Copyright EMAP Publishing 2019 This article is not for distribution except for journal club use

Clinical Practice Keywords Micro-organisms/Gut microbiota/Dysbiosis/ Systems of life This article has been GI tract double-blind peer reviewed In this article... ● Gut microbiota and its role in the ● The diverse effects of the gut microbiota on human physiology ● How imbalances could increase risk of certain diseases and conditions

Gastrointestinal tract 6: the effects of gut microbiota on human health

Key points Authors John Knight is associate professor in biomedical science; Zubeyde Bayram- The community of Weston is lecturer in biomedical science; Yamni Nigam is professor in biomedical micro-organisms science; all at the College of Human Health and Sciences, Swansea University. living in the gastrointestinal tract Abstract The combined gut microbiota (the community of micro-organisms in the exerts powerful and gastrointestinal tract), exerts powerful and diverse effects on physiology. It plays a diverse effects on role in synthesising useful biologically active molecules, modulating immune human physiology responses, behaviour and mood. Dysbiosis, where the balance of the microbiota is disrupted, is associated with increased risk of certain diseases, conditions and Gut have a autoimmune reactions. This article, the last in a six-part series on the gastrointestinal direct influence on tract, examines the gut microbiota and its role in the body. the immune system and the body’s Citation Knight, J et al (2019) Gastrointestinal tract 6: the effects of gut microbiota on ability to deal with human health. Nursing Times [online]; 115: 11, 46-50. disease and infection

Factors such as revious articles in this series on The combined microbial genome is antibiotic therapies the gastrointestinal (GI) tract thought to comprise over 3 million genes, poor diet, sequentially examined the com- which dwarfs the 23,000 genes present in psychosocial stress Pponents of the GI tract from the human genome. This huge microbial and direct exposure mouth to anus and described the processes genome is collectively known as the gut to pathogenic of mechanical and chemical digestion and microbiome and codes for a multitude of organisms can all absorption. This final article examines the microbial metabolites, which are released affect gut microbiota gut microbiota (the community of micro- into the gut and subsequently absorbed organisms living in the GI tract) and the role and distributed throughout the body. The Imbalances in gut it plays in the GI tract and in general health. combined gut microbiota is often referred microbiota could to as a ‘super-organism’, which, as it increase the risk of Overview of the microbiota releases biologically active molecules, can certain diseases The human GI tract has a massive total sur- be thought of as a ‘virtual endocrine organ’ and conditions face of 250-400m2 (Thursby and Judge, that exerts powerful and diverse effects on 2017). This enhances the processes of human physiology (Valdes et al, 2018). With Evidence for the digestion and absorption, and functions as an estimated collective weight of 2kg, the effectiveness of a surface substrate for microbial attach- gut microbiota has a larger mass than the probiotics is ment and colonisation. Larger numbers of liver, which is the largest internal organ. contradictory, but microbes are also found suspended and For many years it has been understood stool pills and faecal replicating within the nutrient-dense that bacteria living in the gut, such as Escher- transplants appear medium of the gastrointestinal secretions ichia coli (E coli), perform vital functions, to be effective in and partially digested food. An estimated such as the biosynthesis of vitamin K (a key reducing Clostridium 100 trillion micro-organisms, including co-factor in the blood clotting cascade), but difficile infection bacteria, viruses, fungi and protozoa, colo- it is only in the last decade that the complex and colitis nise the GI tract, with microbes outnum- interplay between the micro-organisms of bering human cells between three and 10 to the gut microbiota and human tissues is one (European Commission, 2018). gradually being understood. Today it is

