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EXPERT REACTION: Keto diet protects mice from the flu

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US researchers suggest that a diet low in carbohydrates and high in fats - also called a ketogenic (keto) diet - can protect mice from a potentially dangerous influenza A virus. The team says that a keto diet caused specific cells in the mice's lungs to expand, and in turn improved their function as a barrier against viruses. The specific relation of a keto diet on the metabolism is what triggers this defence, say the researchers, as neither a high carb or providing mice with the chemical byproduct of a keto diet had the same effect.

Journal/conference: Science Immunology

DOI: 10.1126/sciimmunol.aav2026

Organisation/s: Yale School of Medicine, USA

Funder: This work was in part supported by funding from the NIH (AI054359, R01EB000487, R01AI127429, R42AI120269, and R21AI131284 to A.I.). A.I. received support from the Claude D. Pepper Older Americans Independence Center at Yale University School of Medicine P30 AG021342 NIH/NIA. A.I. is an investigator of the Howard Hughes Medical Institute. The Dixit lab is supported in part by NIH grants P01AG051459, AI105097, AG051459, and AR070811 and the Glenn Foundation on Aging Research. E.L.G. is supported by NIH grant K99AG058801. Author contributions: A.I. and V.D.D. conceived the overall project, experiments, and data interpretation. E.L.G. and R.D.M. conceived and performed experiments, data analysis, and interpretation. A.I., V.D.D., E.L.G., and R.D.M. prepared the manuscript. Y.K. and S.S. performed RNA-seq analysis. E.K. performed experiments to measure viral titers and performed other experiments.

Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Dr Kirsty Short is an Influenza Virologist at the University of Queensland

In recent years, there has been significant interest in the ketogenic diet (KD) due to suggestions that it is an effective weight loss tool. The study in question is significant because it is the first to show that a KD may help mice resistant infection with the flu virus. Specifically Goldberg and colleagues showed that feeding mice a KD for just one week was sufficient to reduce flu-associated morbidity and mortality.

One week on a KD also reduced the ability of the virus to replicate in the lungs of infected mice. These protective effects were due to an expansion of specific protective immune cell, called gamma-delta T cells, in the lungs of mice on a KD. These cells have a variety of different functions but they may help protect mice from the flu by reducing oxidative stress in the lung and enhancing lung barrier integrity.

Importantly, feeding mice a high fat diet or administering them the primary energy substrate of a KD did not induce the same ‘protective’ effect. These data indicate that the metabolic adaption that occurs in a KD is important in protecting mice from the flu.

The important caveat with this study is that it was performed in mice. Given the known differences between the diets and metabolism of mice and humans, it remains unclear what this would mean for people who follow the KD.

However, where this study is significant is that it adds to the growing body of evidence that our diet plays an important role in determining one’s risk of both non-infectious diseases (e.g. cancer and diabetes) AND infectious diseases (e.g. the flu). This is a key point to remember in light of Australia’s growing obesity epidemic and the constant challenge that the flu virus poses to human health.

Last updated: 15 Nov 2019 11:12am
Declared conflicts of interest:
None declared.
Dr Evangeline Mantzioris is the Program Director of Nutrition and Food sciences at the University of South Australia.

In this paper which used a mouse model, placing the mice on ketogenic diets resulted in improvements in the symptoms of flu. This study gives us really good evidence about how metabolites from ketogenic diets may be useful. But it is important to remember that this is a mouse model and more research is needed to see if it is also the case in humans.

Last updated: 15 Nov 2019 11:12am
Declared conflicts of interest:
None declared.
Dr Michelle Tate is head of the Viral Immunity and Immunopathology laboratory at the Hudson Institute of Medical Research and a NHMRC Career Development Fellow.

The severity of the flu caused by influenza virus can range from symptomless, mild, to severe—resulting in death. We currently do not fully understand why certain people are protected or more susceptible to infection.

Goldberg et al. examined the impact of a ketogenic diet on the immune response and susceptibility of mice to infection. Mice were fed a low carbohydrate, high fat diet for one week before they were infected with an influenza virus strain (which causes disease in mice, but not humans).

Mice on a low carbohydrate, high fat ketogenic diet were shown to be less susceptible to infection because they had greater numbers of protective gamma delta T cells in the lung.

