Tag: risk

How can your gut microbiome affect risk of cancer?

Posted on by lindsey.pike

Dr Kaitlin H. Wade1,2,3

1 Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN

2 Medical Research Council (MRC-IEU), University of Bristol, Bristol, BS8 2BN

3 Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (ICEP), University of Bristol, Bristol, BS8 2BN

The causes of cancer are often preventable

Cancer, a disease that has a profound impact on the lives of individuals all over the world, also has an ever-increasing burden. And yet, evidence indicates that over 40% of all cancers are likely explained by preventable causes. One of the main challenges is identifying so-called ‘modifiable risk factors’ for cancer – aspects of our environment that we can change to reduce the incidence of disease.

Photo by Chloe Russell for ‘Up Your A-Z’, an encyclopaedia of gut bacteria

The gut microbiome could influence cancer risk

The gut microbiome is a system of microorganisms that helps us digest food, produce essential molecules and protects us against harmful infections. There is growing evidence supporting the relationship between the human gut microbiome and risk of cancer, including lung, breast, bowel and prostate cancers. For example, experiments have shown that changing the gut microbiome (e.g., by using pre- or pro-biotics) may reduce the risk of developing colorectal cancer. Research also suggests that people with colorectal cancer have lower microbiota diversity and different types of bacteria within their gut compared to those without a diagnosis.

As the gut microbiome can have a substantial impact on their host’s metabolism and immune response, there are many biological mechanisms by which the gut microbiome could influence cancer development and progression. However, we don’t yet know how the gut microbiome can do this.

Human studies in this context have used small samples of individuals and measure both the microbiome and disease at the same time. These factors can make it difficult to tease apart correlation from causation – i.e., does variation in the gut microbiome change someone’s risk of cancer or is it the existence of cancer that leads to variation in the gut microbiome? This is an important question because the main aim of such research is to understand the causes of cancer and how we can prevent the disease. We want to fully understand whether altering the gut microbiome can reduce the burden of cancer at a population level or whether it is simply a marker of cancer itself.

I’m inviting feedback on your knowledge and understanding of the gut microbiome and cancer – please take this 5-minute survey (click here for survey) to contribute your thoughts.

People are interested in their gut microbiome

Even though we don’t yet know much about the causal relevance of the gut microbiome, there is still a growing market for commercial initiatives targeting the microbiome as a consumer-driven intervention. This usually involves companies obtaining a small number of faecal samples from consumers and prescribing “personalised” nutritional information for a “healthier microbiome”. However, these initiatives are very controversial given uncertainty in the likely relationships between the gut microbiome, nutrition and various diseases. What these activities do highlight is the demand for such information at a population level. This shows there is an opportunity to improve understanding of the causal role played by the gut microbiome in human health and disease.

Photo by Chloe Russell for ‘Up Your A-Z’, an encyclopaedia of gut bacteria

Microbiome and variation in our genes

Using information about our genetics can help us find out whether the gut microbiome changes the risk of cancer, or whether cancer changes the gut microbiome. Genetic variation cannot be influenced by the gut microbiome nor disease. Therefore, if people who are genetically predisposed to having a higher abundance of certain bacteria within their gut also have a lower risk of, say, prostate cancer, this would strongly suggest a causal role of those bacteria in prostate cancer development. This approach of using human genetic information to discern correlation from causation is called Mendelian randomization.

Studies relating human genetic variation with the gut microbiome have proliferated in recent years. They have provided evidence for genetic contributions to features of the gut microbiome including the abundance or likelihood of presence (vs. absence) of specific bacteria. This knowledge has given the opportunity to apply Mendelian randomization to better understand the causal impact of gut microbiome variation in health outcomes, including cancer. There are, however, many important caveats and complications to this work. Specifically, there is a (currently unmet) requirement for careful examination of how human genetic variation influences the gut microbiome and interpretation of the causal estimates derived from using Mendelian randomization within this field.

This is exactly what I will be looking at in my new research funded by Cancer Research UK. For more details on the nuances of this work, please see my research feature for Cancer Research UK and paper discussing these complexities.

What’s next for this research?

