Category Archives: Physiology News

Articles pulled from our magazine, Physiology News.

Stress and the gut – it’s not all in your mind (Part 2)

By Kim E. Barrett, Division of Gastroenterology, Department of Medicine, University of California, San Diego, USA, @Jphysiol_eic.

This article originally appeared in our magazine, Physiology News.

The numerous microbes living inside of us help break down nutrients and “educate” our immune system to fight infection, but how do they help us respond to stress?

The microbiota as a mediator of responses to stress

Gut microbes change when people have intestinal diseases, such as inflammatory bowel diseases and irritable bowel syndrome. Indeed, some of the characteristics of these diseases can be transferred to animals in the lab that lack microbes, using microbes from diseased mice or humans. It is also becoming increasingly clear that gut microbes and their products may have effects well beyond the confines of the intestine itself.

Perhaps the most intriguing aspects of this area of research is that which ties the composition of the gut microbiome to brain function and the brain’s response to stress. Further, the adverse effects of stressful situations on gut function depend on the presence of intestinal microbes. To date, research supports bi-directional communication between the gut and brain (pictured below) that influences the normal function of both bowel and brain alike. This may explain, for example, why some digestive and psychiatric disorders go hand-in-hand (Gareau, 2016).

gut brain

Bi-directional communication between the gut and brain.

Evidence in human patients largely shows correlation not causation so far. Still, it is intriguing to observe that derangements in the microbiome have been associated with many conditions, including depression, autism, schizophrenia and perhaps even Parkinson’s disease (Dinan & Cryan, 2017).

Therapeutic manipulation of the microbiota – from probiotics to transplants

So if both intestinal and neuropsychiatric conditions are potentially caused by changes in the gut microbes (at least in part), and if such alterations also mediate the impact of stress on the relevant organ systems, can we mitigate these outcomes by targeting the microbiota?

Several approaches have been posited to have either positive or negative effects on the make-up of the gut microbiota and its intestinal and extra-intestinal influences.  Perhaps the most obvious of these is the diet. While the gut microbiota was at one time felt to be relatively immutable in adulthood, improved  techniques indicate that its make-up, in fact, is profoundly influenced by the composition of the diet and even by the timing of meals. For example, Western diets, high in meat and fat, decrease the diversity of the microbiota (and may even promote the emergence of pathogenic properties in commensals), whereas diets rich in plant-based fibre increase it.

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Another approach to targeting the microbiota is the use of antibiotics, although for the reasons discussed in Part 1, these are likely to be mainly deleterious, particularly early in life. The composition of the microbiota can also be altered directly by the administration of probiotics, which are commensal microorganisms (the host benefits, while the microbes are unaffected) selected for their apparent health benefits that can be taken orally.  Studies in animal models demonstrate that probiotics can improve both gut and cognitive function in animals exposed to a variety of stressors, or can negate the cognitive dysfunction accompanying intestinal inflammation or infection.  However, not all probiotics are created equal, and much work remains to be done both to validate animal studies in human clinical trials, and to define characteristics of probiotic strains that predict efficacy in a given clinical setting.

Perhaps the approach to targeting the microbiota that has attracted the most recent public attention is the practice known as faecal microbial transplant (FMT), where faecal material is transferred from a healthy donor (often a relative) to someone suffering from a specific intestinal or extraintestinal disease.  Enthusiasm for FMT derived initially from its dramatic efficacy in some patients suffering from disabling and persistent diarrheal disease as well as other symptoms associated with treatment-resistant infections by C. diff (a harmful bacteria).  More recently, there have been encouraging data suggesting that FMT may be effective in producing remission in inflammatory bowel disease, although the long-term consequences are unknown, and larger, well-controlled studies are needed.  Exploratory reports even suggest beneficial effects of FMT on gastrointestinal and behavioural symptoms of autism, or in obesity and metabolic syndrome (a cluster of conditions that occur together and increase your risk of heart disease, stroke and other conditions), but much further work is needed to validate these preliminary data.  Ideally, FMT procedures should be conducted under carefully-controlled and physician-supervised conditions to screen for the potential presence of pathogens or toxins.  Nevertheless, despite the obvious “yuck” factor, “do-it-yourself” instructions can readily be found online (there are even Facebook groups), and some individuals are sufficiently distressed by their condition to give it a try.

