Healthy people need healthy microbiomes from an early age.
- 30 million children worldwide suffer from moderate acute malnutrition.
- Lifelong problems from undernourishment include increased risks of diabetes and heart problems.
- New research shows that targeting the microbiome could help malnourished children grow up healthy.
According to the United Nations Food and Agriculture Organization, an estimated 815 million people — nearly 11 percent of the global population — suffer from chronic undernourishment. While the predominant number of them live in poor countries, some 11 million live in more developed nations. As the pandemic rages on and the effects of climate change continue, those numbers will continue to increase if there are no interventions.
A new study, published in The New England Journal of Medicine by an international team of researchers, investigates one potential solution that could address the 30 million children suffering from moderate acute malnutrition: target the microbiome.
Childhood undernourishment results in a variety of crippling lifelong effects: wasting and stunting (impaired growth and development), immune and metabolic dysfunction, and central nervous system problems top the list. With the pandemic predicted to increase childhood deaths from wasting by 20 percent, the team expresses urgency for this chronic problem.
Feeding the microbiota
For this randomized, controlled study, researchers recruited 118 children between the ages of 12 to 18 months. They split the recruits into two groups: 59 children were given an experimental diet (which they called microbiota-directed complementary food prototype, or MDCF-2), and the other 59 were given a control diet (which was ready-to-use supplementary food, or RUSF). All children lived in Mirpur, an impoverished region of Dhaka, Bangladesh.
Supplementation was given for three months followed by one month of monitoring. The team measured a total of 4,977 proteins and 209 bacterial taxa in fecal samples over the course of the project. Because they had previously observed that malnourished children have less advanced microbiome profiles than healthy children, the goal was to feed and encourage the growth of the bacterial community associated with normal childhood development.
During the first month, mothers brought their children to a regional healthcare center to feed them two daily servings of either MDCF-2 or RUSF. During the second month, one of those two feedings happened at home. By the third month, the children were fed at home. After three months, the children returned to their normal feeding routines and were tested one month later.
The group given MDCF-2 saw improvements in two of four key measurements: weight-for-length and weight-for-age. They also found an important improvement in terms of bodily inflammation. The authors wrote:
"By the end of MDCF-2 supplementation, children in the upper quartile had the largest increases in mediators of bone growth and CNS development and the largest decreases in effectors of inflammation. Together, these results provide evidence that mediators of bone growth, neurodevelopment, and inflammation distinguished the effects of the MDCF-2 nutritional intervention from that of RUSF."
Undernourishment often results in metabolic reprogramming that predisposes children to develop cardiovascular issues, diabetes, and hypertension later in life. This is, in part, why they're seeking early interventions focused on creating healthy microbial communities before such metabolic changes occur.
Stay in touch with Derek on Twitter and Facebook. His most recent book is "Hero's Dose: The Case For Psychedelics in Ritual and Therapy."
Are "humanized" pigs the future of medical research?
The U.S. Food and Drug Administration requires all new medicines to be tested in animals before use in people. Pigs make better medical research subjects than mice, because they are closer to humans in size, physiology and genetic makeup.
In recent years, our team at Iowa State University has found a way to make pigs an even closer stand-in for humans. We have successfully transferred components of the human immune system into pigs that lack a functional immune system. This breakthrough has the potential to accelerate medical research in many areas, including virus and vaccine research, as well as cancer and stem cell therapeutics.
Existing biomedical models
Severe Combined Immunodeficiency, or SCID, is a genetic condition that causes impaired development of the immune system. People can develop SCID, as dramatized in the 1976 movie “The Boy in the Plastic Bubble." Other animals can develop SCID, too, including mice.
Researchers in the 1980s recognized that SCID mice could be implanted with human immune cells for further study. Such mice are called “humanized" mice and have been optimized over the past 30 years to study many questions relevant to human health.
Mice are the most commonly used animal in biomedical research, but results from mice often do not translate well to human responses, thanks to differences in metabolism, size and divergent cell functions compared with people.
Nonhuman primates are also used for medical research and are certainly closer stand-ins for humans. But using them for this purpose raises numerous ethical considerations. With these concerns in mind, the National Institutes of Health retired most of its chimpanzees from biomedical research in 2013.
Alternative animal models are in demand.
Swine are a viable option for medical research because of their similarities to humans. And with their widespread commercial use, pigs are met with fewer ethical dilemmas than primates. Upwards of 100 million hogs are slaughtered each year for food in the U.S.
