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While we all know how our moods can affect gastrointestinal activity, recent evidence shows that changes in the gastrointestinal activity can also affect brain function. The high co-morbidity between gastrointestinal diseases, such as irritable bowel syndrome (IBS), and psychological symptoms such as anxiety and depression has lead many researchers to focus on the pathogenic role of stress. This emerging concept – the gut-brain axis – also involves the bacteria in our gut; for the most part, interactions between commensal microbiota and its host (our gut) are beneficial. Studying the microbes in the gut and how their modification can influence the CNS could aid advancement of new therapeutic strategies for complex CNS disorders.

In mammals, commensal microbiota colonise the gut in early postnatal life and thus remain throughout life. Their presence is crucial for processing nutrients, immunological functioning, and also brain development and function; they communicate with the CNS bi-directionally to influence the brain using neural, immune and endocrine pathways; and seems that the gut-brain axis is hard-wired during early life and adolescence.

How can the gut microbiota change the brain’s wiring to affect behaviour?

The use of germ-free animals has facilitated the evaluation of the role of the microbiota on many aspects of gastrointestinal physiology. Germ-free mice are born without, and protected from commensal microbiota, and show a number of effects distinct from normal mice. By observing what happens when the microbiota are removed, researchers can investigate the role of normal gut flora. Initially germ-free mice demonstrate heightened levels of stress hormones, suggesting that alterations in gut microbiota during early development can influence the wiring of the stress axis (1).

Research published last week indicates that stress-induced changes can lead to intestinal dysbiosis, a key determinant of the aberrant behaviour that characterises early-life stress (2). Clinically this is interesting because psychological problems are common in adolescents, and these could be linked to early life events, as well as diet and microbiota early in life.

Although germ-free mice have a longer lifespan and appear to thrive, when they are exposed to stress they show exaggerated responses compared with normal mice. Furthermore, behavioural traits of donor mice can be transferred into adult germ-free mice of a different strain via the gut microbiota, although little is known about how these microbes could impact brain plasticity and behavioural responses.

IBS & depression are often experienced together

Irritable bowel syndrome (IBS) is characterised by abdominal pain and change in bowel habit and is the most common functional gastrointestinal (GI) disorder, accounting for up to 50% of visits to general practitioners for GI complaints (3).  Mood disorders are common across a diverse array of GI disorders. The gut-brain axis is not limited to gastrointestinal and neurological function, the gut microbiota also interact with the immune system, contributing to its development. Sensors in the gut respond to many mediators including cytokines and inflammatory mediators, produced by gut microbes; the gut microbiota also have a strong influence on the diversified production of protective immunoglobulins by B cells (4). Inflammation is a feature of depression, and gastrointestinal dysregulation may exacerbate neuroinflammation leading to dysfunction in brain regions that are associated with mood regulation.

Evidence suggesting a microbial link between IBS and CNS disorders

  • IBS patients with clinically significant depression and anxiety were correlated with a particular microbial composition ratio (5)
  • IBS patients and healthy controls with higher anxiety scores were associated with lower faecal microbial diversity (6)
  • Evidence has implicated microbial diversity in other neurological disorders, such as autism where significant differences in bacterial phyla were observed (7)

Because of the close interaction between diet and immune system, probiotics (the “good” bacteria that help keep the digestive system healthy by controlling growth of harmful bacteria) and prebiotics (non-digestible fibre substrates for probiotics)

may have roles in personalised diets and disease prevention. Consequently there is considerable commercial interest in the gut microbiota as demonstrated by the expanding probiotics markets. This field shows great promise for treatment based on an individual’s microbiome and it may be possible to stratify patients for the best treatment. Some prebiotics and probiotics have shown significant benefits in the preclinical and clinical settings:

  • Probiotics may prevent the development of brain activity changes in mice in after exposure to chronic stress (8)
  • Probiotic strains may have anxiolytic potential after deleterious infection of the GI tract in mice (9)
  • IBS patients with clinically significant anxiety who received daily treatment with a (galactooligosaccharide) prebiotic for 4 weeks showed reduced anxiety scores and this had a significant positive impact on quality of life (10)

There has been growing interest in the therapeutic potential of faecal microbiota transplantation (11) This has largely stemmed from the demonstrated efficacy of donor faecal infusions in the treatment of recurrent C. Difficile. In the future it may be possible to screen for therapeutic intestinal bacteria and already stool banks like OpenBiome (12) have emerged to provide screened, filtered, and frozen material ready for clinical use in the treatment of C. difficile.