This research has already shown promise in the application of Mendelian randomization to improve our ability to discern correlation from causation between the gut microbiome and cancer. It has importantly highlighted the need for inter-disciplinary collaboration between population health, genetic and basic sciences. Thus, with the support from my team of experts in microbiology, basic sciences and population health sciences, this Fellowship will set the scene for the integration of human genetics and causal inference methods in population health sciences with microbiome research. This will help us understand the causal role played by the gut microbiome in cancer. Such work acts as a new and important step towards evaluating and prioritising potential treatments or protective factors for cancer prevention.

Acknowledgements

The research conducted as part of this Cancer Research UK Population Research Postdoctoral Fellowship will be supported by the following collaborators: Nicholas Timpson, Caroline Relton, Jeroen Raes, Trevor Lawley, Lindsay Hall and Marc Gunter, and my growing team of interdisciplinary PhD students and postdoctoral researchers. I’d also like to thank the following individuals for comments on this feature: Tom Battram, Laura Corbin, David Hughes, Nicholas Timpson, Lindsey Pike and Philippa Gardom. Additional thanks go to Chloe Russell, a brilliant photographer with whom I collaborated to create “Up Your A-Z” as part of Creative Reactions 2019, who provided the photos for this webpage.

About the author

Dr. Wade’s academic career has focused on the integration of human genetics with population health sciences to improve causality within epidemiological studies. Focusing on relationships across the life-course, her work uses comprehensive longitudinal cohorts, randomized controlled trials and causal inference methods (particularly, Mendelian randomization and recall-by-genotype designs). Kaitlin’s research has focused on understanding the relationships between adiposity and dietary behaviours as risk factors for cardiometabolic diseases and mortality. Having been awarded funding from the Elizabeth Blackwell Institute and Cancer Research UK, Kaitlin’s work uses these methods to understand the causal role played by the human gut microbiome on various health outcomes, such as obesity and cancer. Since pursuing a career in this field, Kaitlin has already led and been key in several fundamental studies that with path the way to resolve – or at least quantify – complex relationships between genetic variation, the gut microbiome and human health. In addition to her research, Kaitlin is actively involved in organising and administering teaching and public engagement activities as well as having many mentorship and supervisory roles within and external to the University of Bristol.

Key publications:

Hughes, D.A., Bacigalupe, R., Wang, J. et al. Genome-wide associations of human gut microbiome variation and implications for causal inference analyses. Nat Microbiol 5, 1079–1087 (2020). https://doi.org/10.1038/s41564-020-0743-8.

Kurilshikov, A., Medina-Gomez, C., Bacigalupe, R. et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat Genet 53, 156–165 (2021). https://doi.org/10.1038/s41588-020-00763-1.

Wade KH and Hall LJ. Improving causality in microbiome research: can human genetic epidemiology help? [version 3; peer review: 2 approved]. Wellcome Open Res 4, 199 (2020). https://doi.org/10.12688/wellcomeopenres.15628.3.

 

 

Are teachers at high risk of death from Covid19?

Posted on by lindsey.pike

Sarah Lewis, George Davey Smith and Marcus Munafo

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Due to the SARS-CoV-2 pandemic schools across the United Kingdom were closed to all but a small minority of pupils (children of keyworkers and vulnerable children) on the 20th March 2020, with some schools reporting as few as 5 pupils currently attending. The UK government have now issued guidance that primary schools in England should start to accept pupils back from the 1st June 2020 with a staggered return, starting with reception, year 1 and year 6.

Concern from teachers’ unions

This has prompted understandable concern from the  teachers’ unions, and on the 13th May, nine unions which represent teachers and education professionals signed a joint statement calling on the government to postpone reopening school on the 1st June, “We all want schools to re-open, but that should only happen when it is safe to do so. The government is showing a lack of understanding about the dangers of the spread of coronavirus within schools, and outwards from schools to parents, sibling and relatives, and to the wider community.” At the same time, others have suggested that the harms to many children due to neglect, abuse and missed educational opportunity arising from school closures outweigh the small increased risk to children, teachers and other adults of catching the virus.

What risk does Covid19 pose to children?

