Posted on by Rosanna

What has the gut microbiome got to do with health and disease?

Brace yourself. This is a long one.

I’ve broken into down into six (hopefully helpful) sections so don’t feel you have to tackle it all at once. But you might want to get yourself a cup of (green!) tea before you start…

How the Gut Microbiome Makes Us Healthy

So, you should by now have a basic understanding of what your gut is and what the term “microbiome” refers to. (If not, please go back and have a look at my earlier posts:  Gut Reaction: What is your gut? and What is a microbiome?)

But here comes the exciting stuff…

Now, the first thing I have to qualify here is that research on this subject is moving at such a pace that whatever I write in this blog may become inaccurate, or certainly better understood, over time. Whilst I will do my best to keep things updated, please bear in mind when this was written, and when the studies or review papers I have referred to have been published, when you read it.

Going back to my good old friend, Tim Spector, Professor of Genetic Epidemiology and author of “The Diet Myth” (see my section in About Us), he observed that:

…microbes generally get a bad press, but less than a tiny fraction of the millions of species are harmful to us and most, in fact are crucial to our health.1

It is now generally accepted by the scientific community that many of these microbes have evolved together with us humans over thousands, maybe millions, of years for the benefit of our mutual survival.1-4 Whilst we provide them with a great place to live, they provide us with the means of staying healthy and keeping that “micro accommodation” in good nick.

We are continually learning more and more about the various useful functions these microbes may perform. To name but a few:

  • They have been implicated in the normal development of the brain, gut and immune system from birth5
  • They are thought to be involved in influencing calorie intake and absorption; regulating certain aspects of metabolism; and also in the laying down of fat in different parts of the body for energy storage (particularly helpful when food is scarce)6-9
  • They have been shown to produce several vitamins including vitamins which humans are otherwise incapable of producing5 such as vitamin B12,10,11 folate (vitamin B9),12 vitamin K, riboflavin (vitamin B2), biotin (vitamin B7), nicotinic acid (vitamin B3), panthotenic acid (vitamin B5), pyridoxine (vitamin B6) and thiamine (vitamin B1)13
  • They help to reinforce gut protective mechanisms to stop other microbes from getting access to the rest of our body2,14,15
  • They compete with pathogenic microbes, like the well-known “demon” Clostridium difficile (or C diff), for food and space and, in some circumstances, appear to produce antimicrobial substances to deter or get rid of these invaders; it is thought that they even have ways to encourage their human host to do this for them 16-19
  • They have been shown to influence the production and control of inflammatory mediators both within the gut and at other sites, such as the joints, or even as far afield as the eye 2,14,15
  • They have been shown to communicate both with the gut’s own immune system (remember that fancy term, the enteric nervous system? If not, go back & remind yourself at Gut Reaction: What is your gut?) and also the body’s immune system at large (aka the systemic immune system)2,14,15
  • They may be involved in the regulation of the nervous system and its functions20

Animal Studies and the Microbiome

However, it must be emphasised that not all of these observations have been made in humans – much of the research done has been in animal models. Some of us, me included, may have ethical issues with animal studies, and their value is always limited because ultimately, these animals are not human, and they are not living in the real world.

However, there are occasions where it is hard to see how knowledge could be furthered without them. Their crucial role in the world of microbiome research has been, in particular, in the development and assessment of “germ-free” animals (usually mice). These animals are bred and kept in a completely sterile environment to eliminate microbial colonisation. They can then be assessed in a variety of situations without the effect of their microbiomes, and can have particular microbes introduced to assess the effects of these, and then compare them to others.

One example of a study that used animals to obtain crucial information, where it is hard to see how this would otherwise have been done, is quoted in a review of Faecal Microbiota Transplantation (an emerging therapy that is based purely on the understanding of the need for a “healthy gut microbiome” – taking poo from healthy, unaffected people and putting it into the guts of people with a variety of problems, most successfully in those with Clostridium difficile infections that are resistant to standard antibiotic treatments – yes, really!! Admittedly it sounds disgusting but it truly is revolutionary.).1

This study used “germ-free” mice to prove that the presence of certain key members of the gut microbiome were essential for a particular melanoma (skin cancer) treatment to work.2 The scientists were able to re-colonise the guts of the “germ-free” mice with particular strains of bacteria to assess their different influences on the efficacy of the melanoma treatment.

When they had identified which species seemed to be required for the drug to work, they then analysed the poo of affected humans undergoing treatment to see which types of bacteria were in their gut microbiomes. These were divided into groups depending on the most prominent species and samples were transplanted into “germ-free” mice again to see if the same effect could be replicated in terms of impact on effectiveness of the drug (which it did).

This is obviously very important for patients with this type of skin cancer who may benefit from this type of treatment. There is still more work to be done but as it is not really possible to create “germ-free” humans for testing, it is sometimes an unfortunate, but essential, piece in the puzzle.