In 2012, groups at Iowa State University and Kansas State University, including Jack Dekkers, an expert in animal breeding and genetics, and Raymond Rowland, a specialist in animal diseases, serendipitously discovered a naturally occurring genetic mutation in pigs that caused SCID. We wondered if we could develop these pigs to create a new biomedical model.
Our group has worked for nearly a decade developing and optimizing SCID pigs for applications in biomedical research. In 2018, we achieved a twofold milestone when working with animal physiologist Jason Ross and his lab. Together we developed a more immunocompromised pig than the original SCID pig – and successfully humanized it, by transferring cultured human immune stem cells into the livers of developing piglets.
During early fetal development, immune cells develop within the liver, providing an opportunity to introduce human cells. We inject human immune stem cells into fetal pig livers using ultrasound imaging as a guide. As the pig fetus develops, the injected human immune stem cells begin to differentiate – or change into other kinds of cells – and spread through the pig's body. Once SCID piglets are born, we can detect human immune cells in their blood, liver, spleen and thymus gland. This humanization is what makes them so valuable for testing new medical treatments.
We have found that human ovarian tumors survive and grow in SCID pigs, giving us an opportunity to study ovarian cancer in a new way. Similarly, because human skin survives on SCID pigs, scientists may be able to develop new treatments for skin burns. Other research possibilities are numerous.
The ultraclean SCID pig biocontainment facility in Ames, Iowa. Adeline Boettcher, CC BY-SA
Pigs in a bubble
Since our pigs lack essential components of their immune system, they are extremely susceptible to infection and require special housing to help reduce exposure to pathogens.
SCID pigs are raised in bubble biocontainment facilities. Positive pressure rooms, which maintain a higher air pressure than the surrounding environment to keep pathogens out, are coupled with highly filtered air and water. All personnel are required to wear full personal protective equipment. We typically have anywhere from two to 15 SCID pigs and breeding animals at a given time. (Our breeding animals do not have SCID, but they are genetic carriers of the mutation, so their offspring may have SCID.)
As with any animal research, ethical considerations are always front and center. All our protocols are approved by Iowa State University's Institutional Animal Care and Use Committee and are in accordance with The National Institutes of Health's Guide for the Care and Use of Laboratory Animals.
Every day, twice a day, our pigs are checked by expert caretakers who monitor their health status and provide engagement. We have veterinarians on call. If any pigs fall ill, and drug or antibiotic intervention does not improve their condition, the animals are humanely euthanized.
Our goal is to continue optimizing our humanized SCID pigs so they can be more readily available for stem cell therapy testing, as well as research in other areas, including cancer. We hope the development of the SCID pig model will pave the way for advancements in therapeutic testing, with the long-term goal of improving human patient outcomes.
Adeline Boettcher earned her research-based Ph.D. working on the SCID project in 2019.
Context is everything.
The COVID-19 pandemic has introduced a number of new behaviours into daily routines, like physical distancing, mask-wearing and hand sanitizing. Meanwhile, many old behaviours such as attending events, eating out and seeing friends have been put on hold.
However, one old behaviour that has persisted, and has arguably been amplified due to COVID-19, is sitting — and it is not surprising to see why. Whether sitting during transportation, work, screen time or even meals, everyday environments and activities are tailored nearly exclusively to prolonged sitting. As such, sedentary behaviours, like sitting, make up the vast majority of our waking day.
Pre-COVID-19 estimates place the average Canadian adult's sedentary behaviour at around 9.5 hours per day. Current daily sedentary time is likely even higher as a result of stay-at-home orders, limitations on businesses and recreational facilities, and elevated health anxieties.
Health vs. well-being
This is a problem, given that chronic excessive levels of sedentary time have been linked to greater risk of diabetes, heart disease, mortality and even some cancers. However, for many people, their own judgments and feelings about their quality of life (also known as subjective well-being) may be more important and relevant for informing their health decisions and behaviours than potentially developing chronic diseases.
Subjective well-being encompasses an individual's own evaluation of their quality of life. It includes concepts like affect (positive and negative feelings) and life satisfaction. Interestingly, these evaluations can conflict with physical health outcomes. For example, a person could have diabetes but still report good subjective well-being, while someone with no physical health conditions may report poor subjective well-being.
This is important, as it means how an individual feels about their own health may not always align with what their body may demonstrate. That's why evaluating subjective well-being is vital for painting a holistic picture of health.
