It has long been understood that the gastrointestinal (GI) tract contains many millions of bacteria and other microbes. Historically, interest in this area has focused on harmful pathogenic bacteria such as Campylobacter or Shigella, which cause infectious gastroenteritis. However, the vast majority of gut bacteria do not usually cause infection, and appear to live in harmony with the body; the profound importance of this wider community of gut microbes was not fully appreciated until recently. One major difficulty in investigating this subject before now has been the lack of laboratory techniques to easily identify many of these microbes; however, over the past 20 years, the arrival of a range of cutting-edge scientific techniques has allowed scientists to study them like never before. For example, from a single stool sample from a healthy person, scientists can now identify material from at least hundreds of different bacterial species, and many thousands of different chemicals related to these bacteria. This has been the launchpad for huge advances in understanding the complex collections of microbes within our GI tract, and for the recognition of their major relevance to medicine and nursing.
The Gut Microbiome
Overview
The term ‘gut microbiome’ is now often used as a way of describing the entire collection of microbes, their genes and the environment around them within the GI tract (while another similar term, ‘gut microbiota’, refers just to the collection of microbes themselves) (Marchesi and Ravel, 2015). Terms such as gut ‘flora’ or ‘microflora’ are now outdated. Although much of our understanding focuses on bacteria within the gut, scientists now increasingly understand that the other microbes within the gut—including viruses, and certain forms of fungi—may also be just as important (Vemuri et al, 2020). The scale of the microbiome is huge—each human body contains many billions of bacterial genes and cells (probably about 13 bacterial cells for every 10 human cells at latest estimates (Sender et al, 2016)).
Like many areas of medicine, the study of the gut microbiome has been revolutionised by improvements in computing, and the ability to analyse ‘big data’ has led to major advances in understanding. First, these developments have provided new insights into ‘what is there’, allowing us to quickly and accurately determine the specific mixtures of bacteria present within different parts of the GI tract. Second, scientists can now study ‘what they are doing’; specifically, demonstrating the different means by which these bacteria ‘talk’ to our gut and the rest of our body, and by which our bodies ‘talk back’ to the bacteria for mutual benefit. In particular, it is now understood that many bacteria within the healthy gut are not harmful or ‘passive bystanders’, but are beneficial to the body, with a number of important roles in keeping us healthy (Lebeer and Spacova, 2019), including:
The Gut Microbiome in Health And Disease
A huge variety of different factors that can affect which microbes are present within the gut and how they function have now been identified (see Table 1 and Hasan and Yang (2019) for further details). Some of these factors are somewhat intuitive; for instance, antibiotics may have very marked effects on the gut microbiome. Other factors are more complex and nuanced— for instance, just as the gut microbiome affects the processing of components of a person's diet within the gut, so their diet also impacts upon the composition of their gut microbiome. Other factors recognised to impact the gut microbiome include smoking, immune status and surgical intervention (Table 1). The most marked modifications in the gut microbiome appear to occur within the first few years of life, with mode of delivery, whether a child is breast or bottle feeding, and a range of other environmental factors, all having important influences (Tamburini et al, 2016).
| Factor | Notes |
|---|---|
| Medications | Antibiotics are the major group of medications, but many others (such as proton pump inhibitors) are also implicated |
| Diet | A complex crosstalk occurs between microbes and the human they live in, with diet influencing the microbiome, and the microbiome acting upon components in the diet |
| Age | There is a very dynamic alteration in the gut microbiome within the first few years of life, influenced by factors including mode of delivery, breast or bottle feeding, etc. After this, the gut microbiome reaches a ‘steady state’ from late childhood through to later life. In old age, further changes in the gut microbiome occur, likely reflecting a combination of biological and environmental factors |
| Immune status | Whether or not a patient is immunocompromised |
| Medical comorbidities | As described in Table 2 |
| Surgery | Particularly different forms of intestinal surgery, including bariatric procedures |
| Other lifestyle factorsc | Including smoking and alcohol intake |
| Geography | There is now increasing recognition that gut microbiomes can vary by country, or even between people in different regions within a country |
| Genes | Genetics also appear to have an important influence on the microbiome |
| Disease group | Specific examples |
|---|---|
| Gastrointestinal | Clostridioides difficile infection, inflammatory bowel disease, irritable bowel syndrome, colorectal carcinoma |
| Liver | Hepatic encephalopathy, primary sclerosing cholangitis, alcohol-related liver disease, non-alcoholic fatty liver disease |
| Metabolic | Obesity, type 2 diabetes mellitus, metabolic syndrome |
| Neurological | Autistic spectrum disorders, motor neurone disease, Parkinson's disease |
| Inflammatory disorders | Psoriasis, rheumatoid arthritis |
| Iatrogenic | Immunotherapy-induced colitis |
It is important to note that many of these changes are associations at the moment, although evidence is gradually becoming established for a number of these conditions that the gut microbiome may directly cause or contribute to them
Most gut microbiome analysis has occurred through scientific investigation of stool samples, since these are relatively easy to obtain. Other studies have analysed tissue biopsies, such as those collected at endoscopy or during surgery. What all these studies have shown is that we all have a particular distinctive gut microbiome ‘profile’; even when a group of similarly healthy people are compared, their microbiomes all have a distinctive unique ‘fingerprint’, with no two people, not even genetically identical twins, having exactly the same microbes within their gut (Goodrich et al, 2016). As such, it has been difficult for scientists to describe specifically what a ‘healthy gut microbiome’ is or is not.
