonic inflammation (Hoentjen et al., 2005). It is likely they may be useful in certain gut pathologies. Use of prebiotics has been shown to be very safe, but excessive consumption is linked with bloating and flatulence.
Probiotics
Probiotics are live microorganisms, usually bacteria species, which can be ingested to supplement and modify the gut microbiome to positive effect. The most commonly studied probiotics are bifidobacterium and lactobacillus species.
Probiotics cannot be prescribed on the NHS, but are easily available over the counter in the form of capsules or in yoghurt products and kefir and kombucha drinks. The public interest in probiotics has snowballed in recent years. There is no regulation on the sale of these products, and the variety of bacteria species is vast. Research findings have been mixed. There is little evidence supporting the many claims of benefit in the media or advertising. Most notably, there is no significant evidence to suggest benefit for healthy individuals for routine use of probiotics and no evidence to show probiotics have a positive benefit on eczema.
As discussed previously, they have been shown to be beneficial in the management of IBS. The British Society of Gastroenterology (BSG) suggests it is reasonable to advise patients wishing to try probiotics to take them for up to 12 weeks, and to discontinue them if there is no improvement in symptoms (Vasant et al., 2021).
Conversely, the data on the use of probiotics in IBD is mixed. Probiotics may be effective (equal to 5-aminosalicylic acids (ASAs)) in reducing relapse in patients with quiescent ulcerative colitis (UC) (Yoshimatsu et al., 2015). However, the efficacy of probiotics in Crohn’s disease (CD) still remains uncertain. Thus, the BSG advises that probiotics may have modest benefits in UC but are not recommended in CD.
A recent meta-analysis (Goodman et al., 2020) illustrated that probiotics can help reduce the incidence of antibiotic-associated diarrhoea by 37% and the McFarland (2007) meta-analysis indicates that probiotics can significantly prevent travellers’ diarrhoea. However, there is still no evidence to recommend a particular type or brand, and they cannot yet be prescribed on the NHS. Nonetheless, patients can be reassured that the safety profile of probiotics is good. No increases in harm or adverse effects have been seen with short term probiotic use.
Clinical case scenario 2.
A 38-year-old patient with a long history of IBS attends the surgery. She says she has heard from a friend that her IBS symptoms could be caused by ‘a lack of good bacteria in her gut’ and that taking probiotics might improve her symptoms. She wants to know if this is true and if you can prescribe some probiotics for her.
A thorough history and examination reveal no change in her long-standing symptoms of intermittent loose stools and bloating. There are no new red flag symptoms and nil of note on examination.
You explain that some studies have shown that the makeup of bacteria in the gut does seem to differ in patients with IBS compared with ‘normal’. However, it is unclear if this change is a cause of IBS or a result of IBS, or due to other things such as diet.
There is currently no definitive guidance for use of probiotics in IBS. Although there are multiple studies showing that symptoms of bloating and abdominal pain may improve, there is no evidence to show which probiotic should be used, and therefore, they cannot be prescribed on the NHS.
However, you can reassure her that evidence shows no harm in taking probiotics, and if she wants to try them advise her to try them for at least 4 weeks and monitor for any effect on symptoms.
Drugs
It has long been known that antibiotics affect the gut microbiome. It can take an extended time for commensal gut organisms to recover and the new microbial fingerprint will be changed with certain species growing back at a faster rate. We know this effect to be true in early life, giving strength to the argument for not using antibiotics unnecessarily in the early years of life when the microbiome is at its peak of development.
Recently, is has come to light that proton pump inhibitor (PPI) usage may also cause modulation in the gut microbiome. PPI use is associated with increased risk of enteric infections. In particular 65% increase in incidence of C.Difficile infection (Imhann et al., 2016).The alteration in the microbiome may be a contributing factor.
There is no guidance on changing prescribing practice for PPIs, but the association is worthy of note.
Conclusion
The sub rosa role of the gut microbiome is now starting to be understood. The microbial fingerprint is affected by an array of intrinsic and extrinsic forces, from birth mode to medications. We are only beginning to understand that these ubiquitous microbes have an active role with the human host. The microbiome and its metabolites play a vital role in defending us from disease, developing our immune system, influencing the CNS and our metabolism.
Shifts in diversity of these microbes have been associated with many diseases including IBS, IBD and mood disorders. We are only just beginning to learn how we might modulate the microbiome to aid health and treat disease. This area of research is at an early stage and definitive clinical guidelines on interventions are limited. However, there is some evidence suggesting use of probiotics can improve symptoms of IBS, reduce antibiotic-associated diarrhoea and reduce relapses of UC, alongside the long standing use of FMT in C.Difficile infection.
As cross-discipline research gives more weight to these long ignored and pathologised microbes, There is hope that research within and between different disciplines may inspire new technologies and new, effective and more diverse clinical interventions.
Key points
The gut microbiome is the vast community of microorganisms present on the gut mucosa, their genomes and the environment The gut microbiome acts with the products of digestion to produce multiple compounds that may influence immune function, disease pathogenesis, fat metabolism and CNS modulation Changes in the microbial diversity of the gut have been observed in many diseases (including IBD, IBS, C.Difficile infection, metabolic disorders and mood disorders), but it remains unclear if these changes are the cause or effect of disease Probiotics are ingestible micro-organisms that can modulate the microbiome and studies have shown short term use is safe and may have beneficial effects in IBS, UC and antibiotic-associated diarrhoea There is no recommendation for what types of probiotics to use and they cannot be prescribed on the NHS An individual’s microbiome is both unique and dynamic; it is influenced by birth mode, diet, exercise and drugs and is a potential target for focused novel therapies
