Human Gut Microbiome - 10 Considerations
Published: 22 November 2016
Published: 22 November 2016
With the advent and application of next-generation gene sequencing, the microbiome has been recognised as integral to a number of physiological functions including endocrine, neurology and acquisition of nutrition, and immunity.
The state of a healthy biome is a function of diversity and compositional balance. Dynamic alterations to the microbiome have been attributed to a number of factors such as diet, environmental toxins and medication such as antibiotics. A state of dysbiosis is the abnormal microbial colonisation of the intestine where changes in quantity and quality of flora become pathological and harmful. Dysbiosis has been attributed to significant impacts on health and multiple chronic disease states. There are many implications to understanding this relatively new area of research and the potential for future treatment approaches and options.
As a nurse, you would have undoubtedly come across spectacular claims and speculation about how the human gut microbiome is interrelated to aspects of our health, wellbeing and disease states. Words of wisdom and snippets of discoveries have most likely filtered your way in the form of faecal microbiota transplantation (FMT), probiotic use and rethinking the use of broad-spectrum antibiotics, to allegations that C-sections result in increased rates of autism.
This article is a starting point in defining the human microbiome (MB); identifying what is known, and what continues to be further studied for clinical significance and potential application for human health and disease.
The human microbiome (MB) is a diverse and complex microbial community that resides in our gastrointestinal tracts and has been coined a forgotten target metabolic 'organ' (Blasser 2014). It is estimated that throughout our gastrointestinal tract we harbour 100 trillion microbes, representing 500 different species that outnumber human cells by 10:1. The microbiome is composed of archaea (strict anaerobes) and bacteria (aerobes and anaerobes); viruses; and fungi. It is considered to be one of the most complex ecological systems on the planet(Hollister et al. 2014).
The largest proportion of the MB resides in the colon. Traditionally, investigative studies of the MB have been limited due to culture-based methods that proved difficult to culture the majority of anaerobically-living commensal gut microbiome (Alien 2015). The capacity to investigate the MB's role in disease and health has come to the limelight through the development of culture-independent approaches and has been made possible through advances in gene sequencing technology (Evans et al. 2013). This technology gave rise to the 2002 human genome project, and birth to metagenomics. Now, extension to the human metagenome has led investigators to the necessary tools to study the DNA microbiome human gastrointestinal tract.
MB research is in its infancy and large metagenome projects (such as the National Institute of Health's Human Microbiome Project (HMP)) are identifying the 'who and what' of the MB (Blasser 2014). This research has lead to the significant development of 'the second genome': one inherited from our parents and the other acquired, i.e. the MB. Because of the dynamic nature of the MB, the question is not whether the MB has a role in health and disease, but rather, for current research to provide insight into how the MB contributes, promotes, and sustains a healthy MB (Evans et al. 2013).
A healthy MB is defined by high diversity and an ability to resist change under physiological stress (Lloyd-Price et al. 2016). The far-reach understanding of the MB as integral to health and disease comes from an appreciation of the multiple metabolic and physiological functions that have been attributed to the MB. These include:
(Calafiore et al 2012)
In contrast, MB associated with disease is defined by lower species diversity, fewer beneficial microbes and the presence of pathogenic microbes. Disease states are known to influence the MB and/or be the result of dysbiosis. Dysbiosis is an imbalance (compositional or diversity changes) in the intestinal bacteria that precipitates changes in the normal activities of the gastrointestinal tract (D’Argenio & Salvatore 2015). A state of dysbiosis that changes the quantity and quality of flora results in a pathological and harmful MB.
Dynamic alterations to the microbiome have been attributed to a number of factors such as diet, environmental toxins and medications such as antibiotics. This state of imbalance has been implicated in a number of gastrointestinal diseases such as inflammatory bowel disease, irritable bowel disease and colorectal cancer. Additionally, a complex relationship between diet, microbes and the gut epithelium has implications in systemic diseases such as obesity, diabetes, atherosclerosis and non-alcoholic fatty liver disease (Chan et al. 2013).