Different contexts of sitting
Relatively little research has examined the relationships between sedentary behaviour and subjective well-being. Exploring these relationships is important, as different contexts of sitting — such as socializing versus screen time — may yield different feelings or judgments of subjective well-being, unlike relationships between physical health and sedentary behaviour, which tend to be more consistent.
As health psychologists focused on physical activity and sedentary behaviour, we reviewed the scientific literature describing relationships between measures of sedentary behaviours such as physical inactivity and screen time, and subjective well-being as reflected by affect, life satisfaction and overall subjective well-being.
Our review highlights three main findings. First, sedentary behaviour, physical inactivity and screen time demonstrated weak but statistically significant correlations with subjective well-being. In other words, those who reported sitting more often and spending longer periods with no physical activity reported lower positive affect, higher negative affect and lower life satisfaction than those who sat less and moved more.
We also found that this relationship was most apparent in studies that compared people who were very sedentary to those who had more active lifestyles.
Not all sitting is bad sitting
Our second main finding relates to the context of the sedentary behaviour. While many studies examined overall sedentary behaviour and physical inactivity, some studies looked at specific contexts or domains of sitting and its relationship with subjective well-being. These studies revealed that different domains of sedentary behaviour have unique relationships with subjective well-being.
For example, screen time was consistently and negatively associated with subjective well-being. However, domains like socializing, playing an instrument and reading actually demonstrated positive associations with subjective well-being. These results differ from the traditional health-related sedentary behaviour research, in which all sedentary behaviour is viewed as harmful to health.
Our review suggests that some types of sedentary behaviour may be beneficial to quality of life. Rather, not all sitting is the same in terms of subjective well-being. So when people work towards reducing their sitting time, they should consider not just how much to reduce, but what kind to reduce.
Less sitting is good for everyone
Our third main finding concerns overall sitting and self-perceived levels of sedentary behaviour. Most studies found a weak statistically significant association between higher overall sedentary time and lower subjective well-being. However, in studies where participants were asked to compare their sedentary behaviour to how much they normally sit, those who perceived themselves as more sedentary than usual reported significantly poorer subjective well-being.
These findings suggest that how much an individual sits overall may not be as important as how much an individual sits compared to their usual level of sitting. This infers that anyone, regardless of how much they normally sit or are physically active, may potentially benefit from sitting less.
COVID-19 continues to influence daily life and routines. Even as businesses and gyms eventually reopen, and we feel more comfortable gathering with others and eventually stop wearing masks, we will almost certainly continue to sit and sitting will continue to change how we feel. While we may not be able to eliminate all of our sitting, we can all be mindful of both how much we can reduce it and where we can reduce it from to be healthier and feel better.
Wuyou Sui, Postdoctoral fellow, Behavioural Medicine Lab, School of Exercise Science, Physical & Health Education, University of Victoria and Harry Prapavessis, Professor, Kinesiology, Western University
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The neoliberal call for more 'choice', seems hard to resist.
"Some of them are foreign-born and struggle with the language, and all of them are in distress! But I hardly have the time to explain the essentials to them. There's all the paperwork, and we're constantly understaffed.'
Such grievances have become sadly familiar – not only in medicine, but also in education and care-work. Even in more commercial environments, you're liable to hear similar objections: the engineer who wants to deliver quality but is told to focus on efficiency only; the gardener who wants to give the plants time to grow, but is told to focus on speed. The imperatives of productivity, profitability and the market rule.
Complaints come from the other side of the table as well. As patients and students, we want to be treated with care and responsibility, rather than as mere numbers. Wasn't there a time when professionals still knew how to serve us – a cosy, well-ordered world of responsible doctors, wise teachers and caring nurses? In this world, bakers still cared about the quality of their bread, and builders were proud of their constructions. One could trust these professionals; they knew what they were doing and were reliable guardians of their knowledge. Because people poured their souls into it, work was still meaningful – or was it?
In the grip of nostalgia, it's easy to overlook the dark sides of this old vocational model. On top of the fact that professional jobs were structured around hierarchies of gender and race, laypeople were expected to obey expert judgment without even asking questions. Deference to authority was the norm, and there were few ways of holding professionals to account. In Germany, for example, doctors were colloquially called 'demigods in white' because of their status vis-à-vis patients and other staff members. This is not exactly how we might think that citizens of democratic societies should relate to one other now.
Against this backdrop, the call for more autonomy, for more 'choice', seems hard to resist. This is precisely what happened with the rise of neoliberalism after the 1970s, when the advocates of 'New Public Management' promoted the idea that hard-nosed market thinking should be used to structure healthcare, education and other areas that typically belonged to the slow and complicated world of public red tape. In this way, neoliberalism undermined not only public institutions but the very idea of professionalism.
