DN Forum - Malnutrition: finding solutions through novel dairy research

Malnutrition: finding solutions through novel dairy research

Ireland’s battle with obesity is no stranger to dramatic media attention or Government debate but, alongside this, the largely unrecognised issue of malnutrition is silently knocking on Irish society’s door. Worldwide, 795 million people are malnourished and with 98% of these living in developing countries, it is unsurprising that the majority of cases are driven by hunger or lack of access to nutritious food. Here in the developed world, however, where food is in abundance, malnutrition tends to be driven by inadequate nutrient intake caused by illness, poor dietary choices or loss of independent living.

On any given day in Ireland, an estimated 145,000 people (4% of the population) are considered to be malnourished or at risk of malnutrition. Those over the age of 65 years, living alone or in care institutions are most at risk with the highest concentrations in hospitals (one in three patients). The figures are similar across the EU, where it is estimated that 10% of individuals over 65 years are malnourished.

Malnourished patients typically exhibit higher rates of infection and mortality, with complications such as poorer wound healing, impaired respiratory function, muscle weakness and depression being common. These factors result in people with malnutrition being three times more likely to require hospital admissions and the average hospital stay of a malnourished patient is 30-70% longer.

It has been estimated that malnutrition costs the Irish state €1.42 billion every year, which is greater than the costs associated with obesity and more than 10% of the annual health and social care budget. Unless urgently addressed, the costs associated with dealing with malnutrition could rise as our population ages. Given the significant societal and financial burden of malnutrition, any potential saving that can be made could have a substantial positive impact on our health system. For example, a 1% reduction in medical care costs could deliver €14.2 million in savings to the State annually.

If detected early enough, malnutrition can usually be prevented or treated and, therefore, screening is a vital measure in combating this issue in developed countries. The Malnutrition Universal Screening Tool (MUST) is the recommended approach for nutritional screening. Provision of a balanced diet, which is both energy and nutrient dense, is an obvious treatment approach for malnourished individuals. However, it is not always a feasible solution as their dietary requirements can be significantly altered in illness and chronic loss of appetite is common. Appetite stimulation therefore poses an attractive opportunity for overcoming this challenge.

Novel research by Food for Health Ireland (FHI) is exploring the possibility of using milk-derived bioactive peptides to mimic the action of ghrelin, the body’s appetite stimulating hormone. These peptides therefore have promising potential as functional ingredients in food or oral nutrition supplements to treat malnutrition.

EDITORIAL

In this edition of DN Forum, we address malnutrition, a silent crisis in our burdened healthcare system. Our expert review explores a novel dairy solution to malnutrition, which, surprisingly, is a condition that has a greater economic impact in Ireland than obesity. Together with our Food for Health Ireland (FHI) partners, Dr Jacqueline Lyons and Kenneth Howick from the Appetite Modulation Team at University College Cork, we provide an account of malnutrition in Ireland and a synopsis of some novel Irish research that sets out to combat this growing problem.

This FHI research is aimed at tackling appetite loss, which is one of the key factors driving malnutrition in the elderly and hospitalised. The work explores the potential role of dairy peptides, which could be used to mimic the appetite stimulating effects of ghrelin, better known as the body’s ‘hunger’ hormone. Improving appetite in those at risk of malnutrition from ill health or ageing could help to alleviate the problem.

We hope you enjoy this edition of DN Forum and look forward to any feedback or comments you wish to share: nutrition@ndc.ie

Dr Marianne Walsh Nutrition Manager

(NDC)

Malnutrition: Irish research exploring a novel dairy solution

Life is getting longer

Most of us reading this can expect to live longer than our ancestors ever have. Thanks to improving standards of health and hygiene over the past century in particular, elderly populations in many countries have increased dramatically in size. By 2030, some 72 million people aged 65 years and over are expected to live in the U.S. – a world away from the 1900 figure of three million4. The Irish situation mirrors this trend directly: in 2010, one person in nine was over the age of 65 years; by 2050, that number will have risen to one in four (Table 1). While this is a fantastic achievement for mankind, it does present its own set of challenges, not least in the areas of healthy ageing and the prevention of age-related conditions such as malnutrition.

maintenance of a functioning ghrelin system in elderly people might help maintain a healthy appetite, thereby reducing the likelihood of malnutrition occurring in these individuals.

Ghrelin is a 28-amino acid peptide synthesised and secreted by the gastric oxyntic cells which line the stomach7. It is responsible for a plethora of physiological actions in the body, including regulation of gastric motility, glucose homeostasis and immune function, as well as having a role in reward processes, mood and stress response9. Critically, it is one of the key gut hormones involved in regulating food intake10, 11. Ghrelin’s daily fluctuation aligns itself with meal-times: levels of ghrelin spike immediately before meals, and reduce once food has been consumed12. Elevated ghrelin levels in periods of hunger are also thought to be responsible for our increased perception of food palatability, as well as our motivation to obtain food13, 14

The drivers of malnutrition in Ireland

Disease and malnutrition are closely linked, where either one can be a causative factor for the other. In the majority of cases in Ireland and the developed world, malnutrition affects older people with chronic disease but those with conditions that affect appetite, ability to chew, swallow or digest food are also at risk.