With an eye to future research in the clinical setting, a potential tool for linking mood and food is neuroimaging: it can be performed in vivo, giving a good spatial and temporal profile of changes in the brain. Using neuroimaging in humans, Tillisch et al showed that consumption of fermented milk product with probiotic affected activity of brain regions that control central processing of emotion and sensation (12). These data suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders, although well-designed controlled human trials are needed to further evaluate these ideas.

Using this bidirectionality, an interesting mechanistic line of investigation is that of the behavioural therapies such as cognitive behavioural therapy, relaxation therapy or hypnotherapy. These therapies could potentially modify the gut microbiome via efferent vagal and/or hypothalamic–pituitary–adrenal axis function. Therefore, demonstrable differences in gut microbiota have important implications regarding the development of a disease-specific biomarker(s) as well as treatment and, hopefully, prevention. More studies considering the role microbiota in clinical populations with anxiety disorders, mood disorders, and comorbid psychiatric symptoms are needed.

 

If you would like to comment on any of the issues raised by this article, particularly from your own experience or insight, Healthcare-Arena would welcome your views.

References

  1. Collins J, Borojevic R, Verdu EF, Huizinga JD, Ratcliffe EM. Intestinal microbiota influence the early postnatal development of the enteric nervous system. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society. 2014;26(1):98-107. Epub 2013/12/18.
  2. De Palma G, Blennerhassett P, Lu J, Deng Y, Park AJ, Green W, et al. Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nature communications. 2015;6:7735. Epub 2015/07/29.
  3. Wilson A, Longstreth GF, Knight K, Wong J, Wade S, Chiou CF, et al. Quality of life in managed care patients with irritable bowel syndrome. Managed care interface. 2004;17(2):24-8, 34. Epub 2004/03/25.
  4. Hapfelmeier S, Lawson MA, Slack E, Kirundi JK, Stoel M, Heikenwalder M, et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science. 2010;328(5986):1705-9. Epub 2010/06/26.
  5. Candela M, Biagi E, Maccaferri S, Turroni S, Brigidi P. Intestinal microbiota is a plastic factor responding to environmental changes. Trends in microbiology. 2012;20(8):385-91. Epub 2012/06/08.
  6. Quigley EM. Small intestinal bacterial overgrowth: what it is and what it is not. Current opinion in gastroenterology. 2014;30(2):141-6. Epub 2014/01/11.
  7. De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PloS one. 2013;8(10):e76993. Epub 2013/10/17.
  8. Ait-Belgnaoui A, Colom A, Braniste V, Ramalho L, Marrot A, Cartier C, et al. Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society. 2014;26(4):510-20. Epub 2014/01/01.
  9. Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society. 2011;23(12):1132-9. Epub 2011/10/13.
  10. Silk DB, Davis A, Vulevic J, Tzortzis G, Gibson GR. Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome. Alimentary pharmacology & therapeutics. 2009;29(5):508-18. Epub 2008/12/05.
  11. Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M. Therapeutic potential of fecal microbiota transplantation. Gastroenterology. 2013;145(5):946-53. Epub 2013/09/11.
  12. Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013;144(7):1394-401, 401 e1-4. Epub 2013/03/12.

 

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Microbiome data now being gathered may form the basis for a ‘personalised’ approach to improving individual microbial populations

Image: ©Pixelbliss/Shutterstock #280702511

In May 2015, a molecular microbiology study was published in the Proceedings of the National Academy of Sciences (1). This study showed that gut bacteria could be DNA ‘fingerprinted,’ as their DNA sequences were shown to represent a unique form of identification in more than 80% of individuals examined (1). This study has little to do with ‘CSI’-style forensic identification but does have implications for our health, diet, development and genetics and our ability to defend ourselves from true microbial pathogens (1).

That the human body is believed to contain ten times more microbial cells than human cells (trillions of them) can be an uncomfortable thought. Even more remarkable is that, in terms of numbers, the population of these microbes accounts for up to 90% of the total number of cells associated with our bodies. Our human microbial population weighs between 1% and 3% of our total body mass (1.5 kg); this is equivalent to the weight of the largest human internal organ, the liver (2).