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Yep, this is exactly what you think it is.

Mitigating negative effects of stress

In conclusion, it is clear that our response to stress, whether manifested in our thought patterns or in our gut, is dramatically shaped by the microbiota that resides in the intestines.  Particularly in humans, studies conducted to date have largely been confined to cataloguing the key players in a given setting, but animal data are provocative, and studies focusing on microbes’ roles and functions in humans will doubtless follow.   No matter what, in the coming years, the explosive growth of studies aiming to target the microbiota for health benefits should give us a much better understanding of which approach, if any, is likely to be most beneficial for a given condition and even a given individual, since host factors clearly can also impact our microbial composition.  This work holds the promise of ameliorating negative effects of stress, and perhaps may offer new avenues for the therapy or even prevention of the myriad of stress-related disease states that are increasing in incidence in developed countries.


References

Dinan TG & Cryan JF. (2017). Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration. The Journal of physiology 595, 489-503.

Gareau MG. (2016). Cognitive function and the microbiome. International Review of Neurobiology 131, 227-246.

 

Stress and the gut – it’s not all in your mind (Part 1)

By Kim E. Barrett, Division of Gastroenterology, Department of Medicine, University of California, San Diego, USA, @Jphysiol_eic.

This article originally appeared in our magazine, Physiology News.

We all know that stress has an impact on the function of our digestive system. Whether it is the transient butterflies that accompany an exam or an interview, or the more toxic consequences of chronic stress, our experience of our world and its challenges can profoundly alter our digestion, absorption of nutrients, and excretion.

What has been less fully appreciated, until recently, is that communication between the brain and gut is bi-directional. Gut illnesses may be accompanied by brain disorders, such as anxiety, depression, and memory problems.  The brain and spinal cord are in constant communication with the gut, in part via the “little brain” – the nerves present in the gut that communicate with the brain.

While we humans like to think that we are masters of our own universe, in fact we, along with all other beings, are superorganisms. Our bodies consist not only of our own cells and genome, but also of distinctive populations of ‘friendly microbes’, along with their genes and ability to break down compounds. This so-called “microbiome” is made up mostly of bacteria, the best-studied populations, but also other microbes such as fungi and viruses (which are only now beginning to be examined).  Specialized groups of microbes inhabit various parts of our body, such as the intestines, mouth, skin, lungs, and genitals. The most extensively characterized of these microbiomes is the collection of bacteria in the gut, consisting of thousands of species in a typical healthy human adult. They reside throughout the intestines, but are most heavily concentrated in the colon. There are as many as 1014 of them throughout the gut. That’s ten times the number of human cells in the entire body (Sekirov et al., 2010). Recently, the 10:1 ratio has been disputed, with a claim that the numbers of human cells and gut bacteria are of the same order of magnitude (Sender et al., 2016). Even if this true, the microbes collectively have more genes than our cells do.

We are rapidly learning the ways in which these gut microbes may be important mediators of the cross-talk between the gut and brain. They are, in turn, influenced by environmental conditions, such as stress and diet, in ways that change their impact on both our thinking and digestion.

gut brain

 

Friendly microbes – what do they do for us?

Microbes, in the gut or elsewhere, are not essential for life, as illustrated by the ability to raise animals in a sterile environment in the lab. Nevertheless, the gut microbes in particular offer several advantages to the organism they inhabit. For us, they break down nutrients we can’t, such as dietary fibre, drugs, carcinogens, and compounds that break down into vitamins.  Similarly, the microbiota “educate” the immune system of organs such as our lungs and intestines to fight foreign substances but tolerate the proteins of broken-down food or other harmless microbes.

The organisms of the microbiome also defend against pathogens by crowding them out, producing substances that kill bacteria or keep them from reproducing, or causing the host to create those lethal compounds itself. For this reason, antibiotics that kill beneficial microbes can render patients susceptible to intestinal infections and overgrowth of harmful bacteria, such as Clostridium difficile (C. diff).