It is well known that maintaining a healthy body weight, taking regular exercise and consuming a varied, balanced diet are key to staving off many age-related diseases. However, achieving this is not always as simple as it sounds. Energy requirements decrease in old age, while requirements for a number of micronutrients (vitamins and minerals) increase1. Unfortunately, elderly people often face issues that can combine to make choosing a nutrientdense diet very difficult. Vision or mobility problems can make it physically challenging to purchase and prepare food. Chewing difficulties and a decreased sense of smell and taste can make a range of previously enjoyed foods less appealing. Factors such as depression, loneliness or isolation commonly defeat any motivation to eat well. In addition, anorexia (loss of appetite) is prevalent among the elderly and can seriously compromise food and nutrient intake2. Regardless of body weight, many of our elderly are therefore at risk of becoming malnourished, with those living alone or in nursing institutions being particularly vulnerable3

Ghrelin: the hunger hormone

Changes in the signals or hormones that control appetite and satiety are strongly implicated in the development of poor appetite in the elderly6. Of particular interest is ghrelin, the hunger hormone, discovered in 19997. Dysregulation of the ghrelin system has been observed in appetite-related disorders and elderly populations exhibit a natural decline in ghrelin secretion, which can be accompanied by anorexia and malnutrition8. In theory,

Upon its release into the circulation, ghrelin acts on its receptor, the GHSR-1a. The GHSR-1a is located in two key areas that influence food intake – the gut, and the hypothalamus in the brain15. The hypothalamus in particular is associated with the regulation of metabolism and appetite16. The hypothalamus is surrounded by a rich network of permeable blood capillaries which allows ghrelin to easily access the central nervous system to directly activate appetite centres via the bloodstream in times of hunger17. Secondly, GHSR-1a is present on the vagus nerve, the longest autonomic nerve in the body. The vagus connects the gastrointestinal tract with the hypothalamus. Ghrelin in the bloodstream is known to act on the GHSR-1a in the gut, sending electrical signals to the brain via the vagus nerve to further stimulate the sensation of hunger. Reciprocally, the brain sends nerve signals back to the gut to increase motility in preparation for digestion of an impending meal. Therefore, pathways exist that can convey ghrelin’s appetitive impulses from the gut to the brain, and vice versa18

The magic of dairy: more than nutrition

In addition to its well-known nutritional value, milk contains many specific bioactive peptides (protein fragments with biological activities) with specific health-promoting properties19. These bioactive peptides are contained in the parent whey or casein protein, and are generated upon digestion in the gastrointestinal tract20, 21. For example, angiotensin-converting enzyme (ACE) inhibitory milk peptides have been isolated and clinically shown to have anti-hypertensive properties22. Opioid-like fragments, associated with mood regulation, have also been characterised23 Foods rich in protein, such as milk are recognised to enhance satiety and decrease hunger, with a meta-analysis of clinical trials showing that the consumption of 500ml dairy products increased satiety and was associated with decreased appetite24. However, in contrast, bioactive peptides known to alter levels of the gut hormones involved in increasing appetite, including ghrelin, have recently been isolated and are currently being explored by Food for Health Ireland (FHI).

FHI Appetite Modulation project

Essentially, the ghrelin system is a remote control from the gut to switch on feeding. It therefore represents a promising target for increasing appetite25 and the Appetite Modulation project, funded by Food for Health Ireland, aims to bring this to fruition. Previous

Dr Jacqueline Lyons, Kenneth Howick Food for Health Ireland, Appetite Modulation Team, University College Cork.

Dr Jacqueline Lyons Kenneth Howick

Table 1: Estimated percent of the Irish population in older age groups in 2010 and 20505

work in this lab has identified peptide fragments and mechanisms responsible for attenuating hunger. Conversely, FHI’s current work aims to identify milk-derived bioactive peptides that bind to the ghrelin receptors in the body, and as such, behave like ghrelin to increase appetite. Cell-based assays have discovered such peptide sequences in dairy-derived hydrolysates, which replicate the biological functionality of ghrelin. Ultimately, the project aims to characterise these bioactive peptides, and prove them safe to administer to healthy adults, so that they may be brought forward to hospital-based intervention studies to examine their effect on appetite stimulation in elderly patients.