There have also been human-only studies in this field of research but, to date, they have been rather limited. Epidemiological studies are studies in which Professor Spector specialises. They are usually population-based, observational studies, looking for both patterns in health and disease, and also for risk factors for and protective factors against disease. However, in order to understand the biological mechanisms behind these, we rely on more laboratory-based techniques and interventional studies.

Methods for detecting and analysing the gut flora have been very slow and laborious in the past but, just as our understanding of genetics and the human genome have developed rapidly over the past few decades, so it may be that new laboratory techniques will help to accelerate the research efforts into these tiny creatures who inhabit our bowels and (probably) exert their influence over us.3

Anyway, I am totally digressing… this is why I find these posts take so long to write! Other than trying to fit them in between school pick-ups and drop-offs, toddler groups, meal times, homework, housework, and the builder currently, every time I start out on a topic, I find it takes me in a dozen different directions at once, and I feel like I want to explain them all to you… so I try, and sometimes get rather tangled up in knots. Please remember, whilst I try to be vaguely systematic, I am a clinician rather than academic medic… and mum of three delightful, but at times highly demanding, children.

So, back to the gut microbiome.

What is Gut Dysbiosis? And the Cause or Effect Question.

When this microscopic ecosystem is balanced and working in harmony with its human host, this is sometimes called eubiosis.1 When things get out of kilter, and the system starts to have a negative impact on its human, this is usually called dysbiosis.2,3

It has been shown that microbial dysbiosis in the gut is associated with many different types of disease, such as allergy,4 autoimmunity,2 metabolic dysfunction (including obesity)3,5-9, neurological disease,10 mental health issues10 and cancer;11,12 and in many different parts of the body ranging from the gut itself2,13 to distant locations like the joints2,9 or the brain.10

However, it is not always clear whether the dysbiosis is the cause or the effect of a disease and there is a lot of work being done currently to try to determine this across all of these specialities. When scientists talk about proving causation, they often refer to the Bradford Hill criteria14,15 which involve nine different aspects of the relationship between the two associated factors concerned (strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy).

It is generally accepted that these should be addressed before labelling a factor as causative rather than simply found in association, although there is an argument for accepting fewer criteria in the current technological era where so much more can be understood about underlying mechanisms than was ever dreamt possible when the criteria were first proposed.14

If it helps, here is an example from medical school which helped me to understand a bit more about associations and causal relationships. We were told that it had been proven that smoking causes cancer but if someone did a study and noticed that people who had cancer also drank a lot of coffee, you can’t simply say “coffee must also cause cancer!” (despite what some newspapers might have you believe…!).

You can say there is an association or a link, but you have to do more to find out the nature of that association. Could it be that cancer makes you want to drink more coffee? In that case, cancer would be the cause and drinking coffee, actually the effect. Or could it be that people who drink more coffee also tend to smoke? If the latter were true, coffee drinking would be considered a confounding factor – it is linked to the actual causative factor but it is not a cause itself. This is obviously not a real study but I’m hoping my analogy makes sense to someone!

In summary, it is not clear if gut microbial dysbiosis is causing all of the diseases it is associated with, but the hypotheses are generally plausible, with a lot of work being done on the underlying biological mechanisms, and as the supporting evidence from many wide-ranging fields of study mounts, they are becoming increasingly convincing.

The Gut Microbiome and Cancer

In terms of cancer, we are only in the very early stages of understanding any links between its development and the gut microbiome. An American website called CancerQuest gives a good overview of the relationship between the human microbiome as a whole (i.e. not just limited to the gut) and various specific cancers here.  Like Helen and I, the Director of CancerQuest says that they are dedicated to educating people with reliable, current and comprehensible information, on their part specifically to do with the biology and treatment of cancer, so it’s definitely worth taking a look.

As with many of the other diseases mentioned, research is very much ongoing and to date the clearest links we have are probably in relation to cancers within the gut, for example colorectal cancer. There are a number of recent scientific reviews which explore models of carcinogenesis (the development of cancer), the likely microbial suspects and the associated molecules and pathways they may use to influence tumour development.2-5 They also investigate ways in which manipulating the microbiome through diet, or probiotics and prebiotics (a topic for another day!), show promise in some specific cases.

There are two good, publically available scientific articles, “The microbiome and cancer”6 from Nature Reviews Cancer and “Microbiota as a mediator of cancer progression and therapy”7 from Translational Research, which have reviewed research on the gut microbiome and cancer in general, which are worth reading if you want a bit more detail (from 2013 and 2017 respectively; see References below). However, some of the science, particularly to do with the immune system, is full of receptors and mediators with names that sound like what your computer password should be, i.e. a list of randomly generated letters and numbers, such as Nlrp6 and Myd88, so that even people like me who are familiar with scientific articles to a certain extent, find them a little hard to digest.