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3D cellular model of an intestine by Ben Mellows, PhD Student, University of Reading, UK

Gut microbes and birth

We think that gut microbes exist in the body immediately after birth, although some controversial data suggests the presence of microbes in the fetus before birth. Animals without microbes can be born via Caesarean section (C-section), implying that even if there are microbes in the womb, organisms don’t need them to survive (Perez-Munoz et al., 2017).

For babies delivered vaginally, their gut microbes are initially very similar to the mother’s vaginal microbiota, whereas they differ substantially for babies delivered by C-section. An intriguing recent study partially restored “normal” microbes in the gut, mouth, and skin by exposing babies delivered via C-section to the mother’s vaginal fluids. The authors thought that this might reverse the known association between C-section deliveries and an increased risk for immune and metabolic disorders (Dominguez-Bello et al., 2016).

For the first year or two of life, the baby’s microbes are relatively simple and variable, but they gradually take on the characteristics of a mature, adult-like microbiome. These early years are also a critical period for maturation of the immune system, so it makes sense that disrupting the maturation of the infant’s microbes also predisposes them to autoimmune and allergic diseases. For example, the increasing tendency to protect babies from germs or an excessive early-life use of antibiotics may set them up for an increased later risk of asthma, metabolic disease or obesity. This is called the “hygiene hypothesis” (Schulfer & Blaser, 2015).

Stay tuned for the part 2 of the series next week to learn about how gut microbes respond to stress, and the efficacy of therapeutics, from probiotics to transplants.


References

Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, Gonzalez A, Bokulich NA, Song SJ, Hoashi M, Rivera-Vinas JI, Mendez K, Knight R & Clemente JC. (2016). Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med 22, 250-253.

Perez-Munoz ME, Arrieta MC, Ramer-Tait AE & Walter J. (2017). A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome. Microbiome 5, 48.

Schulfer A & Blaser MJ. (2015). Risks of antibiotic exposures early in life on the developing microbiome. PLoS Pathog 11, e1004903.

Sekirov I, Russell SL, Antunes LC & Finlay BB. (2010). Gut microbiota in health and disease. Physiological reviews 90, 859-904.

Tales of a Nazi-fighting Nobel Prize winner

You probably haven’t heard of AV Hill, but if you’ve ever ridden a bike, watched the football or lifted a finger, you should thank him. The introduction real-estate buffs get of AV Hill, whose Highgate home has recently gone up for sale, certainly illustrates the universal impact of physiology! The house itself sports a Blue Plaque describing A.V. simply as ‘Physiologist,’ unveiled in 2015 in the presence of The Physiological Society. David Miller, Chair of our History & Archives Committees & Hon. Res. Fellow of the University of Glasgow, UK, wrote for Physiology News about the ceremony commemorating the ‘Nazi-fighting Nobel Prize winner.’ 

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The Blue Plaque. Photo credit: David Miller

The [unveiling of AV Hill’s Blue Plaque], sponsored by Atelier and the estate agents Savills, was attended by a number of AV’s extended family, together with dozens of other guests and dignitaries. Jonathan Ashmore, Fran Ashcroft and I represented The Society. Brief speeches were made by Greg Dyke (Chairman of The Football Association and former Director General of the BBC), Dr Julie Maxton (Executive Director, Royal Society), Prof Nicholas Humphrey (psychologist and philosopher), Stephen Wordsworth (CARA – Council for Assisting Refugee Academics) and Sir Ralph Kohn FRS (founder of the Kohn Foundation) who had proposed the Blue Plaque to honour AV’s memory.  Amongst the speeches, Nicholas Humphrey (a grandson of AV) described that regular guests at the house included many Nobel laureates, AV’s brother-in-law, the economist John Maynard Keynes, and friends as varied as Stephen Hawking and Sigmund Freud. The afterdinner conversations involved passionate debates about science and politics. ‘Every Sunday [as a child] we would have to attend a tea party at grandpa’s house and apart from entertaining some extraordinary guests, he would devise some great games for us, such as frog racing in the garden or looking through the lens of a [dissected] sheep’s eye.