MB is a complex and dynamic internal ecosystem. Various ecological principles provide a new appreciation to a dynamic interplay between health and diseases (Rook 2013). For example, symbiosis is the relationship between two or more organisms that live closely together as commensal, mutualistic or independent. In the MB, pathogenic and commensal bacteria coexist and have certain functions (Blasser, 2011). Commensals can be opportunists, and an opportunist in one host can be a primary pathogen in another host. Successful microbes of both classes must find ways to coexist symbiotically to ultimately evolve. Pathogenic MB does not necessarily become pathogenic unless the internal environment does not sustain symbiosis as in the case of c-difficile infections resulting in colitis.
The location and niche of commensal colonisation can result in opportunistic pathogens when the microbe crosses anatomical and biochemical barriers in the host that serve to limit colonisation by commensals. For example, E. coli that cause diarrhoea and urinary tract infections do not occupy the same niche as the commensal strains of E. coli in the colon (Institute of Medicine (US) 2006). The greater application of ecological principles to the MB supports a paradigm shift in understanding germs as greater than 'the bad guys that make us sick' (Blasser 2014). Rather, the state of dysbiosis results in an imbalance between protective and harmful bacteria (Chan et al. 2013).
There are a number of factors that form and contribute to a healthy biome. The state of a biome is not static and the behaviour of a biome has a degree of resilience to external (for example, dietary or pharmaceutical) or internal (for example, age).
Acquisition of the gut microbiome (MB) is thought to have some inoculation in utero, with greater inoculation occurring through the mother’s birth canal. Vaginal deliveries of neonates have the microbiomes of their mother’s vaginal tract and this has been identified as a bonus to the foundation of colonisation. Neonates delivered by C-section have a microbiome consisting largely of typical skin microbiota. Interestingly, mother-child MB transfer has been associated with immunity and health. When C-section neonates were compared to birth canal neonates, the C-section neonates had a greater correlation with childhood diagnoses of allergic rhinitis, asthma, coeliac disease and type 1 diabetes (Murgas &Neu 2011).
Immunological benefits of colostrum are well-known and have been attributed to the probiotic properties ('seeds') of the gut MB (Azad et al. 2013). Development of the MB continues until the age of 2 to 3. Gut MB resembles 40 to 60% of that of an adult distal gut microbiota; stable and colonised predominately with 2 phyla, firmicutes and Bacteroidetes (Koenig et al. 2011), which comprise 90% of the species found. The MB continues to develop during adolescence and then stabilises between the 3rd and 7th decade. With further ageing, the MB becomes less diverse, with reduced stability (Zhang et al. 2014).
Changes in diversity of taxa (microbiome) are related to both biome exposure and diets that are higher in fibre content, similar to that of early human settlement at the time of the birth of agriculture. Comparative studies of biome of African children and western European children have shown marked differences in diversity of taxa (Filippo et al. 2010). Similarly, immigration from developing countries to a high income urban centre leads to a loss of exposure to MB biodiversity. In such immigrant populations there are larger increases in autoimmunity, inflammatory bowel disease, depression and allergic disorders. These epidemiological studies lead to speculation that a lack of microbial species richness and phylogenetic diversity is attributable to multiple factors such as excessively sterile environments, diets low in plant fibre, and repeated exposure to antibiotics (Rook 2013).
At a relatively extreme example of internal ecological collapse, researchers have used an ecological framework to aid in explaining how prolonged stays in ICU lead to sepsis. During critical illness, the normal gut microbiota becomes disrupted in response to host physiologic stress and antibiotic treatment. Researchers compared the MB of healthy volunteers to patients with greater than four week stays in ICU. The ICU patients had the emergence of ultra-low taxa (1-4), compared to healthy volunteers (40 taxa), and they had increased multi-drug resistant pathogenic bacteria communities. Their hypothesis was that the gut MB of the patients experiencing prolonged stays was very abnormal (low in diversity and greater ratios of certain taxa of flora) and had a greater susceptibility to sepsis (Zaborin et al. 2014).