Weighing up the risks to children and teachers

So what do we know about the risk to children and to teachers? We know that children are about half as likely to catch the virus from an infected person as adults, and  if they do catch the virus they  are likely to have only mild symptoms.  The current evidence, although inconclusive, also suggests that they may be less likely to transmit the virus than adults.  However, teachers have rightly pointed out that there is a risk of transmission between the teachers themselves and between parents and teachers.

The first death from COVID-19 in England was recorded at the beginning of March 2020 and by the 8th May 2020 39,071 deaths involving COVID-19 had been reported in England and Wales. Just three of these deaths were among children aged under 15 years and  only a small proportion of the deaths (4416 individuals, 11.3%) were among working aged people.  Even among this age group risk is not uniform; it increases sharply with age from 2.6 in 100,000 for 25-44 years olds with a ten fold increase to 26 in  100,000 individuals for those aged 45-64.

Risks to teachers compared to other occupations

In addition, each underlying health condition increases the risk of dying from COVID-19, with those having at least 1 underlying health problem making up most cases.   The Office for National Statistics in the UK have published age standardised deaths by occupation for all deaths involving COVID-19 up to the 20th April 2020. Most of the people dying by this date would have been infected at the peak of the pandemic in the UK  prior to the lockdown period. They found that during this period there were 2494 deaths involving Covid-19 in the working age population. The mortality rate for Covid-19 during this period was 9.9 (95% confidence intervals 9.4-10.4) per 100,000 males and 5.2 (95%CI 4.9-5.6) per 100,000 females, with Covid-19 involved in around 1 in 4 and 1 in 5 of all deaths among males and females respectively.

Amongst teaching and education professionals (which includes school teachers, university lecturers and other education professionals) a total of 47 deaths (involving Covid-19) were recorded, equating to mortality rates of 6.7 (95%CI 4.1-10.3) per 100,000 among males and 3.3 (95%CI 2.0-4.9) per 100,000 among females, which was very similar to the rates of 5.6 (95%CI 4.6-6.6) per 100,000 among males and 4.2(95%CI 3.3-5.2) per 100,000 females for all professionals. The mortality figures for all education professionals includes 7 out of 437000 (or 1.6 per 100,000 teachers) primary and nursery school teachers and 17 out of 395000 (or 4.3 per 100,000 teachers) secondary school teachers.  A further 20 deaths occurred amongst childcare workers giving a mortality rate amongst this group of 3.4 (95%CI=2.0-5.5) per 100,000 females (males were highly underrepresented in this group), this is in contrast to rates of 6.5 (95%CI=4.9-9.1) for female sales assistants and 12.7(95%CI= 9.8-16.2) for female care home workers.

Covid-19 risk does not appear greater for teachers than other working age individuals

In summary, based on current evidence the risk to teachers and childcare workers within the UK from Covid-19 does not appear to be any greater than for any other group of working age individuals. However, perceptions of elevated risk may have occurred, prompting some to ask “Why are so many teachers dying?” due to the way this issue is portrayed in the media with headlines such as “Revealed: At least 26 teachers have died from Covid-19” currently on the https://www.tes.com website. This kind of reporting, along with the inability of the government to communicate the substantial differences in risk between different population groups – in particular according to age – has caused understandable anxiety among teachers. Whilst, some teachers may not be prepared to accept any level of risk of becoming infected with the virus whilst at work, others may be reassured that the risk to them is small, particularly given that we all accept some level of risk in our lives, a value that can never be zero.

Likely impact on transmission in the community is unclear

As the majority of parents or guardians of school aged children will be in the 25-45 age range, the risk to them  is also likely to be small. Questions remain however around the effect of school openings on transmission in the community and the associated risk. This will be affected by many factors including the existing infection levels in the community, the extent to which pupils, parents and teachers are mixing outside of school (and at the school gate) and mixing between individuals of different age groups. This is the primary consideration of the government Scientific Advisory Group for Emergencies (SAGE) who are using modelling based on a series of assumptions to determine the effect of school openings on R0.