Nursing Times [online] November 2019 / Vol 115 Issue 11 46 www.nursingtimes.net Copyright EMAP Publishing 2019 This article is not for distribution except for journal club use Clinical Practice Systems of life recognised that not only does the micro- Fig 1. Human gut microbiota 2kg of gut microbial biomass found in this biota play a role in synthesising useful bio- location. Increased microbial diversity in logically active molecules, it is intimately the colon reflects significantly reduced involved in modulating immune responses 5% enzyme activity in this region, which is pri- and also influences behaviour and mood. Of marily dedicated to water and salt re- particular interest is the observation that absorption (see part 5). The pH of the colon dysbiosis, where the normal balance of spe- is also more favourable, being slightly cies within the microbiota is disrupted, is 30% acidic to neutral (typical pH5.5-7.0). associated with increased risk of certain dis- eases and medical conditions, including 65% Effects on human physiology Parkinson’s disease, autism, obesity, dia- Research into how the microbiota affects betes and certain autoimmune reactions. physiological processes is still in its infancy. One of the major problems in this field of Microbial species forming study is the inability to culture many of the the gut microbiota key bacterial species found within the gut. A major challenge in trying to identify the Bacteroidetes Culturing is essential to allow investigation microbes that live within the human GI Others of the biochemistry of gut microbes and tract is that many cannot be grown using identify the microbial metabolites that can the standard microbiological culturing modulate human physiology. Despite this techniques. However, the advent of modern bacterial colonisation. Unsurprisingly, problem, useful information on the role genome sequencing has allowed rapid those born via natural vaginal delivery played by the gut microbiota in modulating identification of micro-organisms without have an early gut microbiota that is similar human physiological processes has the need for culturing. The bacterial spe- to the vagina, with groups such as Lactoba- recently been established. cies of the gut have been the most heavily cillus dominating. This contrasts with researched, while knowledge of the viral babies born via caesarean section, who Role in digestion and fungal micro-organisms of the gut have early gut microbiota similar to that The microbial communities of the large microbiota is currently sparse. The low found on the mother’s skin, with groups intestine are predominantly reliant on par- oxygen levels present within the internal such as Corynebacterium and Staphylococcus tially digested food arriving from the small environment of the GI tract favours the species present in high numbers intestine for nutrition and survival. The growth of strict anaerobic species of bac- (Dominguez-Bello et al, 2011). The diversity gut microbiota itself plays an active role in teria, which greatly outnumber facultative of bacterial species generally increases digestion of the carbohydrate, fat and pro- anaerobes (bacteria that can switch with age, as different species are acquired tein components of food. between aerobic and anaerobic metabolism from environmental contact, particularly Bacteria residing in the large intestine depending on oxygen concentration) and from eating different foods and through play a particularly important role in diges- the aerobic species (bacteria that require contact with other people and animals. It is tion of dietary fibre to yield short-chain the presence of oxygen) (Sekirov et al, 2010). thought the acquisition of a mature micro- fatty acids (SCFA) such as acetate, propi- Two major groups of bacteria dominate biota resembling that of an adult is onate, and butyrate. Propionate is thought the GI tract (Fig 1) with the Firmicutes attained in the first three years of life, with to play an important role as a satiety mole- (for example, and Strepto- country of residence also affecting the cule, with the ability to contribute to the coccus species) comprising around 65% of microbiotic profile (Yatsunenko et al, 2012). switching off of hunger, while butyrate the total and the Bacteroidetes (for promotes programmed cell death (apop- example, Bacteroides intestinalis) around Differences along the gut tosis) in malignant epithelial cells lining 30%. The remaining 5% are composed of Due to vastly different conditions, particu- the large intestine, thereby reducing the primitive bacterial groups, including the larly in terms of pH, the populations of risk of bowel cancer. The digestion and fer- proteobacteria (for example, E coli) and the bacteria and other micro-organisms vary mentation of dietary fibre by the gut micro- actinobacteria such as Bifidobacteria spe- markedly in the different gut regions biota yields large quantities of gasses such cies (Yang et al, 2009). (Fig 2, p48). Unsurprisingly, the strongly as odourless methane, carbon dioxide and It is estimated that all individuals have acidic conditions of the stomach limit hydrogen, together with smaller amounts between 500 and 1,000 species of bacteria microbial colonisation and so relatively of pungent odoriferous gasses such as colonising their gut. Population studies few species of bacteria are able to survive hydrogen sulphide (Rowland et al, 2018). indicate much variation between individ- there. Notable exceptions are Lactobacillus uals, with each person having a unique species and Helicobacter pylori, which is a Vitamin biosynthesis profile of microbial species. It is suggested key bacterium linked to the formation of Human cells and tissues are unable to syn- up to 35,000 species form the collective gastric ulcers (see part 2). Similarly, active thesise directly many of the essential vita- human gut bacterial microbiota, with new proteases enzymes, such as trypsin, chy- mins required for health and survival, and species continually being discovered, motrypisin and intestinal peptidases, so these must be acquired through a com- including many previously unknown to limit the growth of bacteria in the small bination of dietary intake and biosynthesis science (Barras, 2019). intestine, which is dominated by Lactoba- by the GI tract microbiota. A healthy, well- cillus and Streptococcal species. balanced microbial community rich in Initial colonisation after birth As can be seen in Fig 2, the colon plays Bifidobacteria, Lactobacilli and E coli is able Babies emerge from the usually sterile host to the most diverse communities of to synthesise many of the water-soluble environment of the uterus with minimal bacteria, with the vast bulk of the estimated vitamins, including key B vitamins – such