The latter of these two articles is the most recent, published in January of this year (2017), and has some good little diagrams for representing the complex relationships between our gut microbiomes and various other factors involved in the development of cancers and in their treatment (if I could copy and paste them here I would but it doesn’t look like they are publicly available images so for now just follow this link: microbiota and carcinogenesis and see Figure 1 in particular). What they highlight, and what is emphasised when you read any other relevant studies or reviews, is that the processes involved are so very complicated and multifaceted. There are so many variations in tumour types, patients’ genetics, environmental exposures, and microbial ecosystems, that it makes it very difficult to generalise either in terms of understanding how and why these cancers develop, or how to treat them.

It is because we and our microbiomes are all so different, that we all need personally tailored health-promotion and treatment advice ideally. However, until we are each able to accurately sequence our own personal genomes and microbiomes, and to understand their complex, interacting functional implications, we may have to muddle through with generalisations, with a bit of partially-informed decision-making, and some good old-fashioned common sense.

However, another reason it may be important to learn more about our microbiomes in terms of cancer is that these microscopic tenants may not only be involved in the disease process, and provide possible future therapeutic options, but they may also have an impact on current treatments, as I touched upon when illustrating the use of animal studies in research, above.  As I outlined in my list of the gut microbes’ potentially useful functions at the beginning of this post, we know that the microbiome interacts with the body’s immune system, and there is evidence for microbes being influential in both inducing and moderating inflammation. There are two good examples on the CancerQuest website of relatively recent studies looking at the way this may have an impact in chemotherapy (“The Microbiome and Cancer Treatment”), but again note that they are both using animal models.1

Amidst all of the uncertainty and tentative conclusions, “Microbiota as a mediator of cancer progression and therapy”7, one of the review articles I mentioned above, summed up the current situation in the most encouraging way – their authors stated that our microbiota “unify numerous processes including nutrition, metabolism and immunity, which represent key biological activities for carcinogenesis.” They said that “it is clear that the microbiota-cancer [hypothesis] is not a flash in the pan but rather a transformative new field of research that will likely impact the way cancer is detected, treated and managed in the future.” As this subject is obviously the cornerstone of this blog, I promise I will come back to visit it in more detail later.

Why do we get Gut Dysbiosis?

So if microbial dysbiosis causes disease, what causes the microbial dysbiosis?

Well, the theory goes that modern, particularly Western, lifestyles have a lot to do with it. This is thought to be due to a vast array of different, complex and interacting reasons including higher rates of Caesarean section deliveries rather than vaginal births,1,2 a lower incidence of breastfeeding,2 widespread antibiotic use (both in humans and in the human food chain),1,2 low-fibre diets with high levels of processed foods,2 and the extreme hygiene practices1,2 that we all aspire to now (is your kitchen like an operating theatre…?!). It may be that we don’t even have enough parasitic infections these days!2

And of course your own genetic make-up plays a key role. So no two people will “attract” the same micro-organisms (one microbe’s meat is another microbe’s poison…) or will have the same reactions to the different environmental factors which might affect them (unless you have an identical twin, but even then, subtle differences in each twin’s environmental exposures may have an impact on the way that their genes work and the diversity of their microbiomes… but that’s another very complicated story!).

There is evidence to support each of the above possible environmental factors being influential, to a greater or lesser extent, in this theoretical dysbiosis epidemic, and we’ll try to explore some of these issues along the way. However, the area we are mainly planning to focus on is diet.

Back to the Blog…

It has been said that…

The diet represents one of the most important factors that determine gut microbiota composition1

…but that is not the only reason that we are concentrating on it.

It is particularly because as a patient, who can otherwise feel quite disempowered by the fact that a disease has taken over your body whilst some strangers in the hospital are going to tell you what to do about it (with a long list of “dos” and “don’ts”!), diet is something that Helen, or anyone, can have some degree of autonomy and control over.

In addition, as her friend, by helping to research the evidence, and to try to make some sort of sense of it in a practical way, it gives me something to do to actively to support her.

So, good therapy all around we thought!

As long as neither of us gets unhealthily obsessed or dogmatic about it of course…

And also as long as we continue to complement, rather than counteract, her conventional NHS therapy.

Surely, if we can achieve that, it’s a win-win situation.
So where on earth do we begin?!

 

Glossary and Useful Links (also see Useful Resources page)

Microbiome: a collection of micro-organisms living together in one place (see What is a microbiome? page and microbes below); also known as microbiota (see below)

Microbes: micro-organisms, “germs”, living things which are too small to see with the naked eye (see What is a microbiome? page) including bacteria, yeasts and viruses

Immune system: the body’s defense system

Metabolism: chemical reactions in a living organism which result in the generation, use (for vital processes) and storage of energy; often related to the breaking down of food for energy; see medicinenet definition

Pathogenic microbes: microbes (see above) which cause harm through infection

Clostridium difficile (or C diff): a pathogenic bacteria (type of microbe) responsible for diarrhoea, often associated with antibiotic use. It may live harmlessly in the gut of many people but when it gets out of control, often after a course of antibiotics which are thought to kill off all of the other “good bacteria” keeping it in check, it can make people very poorly and can sometimes be fatal. The elderly and people whose immune systems are compromised in some way are most at risk of getting it. It can be difficult to treat and has a tendency to recur. Here is a useful patient information leaflet explaining a bit more. However, this was last updated in 2015 and, even since then, more evidence has emerged to support the use of probiotics and Faecal Microbiota Transplant in some cases (see below). As always, there is more research to be done.