The stability of a symbiotic ecosystem is dependent on the complex interplay between diet, MB and the gut epithelium (Chan et al. 2013). Beyond energy harvesting, the MB has a primary function of maintaining the integrity of the intestinal membrane (IM). When this membrane integrity is compromised, a condition coined 'leaky gut' (hyper-permeable tight junctions) (Arrieta et al. 2006) results, and is associated with chronic intestinal symptoms of gas, bloating, diarrhoea and constipation. This condition has also been linked to systemic conditions such as metabolic and cardiac disorders (Kennedy et al, 2002).
The IM is comprised of protein and a cytoskeletal structure with intracellular tight junctions and is in a constant state of remodelling. The IM is essential for absorptive functions without compromising barrier exclusion, whilst regulating intestinal permeability (Blasser 2014). MB contributes to the integrity of the IM through the metabolism of dietary plant-derived polysaccharides to short-chain fatty acids (SCFA) such as pyruvate and acetate.
Humans lack the enzymes to degrade the bulk of dietary fibres, and anaerobic cercal and colonic microbiota provide the fermentation of fibre necessary for SCFA production. These SCFA provide multiple IM sustainability functions including nutrients for colonic epithelial cells, and have been shown to have anti-inflammatory, anti-tumorigenic and antimicrobial effects, and regulate apoptosis and proliferation of the mucosa (Wallace et al. 2011).
Furthermore, when diets are predominately deficient of fibre and high in fat or sugar, there is a notable difference in the ratio of two bacterial phyla of firmicutes to the gram-negative Bacteroides. Firmicutes are beneficial to the IM through their role of metabolising dietary plant-derived polysaccharides to SCFAs. The presence of an imbalance of Bacteroides and firmicutes results in the increase of gram-negative cell-derived endotoxins called lipopolysaccharides (LPS) (De Filippo et al. 2010).
Both the low yield SCFA and the passive diffusion of LPS across the hyper-permeable tight junctions contribute to metabolic toxaemia. Metabolic toxaemia is linked to a two-to-threefold increase in LPS serum concentration. LPS are incorporated into chylomicrons fractions and pro-inflammatory cytokines. The increases in LPS have been positively associated with obesity and type 2 diabetes (Neves, et al, 2013).
a. With increasing revelations of the casual implications of the MB (and disease and health), treatment approaches are changing and treatment practices are being trialled. Already, there has been the experimental application of faecal microbiome transplants occurring in intensive care centres (Kelly et al. 2015). Faecal microbiota transplant (FMT) is the process of transplanting faecal bacteria from a healthy individual into a recipient. For patients who have experienced prolonged ICU stays, clostridium difficile infection (CDI) is prominent, secondary to antibiotic-depleted flora. Experimental studies are limited. However, there is good evidence that FMT has efficacy as a treatment option. In one randomised trial for the treatment of c-difficile with FMT from healthy donors, FMT was significantly more effective than vancomycin alone (Bakken et al. 2011). In the United States, human faeces as an experimental medicine has been regulated by the Food and Drug Administration(FDA) since 2013.
b. The implications of excessive use of multiple doses of broad-spectrum antibiotics highlights that our MB does not fully recover and is replaced by long-term resistant organisms (Blasser 2011). In many western countries, the principal purpose for antibiotics in animal populations is non-therapeutic, and is instead used to 'feed up' livestock.
Blasser highlights that there is excessive use of antibiotics. In the USA, 40% of all adults and 70% of all children take one or more courses of antibiotics every year, accumulating with the excess of antibiotics used in livestock. Speculation is that global antibiotic resistance (Laxminarayan et al, 2013) - an unintended consequence of antibiotic overuse - is fuelling increases in conditions such as obesity and allergies, which are more than doubled in many populations (Blasser 2011).
“There is a rise in obesity, coeliac disease, asthma, allergy syndromes, and Type 1 diabetes. Bad eating habits are not sufficient to explain the worldwide explosion in obesity’’ (Blasser 2011).
c. From a nutritional perspective, being able to manipulate diet to promote a healthy MB is still in its early days. MB is enhanced by prebiotics and probiotics. Prebiotics are defined as non-living, non-digestible fibre or carbohydrates, and probiotics are live, active microorganisms that when administered in an adequate amount will have beneficial effects to their host (Wallace et al. 2011). There has been much speculation as to the benefits of probiotic supplements as a means of improving the health of the biome. Although the current research on probiotics as therapy is promising, there is no regulation of probiotic supplements. Conclusive recommendations for the administration of probiotic supplements is difficult to provide and somewhat tainted by a fivefold increase in sales over the past ten years (Granato et al. 2010).