Nursing Times [online] November 2019 / Vol 115 Issue 11 47 www.nursingtimes.net Copyright EMAP Publishing 2019 This article is not for distribution except for journal club use Clinical Practice Systems of life as folic acid (B ) riboflavin (B ) biotin (B ), 9 2 7 Fig 2. Distribution of major bacterial groups in the GI tract cobalamin (B12), nicotinic acid (B3), pantho- tenic acid (B5), and thiamine (B1) – together with essential fat-soluble vitamins, such Oral cavity as the vitamin K group (Yoshii et al 2019; • Corynebacteria Leblanc et al, 2013). • Lactobacillus • Streptococcus Xenobiotic metabolism • Staphylococcus and interactions Xenobiotics are chemicals found within the Stomach human body, but not actually produced by • Helicobacter pylori it. These chemicals include environmental • Lactobacillus pollutants, such as pesticides and food addi- tives – including preservatives, artificial fla- • Peptostreptococcus vourings, sweeteners, and pharmaceutical • Streptococcus agents in most of the major drug groups. Most xenobiotics are usually metabolised Large intestine by the liver into predictable breakdown • Bacteroides products, which are then excreted into the • Bifidobacteria bile for elimination in the faeces, or into the • Clostridium blood for elimination by the kidneys. • Enterobacteria Metabolism of xenobiotics by the gut • Enterococcus microbiota is currently poorly understood, • Escherichia coli but as knowledge of the microbial commu- nities of the GI tract develops, pharmacolo- • Faecalis gists have to factor in differences in drug • Lactobacillus metabolism by the hugely variable com- munities of microbes present in different Small intestine individuals. This new field of pharmaco- • Lactobacillus logical research is known as pharmacomi- • Streptococcus crobiomics (Das et al, 2016). A recent extensive study examining how 76 common bacterial species from the human gut microbiota metabolised 271 With increasing knowledge of the gut Immune modulation orally administered drugs, found 176 of microbiota, it soon became apparent that The bacteria that colonise the gut have a these were metabolised by at least one of the resident microbial communities and direct influence on the body’s ability to the bacteria investigated. It is hypothesised their cocktails of secreted metabolites deal with disease and infection. It is well that metabolism of a drug by resident bac- could influence the activity of both the understood that breast-fed babies have an teria in the gut may result in metabolites enteric and central nervous systems. This immunological advantage over their that can produce adverse side-effects, while complex interplay between the gut micro- bottle-fed counterparts, due to the passing individuals who lack bacteria capable of biota and the nervous system is referred to of secretory antibodies from mother to metabolising the drug may experience no as the brain-gut-microbiome axis (Martin baby, which confer protection against side-effects (Zimmermann, 2019). et al, 2018). Although this is currently pathogens in early infancy. poorly understood, mainly due to the Until fairly recently breast milk was Gut-brain axis and diversity of chemical signals produced by thought to be sterile and free from micro- brain-gut-microbiome axis the gut microbiota and complexity of the organisms, however, recent research has In part 1 of this series, we briefly examined neural pathways involved, some important indicated that breast milk contains a the role of the enteric nervous system in discoveries have recently been made. variety of ‘friendly’ bacteria (bac- controlling movement of food through the Metabolites from the gut microbiota, teria that promote health) including Lacto- gut by co-ordinating the process of peri- particularly short-chain fatty acids, are able and Bifidobacterium species, which stalsis. This is achieved by a dense network to stimulate the release of hormones from are known to enhance both gut and sys- of nerve fibres known as the myenteric the neuroendocrine cells of the gut; these temic health (Ojo-Okunola et al, 2018). The plexus, which extends into the muscular include peptide YY (PYY), which is a satiety bacteria present within breast milk appear layers of the gut wall. The gut-brain hormone that reduces the urge to eat, and to supplement the friendly bacteria axis refers to the direct and indirect links glucagon-like peptide-1 (GLP-1), which in (mainly Lactobacillus species) that are ini- and signalling between the enteric and addition to promoting satiety enhances the tially acquired through natural vaginal central nervous systems This cross talk is secretion of insulin in response to increased delivery, resulting in a healthy initial gut bi-directional, allowing gut physiology to blood (Farzi et al, 2018). This sug- microbiota. Breast milk also appears to be influenced by the brain, and brain gests that imbalances (dysbiosis) in the gut prevent colonisation of the gut with patho- activity, including cognition and mood, to microbiota could contribute to overeating genic micro-organisms and breast-fed be affected by the gut tissues (Carabotti et and obesity and may be linked to poor glu- babies appear to have a gut microbiome al, 2015). cose homoeostasis and potentially diabetes. that promotes an environment that is