AVHill

AV Hill in 1955. Photo credit: Harold Lewis

Archibald Vivian Hill (1886-1977)–known to all as ‘AV’–was the first British winner of the Nobel Prize for Physiology or Medicine (in 1922/3), honoured for his early work on heat production in muscle. He is widely regarded as a founder of the discipline of biophysics, bringing his command of mathematics and physical principles to his work in physiology.  His research work was fundamental in areas as varied as hormone-, neurotransmitter- and drug-receptor physiology, enzyme kinetics, muscle metabolism, nerve function, the mechanism of muscle mechanical function and more. One reason for the speech from Greg Dyke, representing the FA at the unveiling, is that aspects of AV’s work are also recognised as foundations of Sports Science: AV was himself a gifted athlete. He was mentor to several generations of leading physiologists. He led the physiology department at Manchester University (1920-23) and then at University College London (1923-1951). He joined The Society in 1912 and filled many major roles (Secretary 1927-33, Foreign Secretary 1934-45, served many years on the Editorial Board of The Journal of Physiology). He was elected a Fellow of The Royal Society in 1918, going on to fill several senior roles (Council from 1932-4, Biological Secretary 1935-45, Foreign Secretary 1946) and held a Royal Society Foulerton Professorship. In World War II, he served as the (independent) MP for Cambridge University, his alma mater, and on government wartime science and technical committees.

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A.V. Hill’s Nobel Prize certificate

Beyond his research, mentoring, government work, science administration and teaching, AV’s humanitarian work was exemplary. He played a leading role in setting up CARA (in 1933, with Ernest Rutherford, William Beveridge and others) and thus in the work to assist and support scientists escaping persecution in Nazi Germany. At the Blue Plaque ceremony, Sir Ralph Kohn referred to this endeavour: whilst still a child, Sir Ralph himself had escaped (together with his parents) from Leipzig in 1935. Sir Ralph reminded me that Bernard Katz had also escaped Leipzig the same year. He became a PhD student of AV and lived for some years as a lodger at AV’s home: thus there is a case for a further physiologist’s Blue Plaque at 16 Bishopswood Road.

House

The unveiling of the Blue Plaque, September 2015. Credit: David Miller

Hill said and wrote much that is worthy of being quoted. As a champion of the value of unfettered original research, he observed in his Inaugural Lecture for the Jodrell Chair of Physiology at UCL in 1923 (when he succeeded Ernest Starling), ‘Medicine is continually demanding more information and help in the grievous and urgent problems which it has to solve – useful information, practical information, information which is likely to help heal … minds and bodies. It is impossible not to be moved by this appeal, and in their hearts there are few physiologists who do not hope that their work may prove, in some sense and at some good time, of service to mankind in the maintenance of health, in the prevention of disease, and in the art of science and healing. One’s heart, however, is not always one’s best guide; more useful in the end is the intellectual faith … which urges Tom, Dick and Harry in their humble way to explore each his own little strange and miraculous phenomenon, whether in the organic or inorganic world.’ [as quoted by Brian Jewell in Physiology News, Summer 2008, p12].

Stressing out the immune system

Excerpt from a Physiology News feature by Natalie Riddell, School of Biosciences and Medicine, University of Surrey, UK, @N_Riddell_Immun

Natalie Riddell LatitudeStress can get under our skin. It can influence each and every physiological system, and all of the major contemporary diseases in the UK, including cardiovascular disease, inflammatory disorders, metabolic syndrome, infectious diseases and cancer, have been associated with stress. Stress affects everyone, and levels of anxiety and mental health disorders are increasing with work-related stress now being the second most commonly reported illness in the UK workforce. Over the last four decades, research in the area of Psychoneuroimmunology (PNI) has identified stress induced immune alterations as a potential mediator between chronic stress and ill-health.