Antimicrobial: something that hinders or eradicates microbes

Inflammatory mediators: inflammation is a word we often use colloquially to mean swelling in the body somewhere, usually in response to some sort of injury, e.g. a swollen or inflamed knee after twisting it in football; but when we use it medically, we usually mean a much more complex response to injury which typically involves what we find on examination externally, which the textbooks will tell you includes: redness (rubor), heat, (calor), swelling (tumor – nothing to with cancer in this context) and pain (dolor); and also other unseen, internal responses, which are usually co-ordinated by our body’s immune system (see Systemic Immune System below) which include the relevant blood vessels getting larger to bring more blood to the area of injury along with cells and substances involved in repair and protection from further injury. It is these cells and substances that I would put into my category of inflammatory mediators – they are basically part of the immune system’s arsenal for defense, protection and repair. Of note, inflammation doesn’t always involve visible swelling and there is not always an obvious “injury” – we are talking about something that the cells in the body have detected as being potentially harmful, e.g. When a pathogenic microbe (see above) gets access to part of the body where it may be able to cause infection or, when “normal” levels of substances in the body are out of balance, e.g. such as high fat levels in the blood (hyperlipidaemia), not just a knock or a scrape when you fall over.

Enteric Immune System: part of the body’s defense system located in the gut which communicates with, and helps to co-ordinate, other parts of the systemic immune system

Systemic Immune System (aka the immune system): as above – the body’s defense system as a whole

Microbial colonisation: where the microorganisms set up home and get settled

Faecal Microbiota Transplant (FMT): also known as a stool transplant; a treatment which involves the transfer of healthy bacteria from a donor into the intestines (guts) of a patient (recipient) via a processed mixture of liquid poo. See here for a useful patient information leaflet specifically about treatment in patients with Clostridium difficile infection (see above).

Epidemiological studies: perhaps a more accurate definition than my own comes from the American Centers for Disease Control and Prevention (CDC) self-study course on epidemiology. It states that: Epidemiology is the study (scientific, systematic, data-driven) of the distribution (frequency, pattern) and determinants (causes, risk factors) of health-related states and events (not just diseases) in specified populations (patient is community, individuals viewed collectively), and the application of (since epidemiology is a discipline within public health) this study to the control of health problems. For more detailed information see here.

Clinician: a doctor who works with patients, diagnosing and managing their problems (or trying to!)

Academic medic: a doctor who actively works in the world of research, usually associated with a university or other research organisation

Eubiosis: the microbiome living in harmony, promoting good health for its human host

Dysbiosis: the microbiome in disarray (an “unhealthy imbalance”) unable to adequately fulfil its role of promoting good health for its human host and probably promoting disease

Hypotheses: theories, or as defined by the Cambridge English dictionary online: ideas or explanations for something that are based on known facts but has not yet been proved

Carcinogenesis: the development of cancer; carcinogenic: leads to the development of cancer

Microbiota: a collection of micro-organisms living together in one place (see microbiome)

Probiotics: according to Wikipedia, The World Health Organization‘s (WHO) 2001 definition of probiotics is “live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host”. However, this is apparently controversial in that it is not acceptable to the European Food Safety Authority because it embeds a health claim which is not measurable. See:  https://en.wikipedia.org/wiki/Probiotic . Also see my post on The Gut Microbiome, Probiotics and Prebiotics… when I have written it!

Prebiotics: these are food ingredients that induce the growth or activity of beneficial microorganisms, again according to Wikipedia, taken from the following article:  Hutkins RW; Krumbeck JA; Bindels LB; Cani PD; Fahey G Jr.; Goh YJ; Hamaker B; Martens EC; Mills DA; Rastal RA; Vaughan E; Sanders ME (2016). “Prebiotics: why definitions matter”. Current Opinions in Biotechnology. 37: 1-7. PMC 4744122 PMID 26431716. doi:10.1016/j.copbio.2015.09.001. Again, see my upcoming post on The Gut Microbiome, Probiotics and Prebiotics.