Nursing Times [online] November 2019 / Vol 115 Issue 11 48 www.nursingtimes.net Copyright EMAP Publishing 2019 This article is not for distribution except for journal club use Clinical Practice Systems of life generally anti-inflammatory throughout psychosocial stress and direct exposure to which is depleted in people with Parkin- the body, reducing the risk of inflamma- pathogenic organisms. The dysbiosis son’s disease. Lewy bodies accumulate in tory diseases such as asthma and atopic caused by antibiotic therapies is the best their brains, but have also been discovered dermatitis (Toscano et al, 2017). understood form of gut dysbiosis, with in other regions, including enteric nervous The oligosaccharide (short-chain) broad-spectrum antibiotics indiscrimi- system (Kalia and Lang, 2015). sugars present within breast milk are rich nately wiping out friendly and pathogenic While it is generally believed Parkin- in fructans (short chains of fructose), gut bacteria alike, and leading to major son’s disease begins in the neural tissues of which encourage the growth of probiotic changes in the demographics of the gut the brain, some researchers have sug- bacteria, including both Lactobacillus and microbiota that may favour the growth of gested it originates in the gut, with Bifidobacterium species. This ensures the pathogens (Blumstein et al, 2014). changes to gut microbiota able to influ- initial probiotic populations of breast-fed ence the structure and integrity of the gut babies are maintained in high numbers; “Recent studies have shown tissues (Lionnet, 2018). The disease appears conversely the powdered formula milk to be associated with changes in the com- given to bottle-fed babies seems to several neurodegenerative position of the gut microbiota: a study encourage the growth of potentially path- disorders may be associated examining colonisation of the gut in ogenic entrococcal and enterobacterial with changes to the gut patients with Parkinson’s disease found species (Lazar et al, 2018). microbiome, with links to depletion of 15 species of bacteria, As babies are gradually weaned onto including: Bacteroides massiliensis, Bacte- solid foods they are exposed to more Parkinson’s disease the most roides coprocola, Blautia glucerasea, Dorea diverse populations of bacteria and attain a intensively researched” longicatena, Bacteroides plebeius, Prevotella mature gut microbiota. Gradually the copri, Coprococcus eutactus and Rumino- immune system becomes tolerant to the Dysbiosis and infection coccus callidus. This same research also resident gut bacteria, which are effectively It is well established that certain groups of indicated enhanced colonisation by the regarded as extension of ‘self’ (Lazar et al, friendly bacteria can frequently out-com- bacteria Christensenella, Catabacter, Lacto- 2018). pete pathogenic micro-organisms, bacillus, Oscillospira, Bifidobacterium, Chris- Understanding of the “cross talk” helping maintain gut and tissue health tensenella minuta, Catabacter hongkongensis, between the gut microbiota and the throughout the body. Bacteria, such as Lac- Lactobacillus mucosae, Ruminococcus bromii immune system is currently minimal. tobacillus species, produce acids (lactic and Papillibacter cinnamivorans. The However, a healthy population of probiotic acid) and other and anti- researchers speculated that this demo- bacterial species is generally associated fungal molecules (such as hydrogen per- graphic of gut bacterial species may pre- with a fine-tuned immune system and a oxide and chitinase), which make environ- dispose people to a pro-inflammatory general anti-inflammatory environment. mental conditions in the gut, mouth and environment, where Lewy body deposi- Conversely, reduced numbers of probiotic reproductive tract inhospitable to other tion can occur (Petrov et al, 2017). bacteria increase the risk of colonisation bacteria and yeasts, such as Candida albi- by potentially pathogenic species, which cans (Allonsius et al, 2019). Unfortunately, Dysbiosis and autism spectrum disorder disturbs the fine tuning of immune a course of antibiotics disrupts the natural Autism spectrum disorder is typically responses and increases the risk of inflam- balance of the gut microbiota, potentially characterised by impaired social interac- matory disorders and other forms of depleting populations of friendly bacteria tions and communication, and repetitive immune dysfunction (Cianci et al, 2018). and allowing potentially pathogenic bac- and restrictive behaviour patterns. teria such as C difficile to grow unchecked Although its aetiology is poorly under- Dysbiosis (Mullish, 2018). stood, genetic and environmental factors The diversity of micro-organisms living as a have been associated with an increased community within individual’s GI tracts is Dysbiosis and Parkinson’s disease risk of developing the disorder, including referred to as their enterotype and this may Recent studies have shown several neuro- nutritional imbalance, errors during pre- vary significantly between different people. degenerative disorders may be associated natal development and immune system Dysbiosis can be defined as an imbalance in with changes to the gut microbiome, with dysfunction (Risch, 2014). the numbers or diversity of the microbiota. links to Parkinson’s disease being the most Large numbers of individuals with With knowledge of the gut microbiota still intensively researched (Gerhardt and autism spectrum disorder have significant in its infancy, diagnosing what constitutes a Mohajeri, 2018). GI dysfunction, such as changes to bowel dysbiosis can be difficult, but some general Parkinson’s disease is a progressive habit, frequency, diarrhoea or constipa- features are recognised. neurodegenerative disorder that affects tion, and chronic abdominal pain. Nutri- Dysbiosis in the gut microbiota may movement, with the person developing tional status and GI symptoms experi- have a variety of causes as examined above: resting tremor, rigidity, bradykinesia enced appear to strongly correlate with the vaginally delivered and breast-fed babies (slowness of movement) and postural severity of the disorder (Adams et al, 2011; appear to acquire an initial population of instability, together with other non-motor Horvath and Perman, 2002). A diet high in healthy probiotic bacteria from their symptoms. A pathological hallmark is the fat and sugar during pregnancy and the mothers and are more likely to have a bal- presence of Lewy bodies, which form when presence of gestational diabetes all seem to anced microbiota than their caesarean- a called alpha synuclein is depos- be associated with an increased risk of delivered, bottle-fed counterparts. How- ited in neurons (nerve cells). As Lewy autism spectrum disorder, potentially by ever, even an initial healthy gut microbiota bodies accumulate, they interfere with altering the composition of the gut micro- can rapidly change as a result of environ- neural function and the ability to produce biota (Fattorusso et al, 2019; Connolly, mental factors, including poor diet, neurotransmitters, such as dopamine, 2016). Breast feeding babies for four