 

Sarah Lewis is a Senior Lecturer in Genetic Epidemiology in the department of Population Health Sciences, and is an affiliated member of the MRC Integrative Epidemiology Unit (IEU), University of Bristol

George Davey Smith is a Professor of Clinical Epidemiology, and director of the MRC IEU, University of Bristol

Marcus Munafo is a Professor of Biological Psychology, in the School of Psychology Science and leads the Causes, Consequences and Modification of Health Behaviours programme of research in the IEU, University of Bristol.

 

Drinking in pregnancy: lasting effects of low-level alcohol use?

Posted on by lindsey.pike

Kayleigh Easey, a PhD student and member of the Tobacco and Alcohol Research Group (TARG) at the School of Psychological Science at the University of Bristol, takes a look at a recent systematic review investigating effects of parental alcohol use and offspring mental health.

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It’s generally well known that drinking large amounts of alcohol during pregnancy is linked to Foetal Alcohol Syndrome (FAS), and negative outcomes such as premature birth and an increase in the risk of miscarriage. However, less is known about the effects of low to moderate alcohol use during pregnancy on offspring outcomes after birth, and even less for mental health outcomes in the child, particularly internalising disorders such as depression. Despite government guidelines being updated by the Department of Health in January 2016, advising pregnant women that the safest approach is to abstain from drinking alcohol altogether through their pregnancy, there remains uncertainty amongst the public as to whether a ‘drink or two’ is harmful or not.

Is a ‘drink or two’ harmful during pregnancy?

Researchers within the field mostly agree that abstinence from alcohol during pregnancy is the safest approach, but the evidence to support this is relatively weak, often due to study design and sample limitations. A previous meta-analysis highlighted how there are relatively few studies investigating low levels of alcohol use in pregnancy. Their analyses mainly focused on pregnancy outcomes such as gestational diabetes and childhood outcomes linked to FAS such as behavioural problems. Until now, a comprehensive review had not been undertaken on the effects of light to moderate drinking in pregnancy and offspring mental health.

Our research sought to review and summarise what literature was currently available for drinking alcohol in pregnancy and offspring mental health outcomes. Overall, we found that over half of the analyses included in the review reported an association between drinking in pregnancy and offspring mental health problems, specifically anxiety, depression, total problems and conduct disorder. By excluding FAS samples we were more certain that the findings we were reporting were representative of lower levels of drinking in pregnant women. However, we can’t be certain that many of the included studies are not still capturing higher levels of alcohol use in pregnancy, and potentially children with undiagnosed foetal alcohol spectrum disorders – a known problem in researching prenatal alcohol use.

Our review also highlights the differences across studies measuring drinking in pregnancy and offspring mental health, with all but four studies using a different measure of drinking alcohol in pregnancy, making comparison difficult. This means it is difficult to establish between studies if there is a ‘cut off’ level for what is potentially a hazardous level of alcohol exposure during pregnancy.

Image by Jill Wellington from Pixabay

Abstinence seems to be the safest approach

The associations we find do not provide evidence of a causal effect on their own, which can be difficult to demonstrate. However, it is important for women to understand what the current evidence shows, to allow them to make informed decisions about drinking during pregnancy. Women should be able to use this information to inform their choices, and to avoid potential risks from alcohol use, both during pregnancy and as a precautionary measure when trying to conceive.

As such, people may take from this that the current advice of abstaining from alcohol during pregnancy is certainly sensible, at least until evidence is available to indicate otherwise. We suggest that future work is needed to investigate whether light to moderate alcohol use in pregnancy may be harmful to different mental health outcomes in children from large cohort studies, which is exactly what I am currently doing within my PhD research using the Children of the 90s study.

This blog post was originally posted on the Alcohol Policy UK website.

It’s the mother! Is there a strong scientific rationale for studying pregnant mothers so intensively?

Posted on by lindsey.pike

Dr Gemma Sharp, University of Bristol 

For many years, researchers have been studying how our early life experiences, including those that happen before we are born, can affect our lifelong health. In an article we wrote last year, Debbie Lawlor (University of Bristol), Sarah Richardson (Harvard University) and I show that most of these studies have focused on the characteristics and behaviours of mothers around the time of pregnancy. In a recent paper published in the Journal of Developmental Origins of Health and Disease, Debbie Lawlor, Sarah Richardson, Laura Schellhas and I show that there have been more studies of maternal prenatal influences on offspring health than any other factors (read more here).

