Continued from Part One – Human Gut Microbiome: 10 Considerations
- What factors create and sustain a healthy biome?
- What are changes to current and/or future practice?
- What is relevant to my patients?
- Future treatment options?
7. What Factors Create and Sustain a Healthy Microbiome?
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) changes.
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 and foundation. C-section delivered neonates have a microbiome consisting largely of typical skin microbiotia. Interestingly, the implication of 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 40-60% of that of an adult distal gut microbiota, stable and colonised predominately with 2 phla, firmacutes 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’s MB of these patients experiencing prolonged stays are very abnormal (low in diversity and greater ratios of certain taxa of flora) and have a greater susceptibility to sepsis (Zaborin et al. 2014).
c. Sustainability and Resilience: Diet, MB and the Gut Epithelium
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 necessary 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 byruvate 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/sugar, there is a notable difference in the ratio of two bacterial phala of firmacutes 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 bacteriodes and firmacutes result 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).
8. What are the Changes to Current and/or Future Practice?
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 experimental application of faecal microbiome transplants occurring in intensive care centres (Kelly et al. 2015). Faecal microbiota transplant (FMT), is the process of transplantation of 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 excess use of multiple doses of broad spectrum antibiotics highlights that our MB do not fully recover and are 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 given 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 with the addition of global antibiotic resistance (Laxminarayan et al, 2013), an unintended consequence of antibiotic over use, is the fuelling of increases in conditions – 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’’ Martin Blasser (2011).
c. From a nutritional perspective, how 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 referred to as live, active microorganisms that when administered in adequate amount will have beneficial effects to its 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 a 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 Organization. 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).
9. What is Relevant to My Patients?
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 there is a causal role of the gut microbiota 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. In addition, there is a greater appreciation to the role of the MB in the role of energy harvesting. Different efficiencies in the MB supports a view away from looking at weight balance as ‘kilojoules in equals kilojoules out’ (Kallus & Brandt 2011).
d. To aid patient’s understanding in 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:
- Eat at least two servings of fresh whole fruit and five servings of vegetables a day
- Include more legumes such as chickpeas, lentils and beans in a diet
- Choose minimal processed whole grains, such as oats, barley , quinona, brown rice dense grains and sourdough bread
- Include probiotics in diet such as yogurts that list the name of bacteria added and tell how much bacteria is in the yogurt
- Include prebiotics such as onions, leek, asparagus , garlic , beans and legumes – supplemental fibre psyllium
- Limit highly processed foods and convenience snack foods, as these foods promote the growth of harmful bacteria
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 the rising antimicrobial resistance in conjunction with the decreased rate of newly discovered antibiotics, has drawn world-wide attention to curb the unintended use of antibiotics. Most public awareness campaigns draw patient’s (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), but may also have longer-term consequences.
10 Future Treatment Options
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).
- http://humanfoodproject.com/ diversity
- Allin, KH, Nielsen, T & Pedersen, O 2015, ‘Mechanisms in endocrinology: Gut microbiota in patients with type 2 diabetes mellitus’, European Journal of Endocrinology, vol. 172, no. 4, pp. 167-77.
- Arrieta, MC, Bistritz, L & Meddings, JB 2006, ‘Alterations in intestinal permeability’, Gut, vol. 55, no. 10, pp. 1512-20.
- Azad, MB, Konya, T, Maughan, H, Guttman, DS, Field, CJ, Chari, RS, Sears, MR, Becker, AB, Scott, JA & Kozyrskyj, AL 2013, ‘Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months’, Canadian Medical Association Journal, vol. 185, no. 5, pp. 385-94.
- Bakken, J S, Borody, T, Brandt, LJ, Brill, JV, Demarco, DC, Franzos, MA, Kelly, C, Khoruts, A, Louie, T, Martinelli, LP, Moor, TA, Russell, G & Surawicz, C 2011, ‘Treating Clostridium difficile infection with fecal microbiota transplantation’, Clinical Gastroenterology and Hepatology, vol. 9, no. 12, pp. 1044-9.
- Blaser, M 2011, ‘Antibiotic overuse: stop the killing of beneficial bacteria’, Nature, vol. 476, no. 7361, pp. 393-4.
- Calafiore, A, Gionchetti, P, Calabrese, C, Tambasco, R, Spuri-Fornarini, G, Liguori, G, Riso, D, Campieri, M & Rizzello, F 2012, ‘Probiotics, prebiotics and antibiotics in the treatment of inflammatory bowel disease’, Journal of Gastroenterology and Hepatology Research, vol. 1, no. 6.
- Chan, YK, Estaki, M & Gibson, DL 2013, ‘Clinical consequences of diet-induced dysbiosis’, Annals of Nutrition and Metabolism, vol. 63, no. 2, pp. 28-40.
- D’Argenio, V & Salvatore, F 2015, ‘The role of the gut microbiome in the healthy adult status’, Clinica Chimica Acta, vol. 451, pp. 97-102.
- De Filippo, C, Cavalieri, D, Di Paola, M, Ramazzotti, M, Poullet, J, Massart, S, Collini, S, Pieraccini, G & Lionetti, P 2010, ‘Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and Rural Africa’, Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 33, pp. 14691–6.