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months is associated with a lower risk to be fully evaluated ‘stool pills’ and faecal and immune system interactions in infectious compared with bottle feeding; this may transplants appear to be effective in diseases, immunopathology, and cancer. Frontiers in Immunology; 9: 1830. reflect increased risk of dysbiosis, with reducing C difficile infection and colitis Leblanc JG et al (2013) Bacteria as vitamin babies fed with formula milk having a gut (Wischmeyer et al 2016; Mayor 2017). suppliers to their host: a gut microbiota that favours the growth of pathogenic perspective. Current Opinion in Biotechnology; 24: 2, 160-8. groups of bacteria (Azad, 2013). The gut Conclusion Lionnet A et al (2018) Does Parkinson’s disease microbiota of children with autism spec- Despite the explosion of research into the start in the gut? Acta Neuropathologica; 135; 1–12. trum disorder frequently differs from gut microbiota over the last decade, Mayor S (2017) Faecal transplant given in oral capsule reduces recurrent C difficile, shows study. their neurotypical siblings and healthy knowledge of the role played by this British Medical Journal; 359; j5501. controls (De Angelis et al, 2015). diverse community of micro-organisms is Martin CR et al (2018) The brain-gut microbiome A recent study of 18 participants with still limited and further research is needed axis. Cellular and Molecular Gastroenterology and Hepatology; 6: 2,133–148. autism spectrum disorder and chronic gas- to more comprehensively understand its Mullish BH (2018) Clostridium difficile infection trointestinal problems reported that micro- role in health and disease. NT and antibiotic-associated diarrhoea. 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Current Opinion in Bit.ly/ NTGITract1 releasing the stool pellets into the large Pediatrics; 14: 15, 583–587. Part 2: The stomach Jul intestine, in the hope that the healthy Gerhardt S, Mohajeri MH (2018) Changes of Bit.ly/NTGITract2 colonic bacterial composition in Parkinson’s donor bacteria will begin to colonise the Part 3: The duodenum, liver and pancreas Aug disease and other neurodegenerative diseases. more hospitable environment of the colon. Nutrients; 10:6, E708. Bit.ly/NTGITract3 Direct faecal transplants have also been Kalia LV, Lang AE (2015) Parkinson’s disease. Part 4: The jejunum and ileum Sep used where donor faecal material is Lancet; 386: 9996, 896–912. Bit.ly/NTGITract4 implanted in the recipient, usually via Kang D-W et al (2019) Long-term benefit of Part 5: The large intestine Oct microbiota transfer therapy on autism symptoms Bit.ly/NTGITract5 endoscopic procedures. Although the and gut microbiota. Scientific Reports; 9, 5821. Part 6: Gut microbes Nov effectiveness of these techniques still needs Lazar V et al (2018) Aspects of gut microbiota

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