The terminology of the body’s flora and fauna can be confusing. This could be why someone, probably working in advertising, came up with the phrase ‘friendly bacteria.’ The term ‘microbiota’ is the collective noun that refers to the viruses, fungi and bacteria that inhabit our bodies, mainly in our gut and on the surface of our skin. The microbiota has a commensal and a symbiotic relationship with us. The term, ‘microbiome’ is used to refer to the collection of the genomes of these microbes. These two names, ‘microbiota’ and ‘microbiome,’ are often used interchangeably.

Our view of our personal microbial health has changed during the past 20 years. Until the 1990’s there was the ‘germicidal view’ that all bacteria were harmful and that we should be doing all we could to sterilise our home environment, ourselves and our food. There are now increasing numbers of scientific and healthcare news stories, as well as television commercials, which advise us to encourage and nurture our own, resident, and very personal ‘friendly bacteria.’

As with the dietary anti-oxidant ‘industry’ that arose from cardiovascular research in the 1980’s, the food industry has been swift to promote the sales of dietary probiotic supplements. Global sales of probiotics have been reported as £13.6 billion ($21.6 billion USD) in 2010 and are expected to exceed £19.6 billion ($31.1 billion USD) during 2015 (3).

In February 2015, an editorial collaboration between the journals, Nature and Scientific American, resulted in the publication of a series of special reports entitled, Innovations in the Microbiome(4) These and other recent publications have helped to place the importance of the normal human microbial population further into the medical spotlight.

For almost a century, epidemiological studies have shown that diet has a profound effect on human health. Recently, the link has been made between diet and the gut microbiota, with emphasis on the effects that a ‘western’ diet of refined foods and high protein have on these organisms. In 2011, a study linked long-term dietary patterns to changing gut bacterial enterotypes in humans (5). In 2014, a study in wild mice clearly demonstrated that dietary change can induce gut bacterial ‘enterotype switches’ within hosts (6). ‘Biome reconstitution’ has been proposed as a treatment approach to immune disorders, including allergy and autoimmune disease and to preventing colonic cancer, obesity, diabetes, and metabolic disease (7, 8).

In the past ten years, sequencing technologies have allowed the development of a detailed reference database of the diverse microbes that inhabit our bodies. In 2007, in the US, the National Institutes of Health (NIH) Human Microbiome Project (HMP) Consortium was launched, consisting of more than 200 members, from nearly 80 universities and scientific institutions (9). In its 2012 report, the HMP listed the major ways in which knowledge of the human microbiome may change the future of science and medicine (10). The HMP has considered the potential privacy issues surrounding knowledge of the individual microbiome, the flow between human microbes and those found in nature (in water and soil) (10).

The microbiome data now being gathered may form the basis for a ‘personalised’ approach to improving individual microbial populations. Most importantly, solutions to microbial antibiotic resistance may be found through increasing knowledge of microbial interactions. At this same time comes the realisation that overuse of antibiotics, as part of our ‘war on germs’ mentality, has allowed true microbial pathogens to develop antibiotic resistance. The lack of a functioning and complete personal microbial population leaves us vulnerable to bacterial pathogens that we may be increasingly less able to fight.

In 2013, the Chief Medical Officer for England highlighted the increasing problem of antibiotic resistance. These concerns led to the Department of Health launching a five-year Antimicrobial Resistance (AMR) Strategy, which is supported by NHS England’s Antibiotic Awareness Campaign (11,12). In October 2014, Public Health England produced the first report on the English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) (13). These latest initiatives by the medical profession and healthcare regulators to reduce antibiotic prescribing is just one approach that has to be made.

The European Molecular Biology Laboratory (EMBL) annual conference, held in Heidelberg in June 2015, was devoted to the topic of the Human Microbiome (14). This meeting included discussions on the design of possible therapeutic or dietary interventions to prevent and treat disease. An announcement was made at the meeting of the first results from the Personalised Nutrition Project, run by research groups in Israel (15). The u-Biome Project is a crowdfunded ‘citizen science’ initiative that is set to analyse the microbiome in the context of individual health and is currently recruiting participants (16).

The rationale for learning more about the ‘normal’ or ‘optimal’ microbiome, and how to reconstitute or nurture it, is an important component of individual healthcare (17, 18). For the future development of interventions for resistant microbial pathogens, the human microbiota may play more than just a ‘friendly’ role, it may be life-saving.