Scientists working on the project have been following the traditional development trajectory of in vitro screening, in vivo pre-clinical testing and finally human studies in a bid to explore the potential of such peptides in the therapeutic treatment of malnutrition:

In vitro: To date, the FHI in vitro screening platform has been able to successfully identify milk-derived peptide fractions that mimic the action of ghrelin in directly activating the GHSR-1a receptor (in the in vitro setting). However, unlike orally stable synthetic pharmaceuticals, these natural hydrolysates are susceptible to degradation in the gastrointestinal tract, which would cause them to lose their unique peptide sequence, and bioactive structure. Therefore, in order to progress to animal studies, FHI scientists have had to develop a gastro-resistant delivery system to protect the bioactive peptide from breakdown in the stomach, and allow delayed release in the intestine.

Animal studies: The potential of these hydrolysates to positively affect appetite is currently being investigated in animal models, and is showing evidence of effect. The studies involve treating animals with either a placebo or active peptide formulation, and monitoring subsequent food intake. Changes in appetite-related biomarkers like ghrelin, Insulin-like Growth Factor (IGF-1) and Growth Hormone (GH) are also being studied.

Human studies: Testing is underway in healthy young adults to ensure the safety of the peptides for human use. The effect of the peptides on appetite will also be examined, although it remains to be seen whether appetite will be stimulated in a healthy nonpatient cohort who have no underlying feeding issues. Blood levels of gut hormones and other biomarkers will also be examined to learn more about the bioavailability and pharmacokinetic properties of the peptides.

Future vision

If the bioactive peptides identified as part of the Appetite Modulation project continue to show promise within our in vitro, animal and human study platforms, then a hospital-based intervention study will be planned to look at the effect of the peptides on appetite in malnourished elderly patients. If efficacy is demonstrated, the peptides will be developed as functional food ingredients intended to stimulate appetite and treat malnutrition. The impact of such products could be highly significant. Given the substantial cost of malnutrition and its comorbidities, even small percentage reductions in the scale of malnutrition could deliver large overall savings26. Clinicians would undoubtedly welcome a safe, food-based treatment option for poor appetite in their patients, while the dairy ingredients market would have a novel and clinically significant product to work with. Most importantly, it could mark a step in the right direction when it comes to improving quality of life for older adults.

References:

1. Visvanathan R & Chapman IM. Undernutrition and anorexia in the older person. Gastroenterol Clin N Am 2009; 38: 393-409.

2. Morley JE. Anorexia of aging: physiologic and pathologic. Am J Clin Nutr 1997; 66: 760-73.

3. Kaiser MJ et al. Frequency of malnutrition in older adults: a multinational perspective using the mini nutritional assessment. J Am Geriatr Soc

2010; 58: 1734-8.

4. U.S. Department of Health and Human Services & U.S. Department of Commerce. 65+ in the United States: 2005. U.S. Census Bureau, Current Population Reports. [Online] Available from: https://www.census. gov/prod/2006pubs/p23-209.pdf [Accessed on 07/10/2016].

5. European Commission. Eurostat: Statistics in focus: population and social conditions. [Online] Available at http://ec.europa.eu/eurostat/ documents/3433488/5583040/KS-SF-08-072-EN.PDF/1c8f668a-d1d942cb-80b1-eaf3dfc1b7df [Accessed on 11/10/2016].

6. Chapman IM. Endocrinology of anorexia of ageing. Best Pract Res Clin Endocrinol Metab 2004; 18: 437-52.

7. Kojima M et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656-60.

8. Rigamonti AE et al. Plasma ghrelin concentrations in elderly subjects: comparison with anorexic and obese patients. J Endocrinol 2002;175: R1-5.

9. Müller TD et al. Ghrelin. Mol Metab 2015; 4: 437-60.

10. Inui A et al. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J 2004; 18: 439-56.

11. Cowley MA et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003; 37: 649-61.

12. Cummings DE et al. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001; 50: 1714-9.

13. Schellekens H et al. Ghrelin signalling and obesity: At the interface of stress, mood and food reward. Pharmacol Ther 2012; 135: 316-26.

14. Perello M & Dickson SL. Ghrelin signalling on food reward: a salient link between the gut and the mesolimbic system. J Neuroendocrinol 2015; 27: 424-34.

15. Zigman et al. Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 2006; 494: 528-48.

16. Nakazato M et al. A role for ghrelin in the central regulation of feeding. Nature 2001; 409: 194-8.

17. Cabral A, De Francesco PN, Perello M. Brain circuits mediating the orexigenic action of peripheral ghrelin: narrow gates for a vast kingdom. Front Endocrinol 2015; 6: 44.

18. Date Y. Ghrelin and the vagus nerve. Methods Enzymol 2012; 514: 261-9.

19. Dziuba M, Dziuba Bo, Iwaniak A. Milk proteins as precursors of bioactive peptides. Acta Sci Pol Technol Aliment 2009; 8: 71-90.