- Evans, JM, Morris, LS & Marchesi, JR 2013, ‘The gut microbiome: the role of a virtual organ in the endocrinology of the host’, Journal of Endocrinology, vol. 218, no. 3, pp. 37-47.
- Filippo, C, Cavalieri, D, Di Paola, M, Ramazzotti, M, Poullet, JB, Massart, S, Collini, S, Pieraccini, G & Lionetti, P 2010, ‘Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa’, Proceedings of the National Academy of Sciences, vol. 107, no. 33, pp. 14691-96.
- Granato, D, Branco, GF, Nazzaro, F, Cruz, AG & Faria, JA 2010, ‘Functional foods and nondairy probiotic food development: trends, concepts, and products’, Comprehensive Reviews in Food Science and Food Safety, vol. 9, no. 3, pp. 292-302.
- Hollister, EB, Gao, C & Versalovic, J 2014, ‘Compositional and functional features of the gastrointestinal microbiome and their effects on human health’, Gastroenterology, vol. 146, no. 6, pp. 1449-58.
- Institute of Medicine (US) Forum on Microbial Threats 2006, ‘The Ecology of Pathogenesis’, in Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship: Workshop Summary, National Academies Press (US), Washington, DC, viewed 21 November 2016, https://www.ncbi.nlm.nih.gov/books/NBK57068/
- Kallus, SJ & Brandt, LJ 2011, ‘The intestinal microbiota and obesity’, Journal of Clinical Gastroenterology, vol. 46, pp. 16 –24.
- Kelly, CR, Kahn, S, Kashyap, P, Laine, L, Rubin D, Atreja, A, Moore, T & Wu, G 2015, ‘Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms, and outlook’, Gastroenterology, vol. 149, no. 1, pp. 223-237.
- Kennedy, RJ, Kirk, SJ & Gardiner, KR 2002, ‘Mucosal barrier function and the commensal flora’, Gut, vol. 50, no. 3, pp. 441-2.
- Koenig, JE, Spor, A, Scalfone, N, Fricker, AD, Stombaugh, J, Knight, R, Angenent, LT, & Ley, RE 2011, ‘Succession of microbial consortia in the developing infant gut microbiome’, Proceedings of the National Academy of Sciences, vol. 108, no. 1, pp. 4578-85.
- Knight-Sepulveda, K, Kais, S, Santaolalla, R, & Abreu, MT 2015, ‘Diet and Inflammatory Bowel Disease’, Gastroenterology & Hepatology, vol. 11, no. 8, p. 511.
- Lloyd-Price, J, Abu-Ali, G & Huttenhower, C 2016, ‘The healthy human microbiome’, Genome Medicine, no. 8, vol. 1, p. 1.
- Laxminarayan, R, Duse, A, Wattal, C, Zaidi, AK, Wertheim, HF, Sumpradit, N, Vlieghe, E, Hara, GL, Gould, IM, Goossens, H, Greko, C, So, AD, Bigdeli, M, Tomson, G, Woodhouse, W, Ombaka, E, Peralta, AQ, Qamar, FN, Mir, F, Kariuki, S, Bhutta, ZA, Coates, A, Bergstrom, R, Wright, GD, Brown, ED & Cars, O 2013, ‘Antibiotic resistance—the need for global solutions’, The Lancet Infectious Diseases, vol. 13, no. 12, pp. 1057-98.
- Murgas Torrazza, R & Neu, J 2011, ‘The developing intestinal microbiome and its relationship to health and disease in the neonate’, Journal of Perinatology, vol. 31.
- Neves, AL, Coelho, J, Couto, L, Leite-Moreira, A & Roncon-Albuquerque, R 2013, ‘Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk’, Journal of Molecular Endocrinology, vol. 51, no. 2, pp. 51-64.
- Rook, GA 2013, ‘Regulation of the immune system by biodiversity from the natural environment: an ecosystem service essential to health’, Proceedings of the National Academy of Sciences, vol. 110, no. 46, pp. 18360-7.
- Spector, T 2015, ‘The Diet Myth: The Real Science Behind What We Eat’, Hachette, UK.
- Tosh, PK & McDonald, LC 2011, ‘Infection control in the multidrug-resistant era: tending the human microbiome’, Clinical Infectious Diseases, vol. 54, no. 5, pp. 707-13.
- Wallace, TC, Guarner, F, Madsen, K, Cabana, MD, Gibson, G, Hentges, E & Sanders, ME 2011, ‘Human gut microbiota and its relationship to health and disease’, Nutrition Reviews, vol. 69, no. 7, pp. 392-403.
- Zaborin, A, Smith, D, Garfield, K, Quensen, J, Shakhsheer, B, Kade, M, Tirrell, M, Tiedje, J, Gilbert, JA, Zaborina, O & Alverdy, JC 2014, ‘Membership and behavior of ultra-low-diversity pathogen communities present in the gut of humans during prolonged critical illness’, MBio, vol. 5, no. 5, pp. 1361-14.
- Zhang, H, Liao, X, Sparks, JB & Luo, XM 2014, ‘Dynamics of Gut Microbiota in Autoimmune Lupus’, Applied and Environmental Microbiology, vol. 80, no. 24, pp. 7551-60.