Immunity:  the body’s defense mechanisms against infection and disease (see also Systemic Immune System above)

References

How the Gut Microbiome Makes Us Healthy

  1. Talking about the discovery of microbes and their relevance today, Chapter 1: Not on the Label: Microbes, p15 In: The Diet Myth – The Real Science Behind What We Eat by Tim Spector, Professor of Genetic Epidemiology at King’s College London and author; see http://www.tim-spector.co.uk/
  2. Thursby E, Juge N. “Introduction to the human gut microbiota.” Biochemical Journal. 2017 May 16;474(11):1823-1836. doi: 10.1042/BCJ20160510. Review. PMID: 28512250 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433529/ (Free on Pubmed)
  3. Backhed F. (2005) “Host-bacterial mutualism in the human intestine.” Science307, 1915–1920 doi:10.1126/science.1104816 In: Thursby E, Juge N. “Introduction to the human gut microbiota.” Biochemical Journal. 2017 May 16;474(11):1823-1836. doi: 10.1042/BCJ20160510. Review. PMID: 28512250 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433529/ (Free on Pubmed)
  4. Neish A.S. (2009) Microbes in gastrointestinal health and disease. Gastroenterology136, 65–80 doi:10.1053/j.gastro.2008.10.080 (Free on Pubmed) In: Thursby E, Juge N. “Introduction to the human gut microbiota.” Biochemical Journal. 2017 May 16;474(11):1823-1836. doi: 10.1042/BCJ20160510. Review. PMID: 28512250 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433529/ (Free on Pubmed)
  5. Description of experiments with sterile or “germ-free” mice, Chapter 1: Not on the Label: Microbes, p17 In: The Diet Myth – The Real Science Behind What We Eat by Tim Spector, Professor of Genetic Epidemiology at King’s College London and author; see http://www.tim-spector.co.uk/
  6. Duranti, Ferrario C.,  van Sinderen D., Ventura M. & Turron F.” Obesity and microbiota: an example of an intricate relationship.” Genes & Nutrition. 2017; 12: 18. Published online 2017 Jun 15. doi:  10.1186/s12263-017-0566-2 PMCID: PMC5473000 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473000/ (Free on Pubmed)
  7. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. “The gut microbiota as an environmental factor that regulates fat storage.” Proceedings of the National Academy of Sciences of the USA.2004;101(44):15718–15723. doi: 10.1073/pnas.0407076101. (Free on Pubmed) In: Duranti, Ferrario C.,  van Sinderen D., Ventura M. &  Turron F.” Obesity and microbiota: an example of an intricate relationship.” Genes & Nutrition. 2017; 12: 18. Published online 2017 Jun 15. doi:  10.1186/s12263-017-0566-2 PMCID: PMC5473000 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473000/ (Free on Pubmed)
  8. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. “An obesity-associated gut microbiome with increased capacity for energy harvest.” 2006;444(7122):1027–1031. doi: 10.1038/nature05414. In: Duranti S., Ferrario C.,  van Sinderen D., Ventura M. &  Turron F.” Obesity and microbiota: an example of an intricate relationship.” Genes & Nutrition. 2017; 12: 18. Published online 2017 Jun 15. doi:  10.1186/s12263-017-0566-2 PMCID: PMC5473000 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473000/ (Free on Pubmed)
  9. Arslan N. “Obesity, fatty liver disease and intestinal microbiota.” World Journal of Gastroenterology. 2014 Nov 28;20(44):16452-63. doi: 10.3748/wjg.v20.i44.16452. Review. PMID: 25469013 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248188/ (Free on Pubmed)
  10. LeBlanc J.G., Milani C., de Giori G.S., Sesma F., van Sinderen D. and Ventura M. (2013) “Bacteria as vitamin suppliers to their host: a gut microbiota perspective.” Current Opinion in Biotechnology.24, 160–168 doi:10.1016/j.copbio.2012.08.005 In: Thursby E, Juge N. “Introduction to the human gut microbiota.” Biochemical Journal. 2017 May 16;474(11):1823-1836. doi: 10.1042/BCJ20160510. Review. PMID: 28512250 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433529/ (Free Pubmed Article)
  11. Martens J.H., Barg H., Warren M. and Jahn D. (2002) “Microbial production of vitamin B-12.” Applied Microbiology and Biotechnology.58, 275–285 doi:10.1007/s00253-001-0902-7 In: Thursby E, Juge N. “Introduction to the human gut microbiota.” Biochemical Journal. 2017 May 16;474(11):1823-1836. doi: 10.1042/BCJ20160510. Review. PMID: 28512250 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433529/ (Free Pubmed Article)
  12. Pompei A., Cordisco L., Amaretti A., Zanoni S., Matteuzzi D. and Rossi M. (2007) “Folate production by bifidobacteria as a potential probiotic property.” Applied Microbiology and Biotechnology.73, 179–185 doi:10.1128/AEM.01763-06 In: Thursby E, Juge N. “Introduction to the human gut microbiota.” Biochemical Journal. 2017 May 16;474(11):1823-1836. doi: 10.1042/BCJ20160510. Review. PMID: 28512250 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433529/ (Free Pubmed Article)
  13. Hill M.J. (1997) “Intestinal flora and endogenous vitamin synthesis.” European Journal of Cancer Prevention.6, S43–S45 doi:10.1097/00008469-199703001-00009 In: Thursby E, Juge N. “Introduction to the human gut microbiota.” Biochemical Journal. 2017 May 16;474(11):1823-1836. doi: 10.1042/BCJ20160510. Review. PMID: 28512250 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433529/ (Free Pubmed Article) (Free Pubmed Article)
  14. Morrison D.J. and Preston T. (2016) “Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism.” Gut Microbes7, 189–200 doi:10.1080/19490976.2015.1134082 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939913/  (Free Pubmed Article)
  15. Shi N, Li N, Duan X, Niu H. “Interaction between the gut microbiome and mucosal immune system.” Military Medical Research. 2017 Apr 27;4:14. doi: 10.1186/s40779-017-0122-9. eCollection 2017. Review. PMID: 28465831 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408367/ (Free Pubmed article)
  16. Bäumler A.J. and Sperandio V. (2016) “Interactions between the microbiota and pathogenic bacteria in the gut.” Nature535, 85–93 doi:10.1038/nature18849 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114849/ (free Pubmed article] In: Thursby E, Juge N. “Introduction to the human gut microbiota.” Biochemical Journal. 2017 May 16;474(11):1823-1836. doi: 10.1042/BCJ20160510. Review. PMID: 28512250 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433529/ (Free on Pubmed)
  17. Carlucci C, Petrof EO, Allen-Vercoe E. “Fecal Microbiota-based Therapeutics for Recurrent Clostridium difficile Infection, Ulcerative Colitis and Obesity.” EBioMedicine. 2016 Nov;13:37-45. doi: 10.1016/j.ebiom.2016.09.029. Epub 2016 Oct 1. Review. PMID: 27720396 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264253/ (Free Pubmed Article)
  18. Chanyi RM, Craven L, Harvey B, Reid G, Silverman MJ, Burton JP. “Faecal microbiota transplantation: Where did it start? What have studies taught us? Where is it going?” SAGE Open Medicine. 2017 May 11;5:2050312117708712. doi: 10.1177/2050312117708712. eCollection 2017. Review. PMID: 28540051 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431603/ (Free Pubmed Article)
  19. Sukumar Kandasamy, Anastasia N. Vlasova, David D. Fischer, Kuldeep S. Chattha, Lulu Shao, Anand Kumar, Stephanie N. Langel, Abdul Rauf, Huang-Chi Huang, Gireesh Rajashekara, Linda J. Saif “Unraveling the Differences between Gram-Positive and Gram-Negative Probiotics in Modulating Protective Immunity to Enteric Infections” Frontiers in Immunology. 2017; 8: 334. Published online 2017 Mar 27. doi: 10.3389/fimmu.2017.00334 PMCID: PMC5366325 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366325/ (free article available on Pubmed)
  20. Zhu X, Han Y, Du J, Liu R, Jin K, Yi W. “Microbiota-gut-brain axisand the central nervous system.”Oncotarget. 2017 May 10. doi: 10.18632/oncotarget.17754. [Epub ahead of print] Review. PMID: 28548940 https://www.ncbi.nlm.nih.gov/pubmed/28548940 (Free Article available via Pubmed)