This attack was the culmination of two powerful agendas. The first was an economic argument about the alleged inefficiency of public services or the other non-market structures in which professional knowledge was hosted. Long queues, no choice, no competition, no exit options – that's the chorus that critics of public healthcare systems repeat to this day. The second was an argument about autonomy, about equal status, about liberation – 'Think for yourself!' instead of relying on experts. The advent of the internet seemed to offer perfect conditions for finding information and comparing offers: in short, for acting like a fully informed customer. These two imperatives – the economic and the individualistic – meshed extremely well under neoliberalism. The shift from addressing the needs of citizens to serving the demands of customers or consumers was complete.
We are all customers now; we are all supposed to be kings. But what if 'being a customer' is the wrong model for healthcare, education, and even highly specialised crafts and trades?
What the market-based model overlooks is hyperspecialisation, as the philosopher Elijah Millgram argues in The Great Endarkenment (2015). We depend on other people's knowledge and expertise, because we can learn and study only so many things in our lifetimes. Whenever specialist knowledge is at stake, we are the opposite of a well-informed customer. Often we don't want to have to do our own research, which would be patchy at best; sometimes, we are simply unable to do it, even if we tried. It's much more efficient (yes, efficient!) if we can trust those already in the know.
But it can be hard to trust professionals forced to work in neoliberal regimes. As the political scientist Wendy Brown argued in Undoing the Demos (2015), market logic turns everything, including one's own life, into a question of portfolio management: a series of projects in which you try to maximise the return on investment. By contrast, responsible professionalism imagines work-life as a series of relationships with individuals who are entrusted to you, along with the ethical standards and commitments you uphold as a member of a professional community. But marketisation threatens this collegiality, by introducing competitiveness among workers and undermining the trust that's needed to do a good job.
Is there a way out of this conundrum? Could professionalism be revived? If so, can we avoid its old problems of hierarchy while preserving space for equality and autonomy?
There are some promising proposals and real-life examples of such a revival. In his account of 'civic professionalism', Work and Integrity (2nd ed, 2004), the American education scholar William Sullivan argued that professionals need to be aware of the moral dimensions of their role. They need to be 'experts and citizens alike', and 'learn to think and act cooperatively with us', the non-experts. Similarly, the political theorist Albert Dzur argued in Democratic Professionalism (2008) for a revival of a more self-aware version of 'old' professionalism – one committed to democratic values, and an ongoing dialogue with laypeople. Dzur describes, for example, how experts in the field of bioethics have opened up their discussions to non-experts, reacting to public criticisms, and finding formats for bringing doctors, ethics consultants and laypeople into conversation.
Similar practices could be introduced in many other professions – as well as areas not traditionally understood as specialist vocations, but in which decisionmakers need to draw on highly specialised knowledge. Ideally, this could lead to trust in professionals being not blind, but justified: a trust based on a grasp of the institutional frameworks that hold them accountable, and on an awareness of mechanisms for double-checking and getting additional opinions within the profession.
But in many areas, the pressures of markets or quasi-markets prevail. This leaves our front-line professionals in a difficult spot, as Bernardo Zacka describes in When the State Meets the Street (2017): they are overworked, exhausted, pulled in different directions, and unsure about the whole point of their job. Highly motivated individuals, such as the young doctor I mentioned at the outset, are likely to leave the fields in which they could contribute most. Perhaps this is a price worth paying if it brings huge benefits elsewhere. But that doesn't seem to be happening, and it makes all of us non-experts vulnerable, too. We cannot be informed customers because we know too little – but we can't rely on being simply citizens any longer, either.
Up to a point, professionalisation is built on the persistence of ignorance: specialised knowledge is a form of power, and a form that's rather difficult to control. Yet it's clear that markets and quasi-markets are flawed strategies for dealing with this problem. By continuing to accept them as the only possible models, we forgo the opportunity to imagine and explore alternatives. We must be able to rely on other people's expertise. And for that, as the political philosopher Onora O'Neill argued in her 2002 Reith Lectures, we must be able to trust them.
The young doctor I interviewed had long considered leaving her job – so when the opportunity to get a research-based position came up, she jumped ship. 'The system was forcing me to act against my own best judgment, again and again,' she said. 'It was the opposite of what I thought being a doctor was all about.' Now is the time to help reimagine a system in which she can recover that sense of purpose, to everyone's benefit.