QJM Advance Access originally published online on February 2, 2008
QJM 2008 101(3):237-239; doi:10.1093/qjmed/hcn004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From nurture to Nature—the story of the Aberdeen asthma dietary hypothesis
From the Department of Environmental and Occupational Medicine, University of Aberdeen and Institute of Occupational Medicine, Edinburgh, Scotland, UK
Address correspondence to Professor Anthony Seaton, 8 Avon Grove Cramond, Edinburgh EH4 6RF, Scotland, UK. email: a.seaton{at}abdn.ac.uk
Received 22 November 2007 and in revised form 19 December 2007
 |
Summary |
|---|
 Top Summary The first ideaLooking for evidenceConclusions, but not the...A note of cautionAcknowledgementsReferences |
|---|
This article recounts the story of the dietary hypothesis for the rise in asthma and allergies from the first idea to publication of papers showing an association of maternal diet during pregnancy with rise of asthma in the offspring at 2 and 5 years. The nutrient most consistently associated with this endpoint is vitamin E, and it is suggested that reductions in the intake of this vitamin during pregnancy over past decades could explain up to a third of the excess cases of childhood asthma.
New ideas are often hard to test in the world of medical research and slow to be accepted. This is the story of one such, the hypothesis that changing nurture in the uterus was responsible for the increase in the prevalence of asthma and allergies, how it was tested and the outcome up to the point of a paper in Nature Immunology.
|
The first idea |
|---|
|
TopSummaryThe first ideaLooking for evidenceConclusions, but not the...A note of cautionAcknowledgementsReferences |
|---|
The rise in prevalence of asthma and allergies in the developed world over the past four decades has been well documented, and has been particularly notable among children.1,2 Why should this be? The phenomenon seems to be a consequence of environmental change affecting primarily the prosperous world. Considering changes in our ecology over the period, the obvious causes of lung disease, smoking, infections and air pollution, have all declined. Exposure to allergens is unlikely to have increased.3,4 It seems that our environment has improved rather than become more toxic, but what about our susceptibility to that environment? Usually we think of susceptibility in terms of genetics, but there are also environmental determinants of susceptibility. Expression of bacterial genes may be modified by the culture medium on which the organisms are grown; perhaps expression of our genes is influenced by our mother's or our diet.
In 1994, we proposed the hypothesis, based on personal observation of the changes in the British diet over 50 years and data from the British National Food Survey, that progressive reduction in antioxidant intake had made the population as a whole more susceptible to airway inflammation and the allergens that initiate it.2 In our minds at the time was an idea that the population's diet would be reflected in the diet of pregnant women and that this might influence the susceptibility of the newborn to allergens. In the 1996, Tudor Edwards lecture I asked ‘Could it be that a generation of children has been born with diminished antioxidant defences at the very time they first meet the main antigen, the house-dust mite?’ 5 It was a testable hypothesis, with great potential (if correct) to prevent ill health.
|
Looking for evidence |
|---|
|
TopSummaryThe first ideaLooking for evidenceConclusions, but not the...A note of cautionAcknowledgementsReferences |
|---|
The immediate problem was to obtain some evidence that would persuade research-funding bodies to support the crucial prospective study of pregnant women and their offspring. To embark on a long-term prospective study with little expectation of positive results within less than a decade would have required an act of faith by the funding body that it could hardly justify, together with unusual tolerance of an employer focussed on the next Research Assessment Exercise. It was thus necessary to obtain some indirect evidence, and three opportunities arose in ongoing studies. The first was a study of the relationship of allergies to residence close to oilseed rape cultivation. The second was a 25-year follow-up of an Aberdeen childhood cohort, and the third was a study of childhood asthma in Saudi Arabia. Three separate case-control studies of nutrition were inserted into these projects and, to our surprise, all came up with results suggesting that we were on to something important. Rural Aberdeenshire adults with airway hyperreactivity had diets higher in fats and poorer in vitamins C and magnesium than did those without asthma;6 subjects who had developed asthma only in adult life ate diets poorer in vitamin E and had lower plasma
-tocopherol than those in the same long-term cohort who never had asthma;7 and Saudi children with asthma, eating an Arabic diet, also had lower vitamin E intakes than those without asthma.8 It seemed unlikely to be coincidence, and was enough to persuade Asthma UK to fund a prospective study of a pregnancy cohort. It proved possible to recruit 2000 pregnant women and, towards the end of their pregnancy, to determine their dietary intakes. In a proportion it was also possible to obtain cord blood from the babies, and this showed not only that the newborn child's cord blood mononuclear cells recognized and proliferated in response to mite and grass allergens but also that these responses were influenced by the mother's diet during pregnancy.9,10 Specifically, a low intake of vitamin E was associated with increased responsiveness to allergen. The strength of the proliferative response related to the birth order of the child, suggesting that the fundamental basis of the ‘hygiene’ hypothesis of the rise in allergy was actually present before birth and before the child could have been influenced by the external environment.