Probiotic recommendations have not been endorsed by professional bodies such as the World Gastroenterology Organisation. In reference to inflammatory bowel disease, this is partly due to conflicting data and a lack of sufficiently rigorous studies on Crohn’s disease to yield evidence to support or reject probiotic use for this condition (Calafiore et al. 2012). Additional placebo-controlled double-blind studies in CD and UC, active and inactive, taking into account other medical therapy, are required before recommendations can be offered on routine use of probiotics in IBD (Knight-Sepulveda et al. 2015).
a. Hype or hope? Currently, the science provides proof of concepts and the establishment of correlations and associations. For example, what is known is that the gut microbiota play a casual role in metabolic disease. Most of this evidence is currently based on epidemiological associations and rodent studies. For confidence in recommendations, causality between disease and the gut MB needs to be established. This confidence will transpire through well designed, high-powered perspective studies looking at changes before and after disease states, leading to interventional studies and randomised clinical trials (Allin et al. 2015).
b. An understanding of how ecological principles translate to the internal ecosystem provides a comprehensive insight into the role and function of the MB. The imbalance between protective and harmful bacteria has been implicated in many human conditions, including local gastrointestinal and systemic diseases. This understanding has provided support in a paradigm shift away from 'germs' as bad.
c. Dietary patterns alter the MB ecologically and functionally, resulting in physiological consequences for the host. This understanding then shifts from a medical/nutritional understanding of foods as greater than macronutrients (fat, carbohydrates and protein) to looking at the nutritional properties that aid in sustaining the integrity of the IM and decreasing systemic inflammation. Additionally, there is a greater appreciation for the role of the MB in the role of energy harvesting. Different efficiencies in the MB support a view away from looking at weight balance as 'kilojoules in equals kilojoules out' (Kallus & Brandt 2011).
d. To aid patients' understanding about sustaining a healthy biome, Spector (2015) uses the metaphor 'How does a garden grow?'. There is a need for soil, fertiliser (prebiotics) and seeds (probiotics). Foods known to be high in prebiotic dietary fibre are artichoke, zucchini, asparagus, beetroot, fennel, savoy cabbage, snow peas and green peas, lentils, chickpeas and fruits such as watermelon, grapefruit, peaches, nectarines, pomegranates, dates and figs. Probiotics are contained in foods such as yogurt, aged cheese, and fermented cabbage (Spector 2015).
e. From a dietary perspective, the nourishment of a healthy biome is the combination of prebiotic plant fibres that fertilise and nourish the probiotic bacteria. Basic recommendations are to:
f. Regarding probiotic supplements: when researchers in the area of MB were asked if they take supplementation of probiotics, the majority stated that they instead focus on food choices high in probiotics (Blasser 2011).
g. The widespread use of antibiotics in the past 80 years has been seminal in reducing worldwide mortality rates associated with infectious diseases and control of bacterial pathogens, and has undoubtedly improved our standard of living. However, the unintended consequence of rising antimicrobial resistance in conjunction with the decreased rate of newly discovered antibiotics has drawn worldwide attention to curbing the unnecessary use of antibiotics. Most public awareness campaigns draw patients' (and providers') attention to this issue of non-discriminative utilisation of antibiotics contributing to antibiotic resistance. It is also a good opportunity to aid patients' understanding of the short and long-term health consequences of how non-discriminative use of antibiotics can lead to the short-term depletion in MB (flora), and may also have longer-term consequences.
It is anticipated that in this current era of discovering the MB, new treatment approaches will aid in sustaining a healthy biome. This may include developing and using more microbiome-sparing antimicrobial therapy, developing techniques to maintain and restore indigenous microbiota (for example, supplement with prebiotics and/or probiotics), introducing a new healthy microbial ecosystem by transplanting faecal bacteria from a healthy donor, and discovering and exploiting host protective mechanisms normally afforded by an intact microbiome (Tosh & McDonald 2011).