In the 1970s, Holmes and Rahe developed a scale to subjectively grade stress, [which inspired our recent survey of stress in modern Britain]. They ranked over 40 different types of life stressors, such as the death of someone close to you, changes in relationship status, work-related stress, even Christmas, and they assigned each stressor a score. The total tally of stress scores that a person had experienced in the last year could accurately predict the likeliness of future illness. This demonstrated that stress and illness were closely related. In the 1990’s, Cohen et al., eloquently demonstrated that psychological stress increased the rates of respiratory infections and clinical symptoms in participants inoculated with the common cold (Cohen, Tyrrell et al. 1993). Subsequent studies revealed that every organ, tissue and cell of the immune system could be altered by psychological stress. The involvement of immune alterations in stress induced diseases was recognised and the field of PNI was born.

Defining stress

Stress is highly subjective. Something that I may class as stressful (watching Arsenal this season), may not be stressful to other people (Tottenham supporters). So how can we define stress? In the 1960s, the psychologist Richard Lazarus introduced the concept that stress is a process consisting of three distinct steps. First, a stimulus (i.e., the stressor) has to be present and perceived. Second, the stimulus initiates a conscious or sub-conscious process whereby the stressor is evaluated in relation to available coping options. If the demands of the situation exceed the ability to cope, then the situation is perceived as stressful. Thirdly, this results in a stress response involving emotional (e.g., anxiety, embarrassment) and biological (e.g., autonomic-endocrine) adaptations. Put simply; stress is a situation or event that exceeds, or is perceived to exceed, the individual’s ability to cope, that then triggers an emotional and biological response.

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Image: Darryl Leja, NHGRI

The stress adaptation response and immunity

The biological adaptation to stress is activation of the sympathetic nervous system. The same biological response is induced whether the stressor is psychological, such as anxiety or embarrassment, or physical, for example, exercise, trauma or fever. In the case of psychological stress, the individual perceives an inability to cope and this results in the amygdala, a part of the brain that contributes to emotion processing, sending a distress signal to the nearby hypothalamus. The hypothalamus can communicate with the rest of the body via either of two arms of the involuntary nervous system: “rest and digest” (parasympathetic) or “fight or flight” (sympathetic). During stress, this “fight or flight” system is triggered and various physiological changes occur, including an increase in heart rate, respiration and energy production. This promotes survival of the individual by maximising physical capacity to cope with the stressor.

During stress, signalling from the “fight or flight” sympathetic nervous system causes the adrenal gland to secrete the two main stress hormones; adrenaline and cortisol. These hormones can spread and act throughout the body via the circulation. The sympathetic nervous system innervates all of the organs of the immune system, and individual immune cells can directly respond to changes in circulating levels of adrenaline and cortisol. Stress is therefore able to alter every process of immunity, from the initial development of stem cells into early immune cells in the bone marrow, through to the triggering of immune responses to specific antigens in the lymph nodes. Even when in the peripheral tissues, such as the skin or gut, where mature immune cells are most likely to encounter infections, the cells can be regulated by stress hormones. It is therefore unsurprising that the immune system is a modifiable target of stress.

Read Natalie’s full article in our magazine Physiology News to find out how acute stress changes the composition of the blood, and why our Stone Age brain can’t cope with the constant stress of modern life. Her feature takes a more detailed dive into the effects of stress on the immune system’s day-night (circadian) rhythm, and points to stress management as an easy and affordable way to make us healthier.

Reference

Cohen, S., D. A. Tyrrell and A. P. Smith (1993). Negative life events, perceived stress, negative affect, and susceptibility to the common cold. J Pers Soc Psychol 64(1): 131-140.

 

 

The open science movement: Revolution is underway

By Keith Siew, @keithsiew, University of Cambridge

‘Information is power. But like all power, there are those who want to keep it for themselves. The world’s entire scientific and cultural heritage, published over centuries in books and journals, is increasingly being digitized and locked up by a handful of private corporations.’ Aaron Swartz, in Guerilla Open Access Manifesto, 2008

The world’s first academic science journal, Philosophical Transactions, was published by the Royal Society in 1665. At last count there were some 11,365 science journals spanning over 234 disciplines by 2015, and yet the primary model of scientific publishing remained largely unchanged throughout the centuries.

As a fresh-faced, naïve PhD student, I recall the horror I felt upon learning that my hard work would be at the mercy of a veiled, political peer-review process, that I’d be left with little option but to sign away my rights to publishers, and too often forced to choose between burning a hole in my wallet or forgoing access to a potentially critical paper!