We argue this is because people assume that mothers, through their connection to the developing fetus in the womb, are the single most important factor in shaping a child’s health. This assumption runs deep and is reinforced at every level, from researchers, to research funders, to journalists, to policy makers, to health care professionals and the general public  (see figure 1).

In our article, we question the truth behind this assumption.

Is there a strong scientific rationale for studying pregnant mothers so intensively?

Well, no actually. Although a lot of studies have found correlations between maternal characteristics and offspring health, the evidence that these characteristics actually have a causal effect is pretty weak. And since there haven’t been many studies of the effects of fathers and other factors, it’s difficult to say how important any maternal effect might be compared to any other early life experience.

Focusing so intensively on pregnant mothers, and interpreting all evidence as causal (if a mother does X, their unborn child will have Y), can have very damaging effects. Complex, nuanced scientific findings are being rushed into simplified advice that, although well-meaning, places the burden of blame on individual pregnant women. For example, there has been very little research on the effects of low-level drinking during pregnancy, but the current advice in the United States is for all sexually active women of reproductive age to avoid alcohol completely if they are not using birth control, for fear of fetal harm.

Fig. 1 Assumptions that the health, lifestyle and behaviours of mothers around the time of pregnancy have the largest causal influence on their children’s health and risk of disease drives research at all stages, from study design to research translation, and is also reinforced by research itself.

A culture of blame

The culture of blame is more overt in the media, where articles are often guilty of scaremongering. This feeds into public beliefs about how pregnant women should and shouldn’t behave, which can limit pregnant women’s freedom and even lead to questions around whether their behaviour is criminal. For example, pregnant women have reportedly been refused alcoholic drinks in bars, and taking drugs during pregnancy is legally classed as child abuse in many US states.

In our article, we make a number of recommendations that we hope will create more of a balance. In particular, we call for more research on how child health might be influenced by fathers and other factors, including the social conditions and inequalities that influence health behaviours. We also call for greater attention to be paid to how health advice to pregnant women is constructed and conveyed, with clear communication of the supporting scientific evidence to allow individuals to form their own opinions.

The EPoCH study

In June, I’ll begin work on a new project to investigate how both mothers and fathers’ lifestyles might causally affect the health of their children. Funded by the Medical Research Council, the EPoCH (Exploring Prenatal influences on Childhood Health) study will highlight whether attempts to improve child health are best targeted at mothers, fathers or both parents. I’m excited to work closely with the people behind WRISK to help ensure that findings from this project are communicated effectively and responsibly.

I hope that, along with the rest of the research community, we can produce high quality evidence to support health care and advice that maximises the health of all family members and stops blaming women for the ill health of the next generation.

The original article can be accessed (open access) here, and the authors’ full list of recommendations can be found below.

Full recommendations

Our full recommendations, which apply variously to researchers, journalists, policy makers and clinicians:

  • Collect more and better quality data on partners of pregnant women.
  • In addition to studying the effects of mothers, study and compare the effects of partners/fathers, social and other factors on child health.
  • Look for causal relationships between these factors and child health, not just (potentially spurious) correlations.
  • Publish all results, including negative results, to give a balanced view of the evidence.
  • Be aware and critical of the current imbalance in the scientific literature and how this will bias our overall understanding of the truth.
  • Collaborate with social scientists to consider the social implications of this research and the role of cognitive bias and social assumptions when interpreting findings.
  • When communicating findings, put the risk in context: compare findings to the broader scientific literature and the social environment.
  • Avoid language that suggests individual mothers are responsible for direct harm to their foetuses (most of the evidence will be based on averages in a population and can’t be assumed to apply to all individuals).
  • Where there is evidence of a paternal effect, aim public health advice at both parents.
  • Explain the level of risk in a way that empowers people to assess the evidence and form their own opinions (i.e. avoid over simplification).

This blog post is an edited version of one originally posted on the WRISK project website.

The MRC Integrative Epidemiology Unit at the University of Bristol (IEU) conducts some of the UK's most advanced population health science research. It uses genetics, population data and experimental interventions to look for the underlying causes of chronic disease.