Given the clear importance of the gut microbiome in health, a further area of great recent interest has been regarding its potential role in disease. To investigate this, many studies have compared the gut microbiome of people with a particular condition to that of healthy people to look for differences. Many of these studies have identified that the gut microbiome profiles of those with a wide range of different medical conditions— both those directly related to the gut (such as colorectal cancer), and even many that are not (such as psoriasis or Parkinson's disease)—are different to those of healthy people (see Table 2 and Allegretti et al (2019) for further details). However, exactly what this means remains uncertain in many cases, and there is a debate regarding what is the ‘chicken’ and what is the ‘egg’. For example, one possibility is that certain people develop abnormalities in their gut microbiome, and they directly cause or contribute to a particular medical condition. However, an alternative interpretation is that the gut microbiome patterns seen in people with a particular diagnosis may just be a consequence of having the condition, eg are just representative that the gut is inflamed rather than being what specifically made it inflamed; or reflect the use of medications that have been used to treat the condition; or represent that people with particular conditions eat a more limited diet—or tend to be older—than healthy people (Claesson et al, 2012).
There is also growing recognition that a person's gut microbiome may affect how they process particular medications, which may in turn influence whether the patient gets the full benefit from it, and/or develops side effects. One key example of a class of medications of relevance to this area is anti-cancer treatments, including chemotherapy (Alexander et al, 2017). Very recently, evidence has emerged that novel immune checkpoint inhibitor medications—which have revolutionised the treatment of a range of cancers—may work to different degrees in different patients depending on their gut microbiome, and/or whether they have recently had antibiotics before starting treatment (Pinato et al, 2019).
How Might we Attempt to Alter the Gut Microbiome?
If abnormalities in the gut microbiome may be a risk factor for —or directly contribute to—particular diseases, then attempting to alter the gut microbiome back to a ‘normal’ state may be an attractive novel route to potentially treat the condition. The following is an overview of some of the approaches taken to altering the gut microbiome.
Diet
There is already evidence from clinical trials for particular dietary interventions in treating different conditions, for example:
In both of these examples, at least part of the explanation for the benefits of these interventions may be through modification of the gut microbiome (Svolos et al, 2019; Cox et al, 2020). Additionally, a recent trial suggested that at least one key way in which a Mediterranean diet reduces plasma cholesterol in overweight and obese people is through alteration of the gut microbiome (Meslier et al, 2020). Unfortunately for the proponents of fad diets, this matter is unlikely to be ‘one size fits all’, and it is probable that individuals (and their microbiomes) respond variably to different nutrients. For example, in one study, researchers were able to predict how glucose levels varied widely between individuals in response to identical meals, based in large part on the individual's microbiome (Zeevi et al, 2015). These findings raise the intriguing possibility that future dietary management for conditions such as diabetes mellitus may be more effective if we can harness information from the gut.
Prebiotics and Probiotics
Prebiotics are dietary components that affect the growth or actions of particular bacteria within the gut microbiome, with the aim of a beneficial effect to the health or wellbeing of the person taking them. A good example of this is certain dietary fibres—these are not digested or absorbed from our gut, but are fermented by bacteria within the microbiome of our colon to produce chemicals that are beneficial to the bacteria themselves, as well as being of benefit to our health in a number of ways. A large recent study showed that people with the highest fibre intake had significantly reduced rates of coronary artery disease, stroke, type 2 diabetes mellitus and colorectal cancer (Reynolds et al, 2019).