Analysis of the symptoms of the children at age 1 year found only a weak protective effect of breast-feeding on wheeze and no effect of maternal diet. At 2 years, however, there was an association of wheezy illness with low maternal vitamin E intake, largely confined to those who had atopic mothers, and also an association with low blood levels of selenium in the mother.11,12 In this analysis vitamin C appeared to have an adverse effect. But at age 5 years there was a clear association of asthma, allergic sensitization, wheeze and reduced ventilatory function with low maternal intake of vitamin E during the pregnancy, the children of the mothers with the lowest quintile of intake having a 4-fold increase in such symptoms.13 In contrast, the child's diet had no additional influence at this stage. By this age, the associations with selenium and vitamin C had disappeared, but further analysis showed an apparently protective effect of maternal consumption of apples and fish.14 Meanwhile colleagues in the United States had embarked on a similar study in a population with differing socio-economic, ethnic, smoking and dietary profiles, which replicated our reported associations between maternal vitamin E intake during pregnancy and neonatal cord blood mononuclear cell responses and wheezing symptoms at the age of 2 years.15,16 They also found an association at 2 years with maternal vitamin D intake,17 and this led us to analyse our data and to replicate their finding.18
|
Conclusions, but not the conclusion |
|---|
|
TopSummaryThe first ideaLooking for evidenceConclusions, but not the...A note of cautionAcknowledgementsReferences |
|---|
The original hypothesis was that changes in diet had increased population susceptibility to allergens and thus increased the incidence of asthma. In order to give this idea plausibility, we had suggested that relative antioxidant deficiency was the cause. It is now clear that this is, at the most, a minor mechanism. But it seems very likely indeed, on the basis of the strength, specificity, coherence, consistency and plausibility of our results that maternal intake of vitamin E (and perhaps also of vitamin D) is protective against asthma and that this effect is of serious epidemiological and public health significance, indeed sufficient to explain about a third of the increase in asthma in the UK. The effect seems to be present in the cord blood (and these responses relate to later risk of asthma19), is not manifest at age 1 year, and becomes stronger as time passes, in keeping with the concept that it increases susceptibility to provocation by allergens or other agents and thus manifests as the child's cumulative exposure increases. The mechanisms remain undiscovered as yet, but may be found in the early development of the airways or in modification of the immune responses to the initial exposures to allergens, as discussed in Nature Rev Immunology.20
|
A note of caution |
|---|
|
TopSummaryThe first ideaLooking for evidenceConclusions, but not the...A note of cautionAcknowledgementsReferences |
|---|
Following the example of John Snow, epidemiology should have a practical outcome in terms of disease prevention. A natural impatience says that we should persuade the Departments of Health to give advice to pregnant women on appropriate dietary modification to increase intake of vitamin E. Analogous advice has in the past been based on less evidence; for example, nuts are warned against yet they are a rich source of vitamin E. Scientific caution, however, urges that we should carry out an intervention trial, since so far we have only noted associations, and that is what we intend. The results of this will be some years in coming. Meanwhile, the mechanistic explanation of our results remains to be found, opening up plenty of research opportunities.
|
Acknowledgements |
|---|
|
TopSummaryThe first ideaLooking for evidenceConclusions, but not the...A note of cautionAcknowledgementsReferences |
|---|
I am grateful to the many colleagues who have contributed to this work, especially Drs Graham Devereux, Geraldine McNeill, Rob Barker, Coreen Bodner and Sheelagh Martindale.
Conflict of interest: None declared.
|
References |
|---|
|
TopSummaryThe first ideaLooking for evidenceConclusions, but not the...A note of cautionAcknowledgementsReferences |
|---|
1. Burney PGJ, Chinn S, Rona RJ. Has the prevalence of asthma increased in children? Evidence from the National Study of Health and Growth. 1973-1986. Br Med J (1990) 300:1306–10.