If you would like to comment on any of the issues raised by this article, particularly from your own experience or insight, Healthcare-Arena would welcome your views.

References

(1) Franzosa EA, Huang K, Meadow JF, Gevers D, Lemon KP, Bohannan BJ, Huttenhower C. Identifying personal microbiomes using metagenomic codes. Proc Natl Acad Sci U S A. 2015;pii 201423854. http://www.pnas.org/content/early/2015/05/08/1423854112 Accessed June 10, 2015

(2) The Human Microbiome Project. Structure, function and diversity of the healthy human microbiome. Nature 2011;486:207-14. http://www.nature.com/nature/journal/v486/n7402/full/nature11234.html Accessed June 10, 2015

(3) Business Communications Company (BCC) market research data for sales of probiotic foods and supplements, 2010 and 2015. http://www.bccresearch.com/pressroom/fod/global-market-for-probiotics-reach-$36.7-billion-2018 Accessed June 10, 2015

(4) Special Report. Innovations in the Microbioma. Scientific American Vol 312, Feb 2015. http://www.scientificamerican.com/editorial/innovations-in-the-microbiome/ Accessed June 10, 2015

(5) Wu GD, Chen J, Hoffmann C, et al. Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes. Science 2011;334(6052):105-108. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368382/ Accessed June 10, 2015

(6) Wang J, Linnenbrink M, Kunzel S, et al. Dietary history contributes to enterotype-like clustering and functional metagenomic content in the intestinal microbiome of wild mice. Proc Natl Acad Sci USA 2014; 111:E2703-E2710. http://www.pnas.org/content/111/26/E2703.full Accessed June 10, 2015

(7) Parker W, Ollerton J. Evolutionary biology and anthropology suggest biome reconstitution as a necessary approach toward dealing with immune disorders. Evolution, Medicine, and Public Health 2013;2013(1):89-103. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868394/ Accessed June 10, 2015

(8) Grice EA, Segre JA. The Human Microbiome: Our Second Genome. Annual Review of Genomics and Human Genetics 2012;13:151-170. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518434/ Accessed June 10, 2015

(9) The National Instututes of Health (NIH) Human Microbiome Project website http://commonfund.nih.gov/hmp/index Accessed June 10, 2015

(10) National Institutes for Health (NIH). Human Microbiome Project defines normal bacterial makeup of the body. Genome sequencing creates first reference data for microbes living with healthy adults. June 13th 2012. http://www.nih.gov/news/health/jun2012/nhgri-13.htm Accessed June 10, 2015

(11) The Department of Health Antimicrobial Resistance (AMR) Strategy 2013 to 2018. First published September 10, 2013. https://www.gov.uk/government/publications/uk-5-year-antimicrobial-resistance-strategy-2013-to-2018 Accessed June 10, 2015

(12) NHS Antibiotic Awareness Campaign. Last revised 24th Sept 2014. http://www.nhs.uk/NHSEngland/ARC/Pages/AboutARC.aspx Accessed June 10, 2015

(13) Public Health England. English Surveillance Programme Antimicrobial Utilisation and Resistance (ESPAUR) Report. Published Oct 10, 2014. https://www.gov.uk/government/publications/english-surveillance-programme-antimicrobial-utilisation-and-resistance-espaur-report Accessed June 10, 2015

(14) European Molecular Biology Laboratory (EMBL) website. http://www.embl.de/aboutus/general_information/index.html Accessed June 10, 2015

(15) The Personalised Nutrition Project website. http://newsite.personalnutrition.org/WebSite/Home.aspx Accessed June 10, 2015

(16) u-Biome – Sequencing Your Microbiome website. https://www.indiegogo.com/projects/ubiome-sequencing-your-microbiome#/story Accessed June 10, 2015

(17) Grogan D. Microbes in the Gut Are Essential to Our Well-Being. Scientific American. Feb 17, 2015. http://www.scientificamerican.com/article/microbes-in-the-gut-are-essential-to-our-well-being/ Accessed June 10, 2015

(18) Parums D. ‘Indigenous’ Human Microbes – the Microbiota and the Microbiome. Thomson Reuters Life Sciences Connect. May 26, 2015. http://lsconnect.thomsonreuters.com/indigenous-human-microbes-the-microbiota-and-the-microbiome/ Accessed July 6, 2015

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