20. Meisel H. Biochemical properties of regulatory peptides derived from milk proteins. Biopolymers 1997; 43: 119-28.

21. Korhonen H & Pihlanto A. Food-derived bioactive peptides – opportunities for designing future foods. Curr Pharm Des 2003; 9: 1297-308.

22. Phelan M & Kerins D. The potential role of milk-derived peptides in cardiovascular disease. Food Funct 2011; 2: 153-67.

23. Nagpal R et al. Bioactive peptides derived from milk proteins and their health beneficial potentials: an update. Food Funct 2011; 2: 18-27.

24. Onvani et al. Dairy products, satiety and food intake: A meta-analysis of clinical trials. Clin Nutr 2016; In Press.

25. DeBoer MD. Ghrelin and cachexia: Will treatment with GHSR-1a agonists make a difference for patients suffering from chronic wasting syndromes? Mol Cellular Endocrinol 2011; 340: 97-105.

26. UCD Institute of Food and Health. Nutrition and Health in an Aging Population. [Online] Available from: http://www.ucd.ie/t4cms/UCD_ Ageing_Policy_Doc_June_10.pdf [Accessed on 07/10/2016].

EVIDENCE TO PRACTICE

This research has a range of applications:

A. THE PUBLIC

Any measure that can contribute to reducing malnutrition can either benefit those that are directly or indirectly affected, by reducing the burden on the healthcare system.

B. HEALTH PROFESSIONALS

The possibility of foods or supplements containing a functional ingredient that can help to stimulate appetite in the malnourished has the potential to assist health professionals as they encourage patients to consume more food despite barriers such as anorexia and cachexia.

C. INDUSTRY

The potential outcomes of this research could be used in the development of new functional food products or supplements, providing higher value and application for dairy ingredients.

Key Points

• Malnutrition affects one in three hospital patients in Ireland and is also prevalent in those over the age of 65 that live alone or in care institutions. It increases the risk of infections and medical complications, thereby prolonging hospital stays and reducing quality of life.

• Altered nutrient requirements in addition to loss of appetite caused by illness, depression or old age make the elderly particularly vulnerable to malnutrition. As Ireland

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has an ageing population, with those over the age of 65 years predicted to double by 2050, there is a significant risk that malnutrition will become a larger problem in the coming years.

• Dysregulation of the body’s ability to secrete ghrelin (the hunger hormone) has been observed in appetite-related disorders and elderly populations exhibit a natural decline in ghrelin production, which is accompanied by loss of appetite and increased risk of malnutrition.

• Food for Health Ireland is conducting novel research, which is indicating a role for unique dairy bioactive peptides to mimic the action of ghrelin in the body. These peptides have potential as functional ingredients to promote appetite in those with, or at risk of, malnutrition. This research may help to reduce the financial and social burden caused by malnutrition now and in the future.

The ‘Nutrition & You’ series has been developed by the National Dairy Council and endorsed by the Irish Nutrition and Dietetic Institute to highlight the importance of a healthy diet throughout the life stages.

A FOCUS ON TEENAGERS

During the teenage years, as children start the transition to adulthood, it is particularly important to meet nutritional needs to support this phase of rapid growth and development. This booklet provides concise and relevant information to inspire teenagers to take up healthy habits for life by making positive nutrition choices and participating in physical activity. Booklets may be downloaded from http://www.ndc.ie/our-business/our-latest-publications or a limited number of copies may be ordered by contacting hello@ndc.ie

A summarised version of this edition of DN Forum is also available as an e-book.

Contact us....

THE NATIONAL DAIRY COUNCIL (NDC)

The National Dairy Council

The Studio, Maple Avenue, Stillorgan, Co. Dublin, Ireland

Tel: +353 (0)1  290 2451

Email: info@ndc.ie

Web: www.ndc.ie

FOOD FOR HEALTH IRELAND (FHI)

Food for Health Ireland

Science Centre South University College Dublin

Tel: + 353 (0)1 716 2391

Email: fhi@ucd.ie Web: www.fhi.ie NDCIreland

Mission: To deliver real and unique value to Irish dairy farmers by protecting and promoting the image, quality, taste and nutritional credentials of Irish dairy produce to a wide variety of audiences in a clearly defined, focused and effective manner.

Mission: To leverage the world-class capabilities of the Irish academic partners, with the market expertise of the industry partners, into a pipeline of innovative, nutritional functional ingredients/products for the global food industry.

While the NDC and FHI have made all reasonable efforts to ensure the accuracy of the information presented in this document no responsibility is taken by the NDC or FHI for any errors or omissions. The individual views expressed in this publication do not necessarily constitute the views or policies of the NDC or FHI.