Animal Studies and the Microbiome

  1. Chanyi RM, Craven L, Harvey B, Reid G, Silverman MJ, Burton JP. “Faecal microbiota transplantation: Where did it start? What have studies taught us? Where is it going?” SAGE Open Medicine. 2017 May 11;5:2050312117708712. doi: 10.1177/2050312117708712. eCollection 2017. Review. PMID: 28540051 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431603/ (free article via PubMed)
  2. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Bérard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L. “Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.” Science.2015 Nov 27;350(6264):1079-84. doi: 10.1126/science.aad1329. Epub 2015 Nov 5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721659/ (Free Pubmed Article) In: Chanyi RM, Craven L, Harvey B, Reid G, Silverman MJ, Burton JP. “Faecal microbiota transplantation: Where did it start? What have studies taught us? Where is it going?” SAGE Open Medicine. 2017 May 11;5:2050312117708712. doi: 10.1177/2050312117708712. eCollection 2017. Review. PMID: 28540051 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431603/ (Free Pubmed Article)
  3. Lee PY,Chin SF, Neoh HM, Jamal R. “Metaproteomic analysis of human gut microbiota: where are we heading?” Journal of Biomedical Science. 2017 Jun 12;24(1):36. doi: 10.1186/s12929-017-0342-z. https://www.ncbi.nlm.nih.gov/pubmed/28606141 (free full text available on BioMed Central and Pubmed)

What is Gut Dysbiosis? And the Cause or Effect Question.