2. Seaton A, Godden DJ, Brown KM. Increase in asthma: a more toxic environment or a more susceptible population? Thorax (1994) 49:171–4.
3. Rao VRM, Dean BV, Seaton A, Williams DA. A comparison of mite populations in mattress dust from hospital and from private houses in Cardiff, Wales. Clin Allergy (1975) 5:209–15.[Medline]
4. Seaton A, Soutar A, Mullins J. The increase in hay fever: pollen, particulate matter and SO2 in ambient air. Q J Med (1996) 89:279–84.
5. Seaton A. The lung and the world about it. The Tudor Edwards lecture. J Roy Coll Phys Lond (1996) 30:232–7.[Web of Science][Medline]
6. Soutar A, Seaton A, Brown K. Bronchial reactivity and dietary antioxidants. Thorax (1997) 52:166–70.[Abstract]
7. Bodner C, Godden D, Brown K, Little J, Ross S, Seaton A. Antioxidant intake and adult-onset wheeze: a case-control study. Eur Respir J (1999) 13:22–30.[Abstract]
8. Hijazi N, Abalkhail B, Seaton A. Diet and childhood asthma in a society in transition; a study in urban and rural Saudi Arabia. Thorax (2000) 55:775–9.
9. Devereux G, Seaton A, Barker R. In utero priming of allergen-specific helper T-cells. Clin Exp Allergy (2001) 31:1686–95.[CrossRef][Web of Science][Medline]
10. Devereux G, Barker R, Seaton A. Ante-natal determinants of neonatal immune responses to allergens. Clin Exp Allergy (2002) 32:43–50.[CrossRef][Web of Science][Medline]
11. Martindale S, McNeill S, Devereux G, Campbell D, Rusell G, Seaton A. Antioxidant intake in pregnancy in relation to wheeze and eczema in the first two years of life. Am J Resp Crit Care Med (2005) 171:221–8.
12. Devereux G, McNeill G, Newman G, Turner S, Craig L, Martindale S, et al. Early childhood wheezing symptoms in relation to plasma selenium in pregnant mothers and neonates. Clin Exp Allergy (2007) 37:1000–08.[CrossRef][Web of Science][Medline]
13. Devereux G, Turner SW, Craig LCA, McNeill G, Martindale S, Harbour PJ, et al. Low maternal vitamin E intake during pregnancy is associated with asthma in 5-year-old children. Am J Resp Crit Care Med (2006) 174:499–507.
14. Willers SM, Devereux G, Craig LCA, Mcneill G, Wijga A, Abou El-Magd W, et al. Maternal diet during pregnancy and asthma: respiratory and atopic symptoms in 5-year-old children. Thorax (2007) 62:773–9.
15. Litonjua AA, Tantisira KG, Finn PW, Finn B, Schaub C, Schroeter D, et al. Maternal antioxidant intake during pregnancy and cord blood lymphoproliferative responses. Am J Resp Crit Care Med (2004) 169:A501.
16. Litonjua AA, Rifas-Shiman S, Ly NP, Tantisira KG, Rich-Edwards JW, Camargo CA, et al. Maternal antioxidant intake in pregnancy and wheezing illnesses in children at 2 years of age. Am J Clin Nutr (2006) 84:903–11.
17. Camargo CA, Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST, Gold DR, et al. Prospective study of maternal intake of vitamin D during pregnancy and risk of wheezing illnesses in children at age 2 years. Am J Clin Nutr (2007) 85:788–95.
18. Devereux G, Litonjua AA, Turner SW, Craig LCA, McNeill G, Martindale S, et al. Maternal vitamin D intake during pregnancy and early childhood wheeze. Am J Clin Nutr (2007) 85:853–9.
19. Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt PG. Development of allergen-specific T-cell memory in atopic and normal children. Lancet (1999) 353:196–200.[CrossRef][Web of Science][Medline]
20. Devereux G. The increase in asthma and allergy: food for thought. Nat Rev Immunol (2006) 6:869–74.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  U. Mabalirajan, J. Aich, G. D. Leishangthem, S. K. Sharma, A. K. Dinda, and B. Ghosh Effects of vitamin E on mitochondrial dysfunction and asthma features in an experimental allergic murine model J Appl Physiol, October 1, 2009; 107(4): 1285 - 1292. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||