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Derivative of ‘Open Access Explained!’ [https://www.youtube.com/watch?v=L5rVH1KGBCY] by ©PhDComics.com Licensed under CC BY.

The open science movement offers an alternative to this unjust system. In its purest form, the movement advocates for making scientific research and its dissemination an entirely transparent process, freely accessible to all levels of society.

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Read more here in Physiology News about some of the more radical elements of the movement, existing open science opportunities and the reasons behind life scientists’ relatively slow adoption of open science. The full article also discusses the ongoing struggle for open access, the growing angst towards closed peer review and fundamental shifts on the horizon in both the ways we communicate (i.e. preprints) and carry out science (i.e. open data and open notebook science).

The dangers of careless press releases

by Simon Cork, Imperial College London, @simon_c_c

This article originally appeared in Physiology News

Simon Cork

You open the morning paper and are excited to find an article about a newly published study in your area of interest. You start reading it and quickly realise that the journalist has completely taken the press release out of context. What was originally some preliminary cell culture work has turned into a front page splash solving an age-old problem or heralding a new cure. Sound familiar?

We live in a world of 24-hour rolling news coverage. The necessity to write punchy news headlines and be the first to break stories has never been greater. Because of this, it’s very easy for journalists to take press releases out of their original scientific context, and ‘sex’ them up in a way that sells. This is particularly the case for my own area of research, obesity.

The world is suffering from an obesity epidemic especially (but not exclusively) in the Western world. Reports suggest around two-thirds of people are dieting at any one time, and most of these diets don’t work. This is why stories about miracle weight loss cures and therapies are cat nip to journalists and readers alike.

Frustrated by the misrepresentation of obesity in the press, I decided to sign up to the Science Media Centre (SMC), not knowing it would lead to my television debut.

The remit of the SMC is to provide journalists with expert quotes on scientific studies that are likely to garner media attention. In the world of obesity and diabetes, this usually involves studies showing that eating too much of X will lead to diabetes, or that cutting Y out of your diet reduces body weight.

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I recently commented on a new study, which had followed approximately 20,000 children over a 10-year period, some born via caesarean and some born naturally, and found that those who were born via caesarean were more likely to be obese in later life. I was asked to comment whether or not the conclusions of the study were sound, and offer a possible explanation for the findings. In fact, this study adds to other literature supporting this relationship, and the most likely cause is exposure to different microbes when born naturally versus via caesarean, although the link hasn’t fully been proven.

Since the study used a large cohort, the results were more statistically significant. However, since it was an observational study there isn’t a causative link.

My comments were picked up by a number of news agencies, including The Guardian, Daily Mail and the BBC News website. Nerve-rackingly, I even got a call from the producer of BBC Radio 4’s Today Programme, who was interested in picking this piece up and wondered if I would pop into the studio the next morning. This was swiftly followed by Sky News, Jeremy Vine and BBC News.

Now all of this was a far cry from the ELISA that I was planning on carrying out that day, but was an interesting insight into the angle journalists take on scientific stories. Having received the call asking if I’d like to go on the Today programme at 11 pm the previous evening, I spent a number of hours doing a comprehensive PubMed search of all the most recent meta-analysis studies investigating caesarean births and obesity risk. Turns out all they’re really interested in is why. If the Brexit debate has taught us anything, it’s that the public switch-off at the sight of a percentage symbol or talk of numbers. What people want to know is why and how it affects them. So my interviews mostly revolved around why caesarean births seem to increase the risk of obesity and whether there is anything we can do to mitigate the risk. That and trying to politely convince a caller to the Jeremy Vine Show that her child’s obesity was probably more the result of her confessed feeding of copious amounts of chocolate to him, rather than his method of birth.

If, like me, you find yourself at odds with journalistic reporting of science stories, I would urge you to join the database at the Science Media Centre. You’re not guaranteed to get TV time, but you might get your name in the paper. Just make sure that you at least know enough about whatever it is you’re commenting on to make it through a 30-minute conversation with Jeremy Vine and John Humphrys!