In contrast, probiotics are live bacteria and yeasts that are administered to people with the aim of improving their health, and are thought to produce these benefits through effects upon the gut microbiome of the patient. Probiotics may be administered in different ways, eg as pills, yoghurt or a drink. They are typically recognised as a food supplement rather than as a drug or medicine. There are certain medical conditions where trials have shown that probiotics appear to provide at least a degree of benefit, such as symptomatic improvement in certain patients with IBS (Ford et al, 2018). However, the outcomes of studies of probiotics in IBS—as they are for probiotic studies in several other conditions—are very variable. This may partly reflect how the studies are designed, including the varied probiotic preparations used (and/or different numbers of bacteria administered) between studies (Rondanelli et al, 2017).
Antibiotics
Although we think of antibiotics primarily as treatment for infections, there are certain non-infectious conditions where antibiotics are a beneficial treatment through their ability to alter the gut microbiome. For instance, hepatic encephalopathy (HE) is a complication of cirrhosis, whereby patients develop a variety of neurological and psychological/behavioural abnormalities. HE is believed to be caused by ammonia and other toxins produced by bacteria within the gut, which then enter the circulation; while people with functioning livers can break down these toxins, those with cirrhosis cannot, and these toxins pass up through the circulation and into the brain. One effective treatment for HE is rifaximin, an orally administered antibiotic that is not absorbed from the gut; rifaximin may mediate these benefits through killing those gut bacteria producing ammonia and other toxins (Shawcross 2018).
Given the association between the gut microbiome and a wide range of medical conditions, coupled with the growing understanding of the impact of the antibiotics upon the gut microbiome, there is growing recognition that ‘collateral damage’ from the use of antibiotics may be an impact on human health in a much more complex way than originally appreciated. More specifically, antibiotics may potentially influence propensity to (or severity of) a variety of non-infectious diseases, which may even include complex conditions such as obesity (Ianiro et al, 2016).
Faecal Microbiota Transplant
The ultimate way of trying to alter and ‘reset’ a gut microbiome in a patient with disease is to try and remove the gut microbiome in its entirety from a healthy person (who, it is believed, should have a ‘normal’ gut microbiome), and transfer it into an affected person. Given that stool samples are an easily accessible way of sampling the gut microbiome of healthy people, the idea arose that faecal microbiota transplant (FMT) may be an effective approach to therapy. The process is as follows:
Despite the unusual nature of this approach, FMT has now been shown in a number of trials to be a highly effective therapy for the treatment of recurrent Clostridioides difficile infection (CDI), a bacterial infection of the gut. The major risk factor for CDI is the use of broad-spectrum antibiotics, such as those used to treat a chest or urinary tract infection. Although these antibiotics effectively treat the initial infection, they have the unintended side effect of killing off beneficial bacteria within the gut microbiome that protect us from harmful bacteria, which may cause infections (Rupnik et al, 2009). Therefore, if patients then have any exposure to C. diff bacteria, they can easily invade the gut and produce toxins that cause diarrhoea and other features of gut infection. Although there are specific antibiotic treatments that kill C. diffbacteria in those with recurrent CDI, FMT appears to work just as effectively (Hvas et al, 2019). FMT's effect is likely through the restoration of those beneficial bacteria to the gut microbiome that were present before the patient was initially exposed to antibiotics, which have the ability to ‘fight off ’ and overcome the C. diff from remaining present within the gut.
Remarkably, when FMT is used in the treatment of recurrent CDI, over 80% of patients are cured after only 1-2 treatments (Mullish et al, 2018). There are obviously a large number of variables to consider when trying to provide FMT safely and effectively, including optimal screening and selection of donors, and methods for preparing and administering the material; these are discussed further in Table 3 and in greater depth in Mullish et al (2018), Allegretti et al (2019) and Mullish et al (2020). The importance of careful donor screening in particular has been brought to light recently, when two patients obtained infection with antibiotic-resistant bacteria by FMT after transmission from an unscreened donor, and one of them died (DeFilipp et al, 2019). In the current climate, it is clearly also important to consider appropriate donor screening for past or present SARS-CoV-2 carriage/COVID-19 infection (Ianiro et al, 2020). There are now a number of centres within the UK performing FMT as an NHS service for recurrent CDI, and there are recent joint national guidelines to direct best practice in this area (Mullish et al, 2018).
| Factor | Discussion |
|---|---|
| Recipient selection |
|
| Donor selection |
|
| FMT administration |
|
CDI=Clostridioides difficile infection; FMT=faecal microbiota transplant; GI=gastrointestinal PEG=percutaneous endoscopic gastrostomy
*This table is focused on factors as they apply to FMT as a treatment of recurrent CDI, but also considers its experimental use in the treatment of other conditions
Given the success of FMT as a treatment for recurrent CDI, there is great interest in using it as a potential novel therapy in other conditions associated with gut microbiome alterations. Although there have been some promising early results in the trials in this area published to date (particularly regarding ulcerative colitis), it remains at too early a stage for FMT to be recommended as a treatment for any condition other than recurrent CDI (Allegretti et al, 2019).