  1. Iebba V, Totino V, Gagliardi A, Santangelo F, Cacciotti F, Trancassini M, Mancini C, Cicerone C, Corazziari E, Pantanella F, Schippa S.“Eubiosisand dysbiosis: the two sides of the microbiota.” New Microbiologica. 2016 Jan;39(1):1-12. Review. PMID: 26922981 http://www.newmicrobiologica.org/PUB/allegati_pdf/2016/1/1.pdf (free article via Pubmed)
  2. Shi N, Li N, Duan X, Niu H. “Interaction between the gut microbiome and mucosal immune system.” Military Medical Research. 2017 Apr 27;4:14. doi: 10.1186/s40779-017-0122-9. eCollection 2017. Review. PMID: 28465831 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408367/ (Free Pubmed article)
  3. Carlucci C, Petrof EO, Allen-Vercoe E. “Fecal Microbiota-based Therapeutics for Recurrent Clostridium difficile Infection, Ulcerative Colitis and Obesity.” EBioMedicine. 2016 Nov;13:37-45. doi: 10.1016/j.ebiom.2016.09.029. Epub 2016 Oct 1. Review. PMID: 27720396 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264253/ (Free Pubmed Article)
  4. Stiemsma LTand Turvey SE “Asthma and the microbiome: defining the critical window in early life.” Allergy Asthma and Clinical Immunology. 2017; 13: 3. Published online 2017 Jan 6. doi:  1186/s13223-016-0173-6 PMCID: PMC5217603 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217603/
  5. Duranti, Ferrario C.,  van Sinderen D., Ventura M. & Turron F.” Obesity and microbiota: an example of an intricate relationship.” Genes & Nutrition. 2017; 12: 18. Published online 2017 Jun 15. doi:  10.1186/s12263-017-0566-2 PMCID: PMC5473000 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473000/ (Free on Pubmed)
  6. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. “The gut microbiota as an environmental factor that regulates fat storage.” Proceedings of the National Academy of Sciences of the USA.2004;101(44):15718–15723. doi: 10.1073/pnas.0407076101. (Free on Pubmed) In: Duranti, Ferrario C.,  van Sinderen D., Ventura M. &  Turron F.” Obesity and microbiota: an example of an intricate relationship.” Genes & Nutrition. 2017; 12: 18. Published online 2017 Jun 15. doi:  10.1186/s12263-017-0566-2 PMCID: PMC5473000 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473000/ (Free on Pubmed)
  7. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. “An obesity-associated gut microbiome with increased capacity for energy harvest.” 2006;444(7122):1027–1031. doi: 10.1038/nature05414. In: Duranti S., Ferrario C.,  van Sinderen D., Ventura M. &  Turron F.” Obesity and microbiota: an example of an intricate relationship.” Genes & Nutrition. 2017; 12: 18. Published online 2017 Jun 15. doi:  10.1186/s12263-017-0566-2 PMCID: PMC5473000 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473000/ (Free on Pubmed)
  8. Arslan N. “Obesity, fatty liver disease and intestinal microbiota.” World Journal of Gastroenterology. 2014 Nov 28;20(44):16452-63. doi: 10.3748/wjg.v20.i44.16452. Review. PMID: 25469013 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248188/ (Free on Pubmed)
  9. Morrison D.J. and Preston T. (2016) “Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism.” Gut Microbes7, 189–200 doi:10.1080/19490976.2015.1134082 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939913/  (Free Pubmed Article)
  10. Zhu X, Han Y, Du J, Liu R, Jin K, Yi W. “Microbiota-gut-brain axisand the central nervous system.”Oncotarget. 2017 May 10. doi: 10.18632/oncotarget.17754. [Epub ahead of print] Review. PMID: 28548940 https://www.ncbi.nlm.nih.gov/pubmed/28548940 (Free Article available via Pubmed)
  11. Gagnière J, Raisch J, Veziant J, Barnich N, Bonnet R, Buc E, Bringer MA, Pezet D, and Bonnet“Gut microbiota imbalance and colorectal cancer.” World Journal of Gastroenterology. 2016 Jan 14; 22(2): 501–518. Published online 2016 Jan 14. doi:  10.3748/wjg.v22.i2.501 PMCID: PMC4716055 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716055/ (free article via Pubmed)
  12. Gao R, Gao Z, Huang L, and Qin “Gut microbiota and colorectal cancer” European Journal of Clinical Microbiology & Infectious Diseases. 2017; 36(5): 757–769. Published online 2017 Jan 7. doi:  10.1007/s10096-016-2881-8 PMCID: PMC5395603 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395603/ (free article via Pubmed)
  13. Thursby E, Juge N. “Introduction to the human gut microbiota.” Biochemical Journal. 2017 May 16;474(11):1823-1836. doi: 10.1042/BCJ20160510. Review. PMID: 28512250 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433529/ (Free on Pubmed)
  14. Fedak KM, Bernal A, Zachary A. Capshaw, and Gross S “Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology.” Emerging Themes in Epidemiol 2015; 12: 14. Published online 2015 Sep 30. doi:  10.1186/s12982-015-0037-4 PMCID: PMC4589117 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589117/
  15. Wikipedia: https://en.wikipedia.org/wiki/Bradford_Hill_criteria

