Dr Kaitlin H. Wade^1,2,3

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

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

³Cancer 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.

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.

Amanda Hughes, Kaitlin H. Wade, Matt Dickson, Frances Rice, Alisha Davies, Neil M. Davies & Laura D. Howe

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Young people with health problems tend to do less well in school than other students, but it has never been clear why. One explanation is that health problems directly damage educational outcomes. In that case, policymakers aiming to raise educational standards might want to focus first on health as a means of improving attainment.

But are there other explanations? What if falling behind in school can affect health, for instance causing depression? Also, many health problems are more common among children from less advantaged backgrounds – for example, from families with fewer financial resources, or whose parents are themselves unwell. These children also tend to do less well in school, for reasons that may have nothing to do with their own health. How do we know if their health, or their circumstances, are affecting attainment?

It is also unclear if health matters equally for education at all points in development, or particularly in certain school years. Establishing how much health does impact learning, when, and through which mechanisms, would better equip policymakers to improve educational outcomes.

Using genetic data helps us understand causality

Genetic data can help us answer these questions. Crucially, experiences like family financial difficulties, which might influence both a young person’s health and their learning, cannot change their genes. So, if young people genetically inclined to have asthma are more absent from school, or do less well in their GCSEs, that would strongly suggest an impact of asthma itself. Similarly, while falling behind in school might well trigger depression, it cannot change a person’s genetic propensity for depression. So, a connection between genetic propensity for depression and worse educational outcomes supports an impact of depression itself. This approach, of harnessing genetic information to better understand causal processes, is known as Mendelian randomization.

To find out more, we investigated links between

health conditions in childhood and adolescence
school absence in years 10 & 11
and GCSE results.

We used data from 6113 children born in the Bristol area in 1991-1992. All were participants of the Avon Longitudinal Study of Parents and Children (ALSPAC), also known as Children of the 90s. We focused on six different aspects of health: asthma, migraines, body mass index (BMI), and symptoms of depression, of attention-deficit hyperactivity disorder (ADHD), and of autism spectrum disorder (ASD). These conditions, though diverse, have two important things in common: they affect substantial numbers of young people, and they are at least in part influenced by genetics.

Alongside questionnaire data and education records, we also analysed genetic information from participants’ blood samples. From this information, we were able to calculate for each young person a summary score of genetic propensity for experiencing migraines, ADHD, depression, ASD, and for having a higher BMI.

We used these scores to predict the health conditions, rather than relying just on reports from questionnaire data. In this way, we avoided bias due to the impact of the young people’s circumstances, or of their education on their health rather than vice versa.

Even a small increase in school absence predicted worse GCSEs.

We found that, for each extra day per year of school missed in year 10 or 11, a child’s total GCSE points from their best 8 subjects was a bit less than half (0.43) of a grade lower. Higher BMI was related to increased school absence & lower GCSE grades.

Using the genetic approach, we found that young people genetically predisposed towards a higher BMI were more often absent from school, and they did less well in their GCSEs. A standard-deviation increase* in BMI corresponded to 9% more school absence, and GCSEs around 1/3 grade lower in every subject. Together, these results indicate that increased school absence may be one mechanism by which being heavier could negatively impact learning. However, in other analyses, we found a substantial part of the BMI-GCSEs link was not explained by school absence. It’s unclear which other mechanisms are at play here, but work by other researchers has suggested that weight-related bullying, and negative effects of being heavier on young people’s self-esteem, could interfere with learning.

*equivalent to the difference between the median (50^th percentile) in population and the 84^th percentile of the population

Diagram showing the pathways through which higher BMI could lead to lower GCSEs; either through more schools absence aged 14-16, or other processes such as weight-related bullying. — Our results suggest increased school absence may partly explain impact of higher BMI on educational attainment, but that other processes are also involved.

ADHD was related to lower GCSE grades, but not increased school absence.

In line with previous research, young people genetically predisposed to ADHD did less well in their GCSEs. Interestingly, they did not have increased school absence, suggesting that ADHD’s impact on learning works mostly through other pathways. This is consistent with previous research highlighting the importance of other factors on the academic attainment of children with ADHD, including expectations of the school environment, teacher views and attitudes, and bullying by peers.

We found little evidence for an impact of asthma, migraines, depression or ASD on school absence or GCSE results

Our genetic analyses found little support for a negative impact of asthma, migraines, depression or ASD on educational attainment. However, we know relatively little about the genetic influences on depression and ASD, especially compared to the genetics of BMI, which we understand much better. This makes genetic associations with depression or ASD difficult to detect. So, our results should not be taken as conclusive evidence that these conditions do not affect learning.

What does this mean for students and teachers?

Our findings provide evidence of a detrimental impact of high BMI and of ADHD symptoms on GCSE attainment, which for BMI was partially mediated by school absence. When students sent home during the pandemic eventually return to school, the impact on their learning will have been enormous. And while all students will have been affected, our results highlight that young people who are heavier, who have ADHD, or are experiencing other health problems, will likely need extra support.

Contact the researchers

Amanda Hughes, Senior Research Associate in Epidemiology: amanda.hughes@bristol.ac.uk

Tag: Kaitlin Wade

How can your gut microbiome affect risk of cancer?