The Gut Microbiome in Clinical Practice: Critical Care
Given the established role of the gut microbiome in healthy states in influencing our immune response and colonisation resistance, one area of particular growing recent interest has been regarding the relevance of the gut microbiome to critical care.
Patients in intensive care units (ICUs) show a very marked change in the pattern of their gut microbiome between the point when they are admitted to the unit and that when they leave, with a loss of many of the gut bacteria thought of as beneficial, and their replacement with microbes that may potentially cause disease and infection, including bacteria (McDonald et al, 2016), as well as certain forms of fungi, such as Candida (Vila and Martínez, 2007). There are likely to be many factors contributing to this finding, including the underlying condition itself, use of antibiotics and other medications, and/or a change of diet in ICU (Dickson, 2016). The effect of antibiotics is a particular concern, given the rising rates globally of antibiotic resistance and the potential unintended consequences associated with their use. A focus over recent years has been on improved antibiotic stewardship, and the use of shorter course, pathogen-directed therapy. Further research in critical illness has shown some surprising findings, such as that bacteria can move from the gut microbiome to other organs and may contribute to infections there, as well as showing that the gut microbiome may influence how the immune system responds to infection or inflammation (Kim et al, 2020).
Pneumonia, acquired both prior to and secondary to hospital admission, is common, and may be fatal in the critical care setting. The microbiome of the lung is less well studied than the gut, but this is another area of increasing interest. The development of acute respiratory distress syndrome (ARDS) is associated with the presence of bacteria that appeared to have unexpectedly moved via the circulation from the gut microbiome into the lung microbiome. It has been proposed that the drainage of chyle from the lower GI tract via the lymphatic system, into the thoracic duct, and onwards to the capillary blood vessels of the lungs (the ‘gut-lymph hypothesis’) may explain the presence of gut constituents in the lungs (Deitch, 2012). Furthermore, recent studies have suggested that certain constituents of the lung microbiome may predict poorer outcomes in critically ill patients, even after accounting for the severity of their illness (Panzer et al, 2018; Dickson et al, 2020).
Whether different forms of enteral feeds, through their impact upon the gut microbiome, may influence outcomes from sepsis is an area of interest to researchers, but there is not enough knowledge and experience about this to make recommendations in clinical guidelines at present (van Niekerk et al, 2020). Prebiotics have not been well-researched in critical care, although there are some preliminary experiments suggesting that these may potentially boost the response of the immune system (Wu et al, 2017). There have been more than 30 human trials of probiotics in critical care, and it appears that these may overall have at least some benefit in reducing rates of infection; however, as described above, variability in the design of different probiotic trials make it difficult to make general conclusions (Manzanares et al, 2016). However, some probiotic trials have shown the opposite result; for example, in a large trial, where critically ill patients with severe acute pancreatitis were randomised to receive either probiotics or placebo, there was a much higher death rate in patients treated with the probiotic compared to those treated with placebo (Besselink et al, 2008).
A number of different trials have also looked at ‘selective decontamination of the digestive tract (SDD)’, ie administering antibiotics to the mouth or GI tract of critically ill patients without active infection, with the aim of trying to remove bacteria from the gut microbiome that could potentially cause future infections. Trials to date show that SDD may be of clinical benefit to patients in intensive care (Price et al, 2014), although there are still some outstanding questions about this approach, such as the potential risk of increasing rates of antibiotic resistance. Although experience of FMT in critically ill patients is still at an early stage, it appears that this may be a relatively safe and effective procedure—either when used in patients with recurrent CDI or otherwise (McClave et al, 2018)—as long as careful adherence to appropriate administration procedures is followed. There have been some animal experiments recently performed that demonstrate that FMT may even directly have a role as a potential treatment for bacterial sepsis itself (Kim et al, 2020), but much more research will be required before this could be considered for use in humans.
Conclusion
We are entering an exciting era in which the importance of the gut microbiome to health and disease is increasingly clear. However, this era remains at an early stage, and there are still many unknowns, as well as the risk of doing more harm than good (as shown by the recent report of infections transmitted through FMT) if appropriate processes are not followed. Over the next few years, there is likely to be a growing role for the gut microbiome in diagnostics and, in particular, in new therapeutics, which may hugely impact upon the patient journey for people with a range of different conditions.