The Gut Microbiome and Cancer

  1. Microbiome and Cancer: https://www.cancerquest.org/cancer-biology/microbiome?gclid=CjwKEAjwppPKBRCGwrSpqK7Y5jcSJACHYbWY32C4KJY9zWIadThmrYqqT6Rm9bCzvC_FgWO8RCRQYhoCmYrw_wcB
  2. Gagnière J, Raisch J, Veziant J, Barnich N, Bonnet R, Buc E, Bringer MA, Pezet D, and Bonnet“ “Gut microbiota imbalance and colorectal cancer.” World Journal of Gastroenterology. 2016 Jan 14; 22(2): 501–518. Published online 2016 Jan 14. doi:  10.3748/wjg.v22.i2.501 PMCID: PMC4716055 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716055/ (free article via Pubmed)
  3. Gao R, Gao Z, Huang L, and Qin “Gut microbiota and colorectal cancer” European Journal of Clinical Microbiology & Infectious Diseases. 2017; 36(5): 757–769. Published online 2017 Jan 7. doi:  10.1007/s10096-016-2881-8 PMCID: PMC5395603 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395603/ (free article via Pubmed)
  4. Inés Mármol,Cristina Sánchez-de-Diego,Alberto Pradilla Dieste, Elena Cerrada, and María Jesús Rodriguez Yoldi“Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer” Intermational Journal of Molecular Sci 2017 Jan; 18(1): 197. Published online 2017 Jan 19. doi:  10.3390/ijms18010197 PMCID: PMC5297828 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297828/ (free article via PubMed)
  5. Tomasello G, Tralongo P, Damiani P,  Sinagra E, Di Trapani B,  Zeenny MN, Hajj Hussein I,  Jurjus A, and Leone A “Dismicrobism in inflammatory bowel disease and colorectal cancer: Changes in response of colocytes” World Journal of Gastroenterology. 2014 Dec 28; 20(48): 18121–18130. Published online 2014 Dec 28. doi:  3748/wjg.v20.i48.18121 PMCID: PMC4277951 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277951/ (free article via PubMed)
  6. Robert F. Schwabeand Christian Jobin “The microbiome and cancer” Nature Reviews Cancer. Author manuscript; available in PMC 2014 Apr 14.Published in final edited form as: Nature Reviews Cancer. 2013 Nov; 13(11): 800–812. Published online 2013 Oct 17. doi:  1038/nrc3610 PMCID: PMC3986062 NIHMSID: NIHMS564722 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986062/ (free full article via PubMed)
  7. Pope, JL, Tomkovich, S,  Yang, Y, Jobin, “Microbiota as a mediator of cancer progression and therapy” Translational Research: Journal of Laboratory and Clincial Medicine January 2017 Volume 179, Pages 139–154 http://www.translationalres.com/article/S1931-5244(16)30155-4/fulltext (free full text via PubMed)

Why do we get Gut Dysbiosis?

1.     Houghteling PD and  Walker WA. “From birth to ‘immuno-health’, allergies and enterocolitis” Journal of Clinical Gastroenterology. Author manuscript; available in PMC 2016 Nov 1. Published in final edited form as: Journal of Clinical Gastroenterology. 2015 Nov-Dec; 49(0 1): S7–S12. doi:  10.1097/MCG.0000000000000355 PMCID: PMC4602161 NIHMSID: NIHMS685391 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602161/ (free article via PubMed)

2. Houghteling PD and  Walker “Why is initial bacterial colonization of the intestine important to the infant’s and child’s health?” Journal of Pediatric Gastroenterology and Nutrition. Author manuscript; available in PMC 2016 Mar 1. Published in final edited form as: Journal of Pediatric Gastroenterology and Nutrition. 2015 Mar; 60(3): 294–307. doi:  10.1097/MPG.0000000000000597 PMCID: PMC4340742 NIHMSID: NIHMS634789 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340742/ (free article via PubMed)

Back to the Blog…

  1. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, et al. “Diet rapidly and reproducibly alters the human gut microbiome.” Nature. 2014;505(7484):559–563. doi: 10.1038/nature12820. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957428/ (Free Pubmed Article). In: Duranti, Ferrario C.,  van Sinderen D., Ventura M. & Turron F.” Obesity and microbiota: an example of an intricate relationship.” Genes & Nutrition. 2017; 12: 18. Published online 2017 Jun 15. doi:  10.1186/s12263-017-0566-2 PMCID: PMC5473000 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473000/ (Free on Pubmed)
Proudly powered by WordPress