Mice fed a high carbohydrate, high fat diet also had a greater number of gamma delta T cells in the lung, however, this did not result in protection against infection. The authors suggest that enhanced metabolism of fatty acids is required for the protection.

There is increasing interest as to whether diet can impact immunity to infection and this article demonstrates there is a link. The results are interesting, however how a high fat diet promotes expansion of protective gamma delta T cells is not clear.

It is important to note the study was performed in mice, which may not correlate to humans particularly as differences in metabolism exist. In addition, the study was performed using genetically altered mice which differ to conventional laboratory mice, and a strain of influenza virus that causes disease in mice but not humans was used. Additional studies in humans and with human influenza viruses are warranted.

Last updated: 15 Nov 2019 11:11am
Declared conflicts of interest:
None declared.
Dr Rosemary Stanton OAM, Nutritionist, Visiting Fellow, School of Medical Sciences, University of New South Wales

In this study, a small number of specially bred mice were fed one of three different diets for seven days before being infected with an influenza A virus and their survival noted over the following days. The researchers also looked at a range of factors within lung cells that they thought might provide insight into the differing rates of survival.
 
The two diets initially used were:
• standard chow (3.1 Cals/g: 18% from fat, 58% from carbohydrate and 24% from protein) fed to 5 mice;
• a keto diet (6.76 Cals/g: 90% from fat. 1% from carbohydrate; 9% from protein) fed to 7 mice
 
The mice on the keto diet showed greater resistance to the virus and greater survival compared with the mice fed normal chow.
 
Not surprisingly, the mice on the keto diet – which had more than twice as many calories as the normal chow – were able to preserve their body weight. To check if this was due to the extra calories, a third group of 9 mice were fed a high fat diet (5.21 Cals/g: 60% from fat, 20% from carbohydrate, 20% from protein). When challenged with the influenza A virus these mice (still getting fewer calories than the mice on the keto diet) also lost weight from day two after being given the influenza A virus. Most died by day four.
 
Relating the results of these tests on mice to any comparable effect in humans would be drawing a very long bow. 
 
The different (and small) numbers of mice in each group and the differences in the diets in energy, protein, fat and carbohydrate would all need to be addressed. And as the researchers note, the precise mechanisms by which a keto diet might change the ability of the lungs to resist Influenza A will require further study.
 
Even if the mechanisms in mice are solved, assuming the results might also apply to humans is another ball game.

Last updated: 15 Nov 2019 11:09am
Declared conflicts of interest:
None declared.
Professor Nikolai Petrovsky is from the College of Medicine and Public Health at Flinders University

In an intriguing, but highly unlikely to be clinical significant finding, this work showed that a ketogenic high fat-low carbohydrate diet synonymous with the well known Atkins diet, caused an increase in immune cells of a particular type (gamma delta T cells) in the lungs which in turn had the effect of marginally reducing the severity of influenza infection. 

Interestingly, they showed that some of these effects on increased immune cells in the lung were driven purely by the high fat diet. In fact, in similar findings several years ago researchers at the University of Newcastle showed that lung inflammation rose dramatically in response to a high fat meal, suggesting a potential link between high fat diets and asthma.

This effect might even be an effect of fat in the diet on the gut microbiome that then might indirectly affect the lung microbiome, triggering an immune response in the lung. However, on top of this, they showed that the ketogenic diet had additional immune effects as they didn't see an effect on influenza severity of a high fat and carbohydrate diet. 

Notably the effects shown here on influenza infection with the ketogenic diet were marginal at best, with most of the mice still dying of infection, and hence this finding is of academic rather than practical interest, particularly if such a diet might increase the risk of asthma and other lung problems due to the increased lung inflammation. 

So it is unlikely that clinicians will ever recommend going on a ketogenic diet to potentially slightly reduce the severity of influenza illness.

Last updated: 15 Nov 2019 11:09am
Declared conflicts of interest:
Nikolai has declared no conflicts of interest.
Professor Margaret J. Morris is from the School of Medical Sciences and Head of the Environmental determinants of obesity group at the University of New South Wales (UNSW)

What is remarkable about this study is that ‘protective effects’ of a ketogenic diet (KD) were observed in mice fed KD for just seven days before infection with influenza virus.

Mice were protected from bodyweight loss and had improved survival relative to infected mice on a normal chow diet.

It is noteworthy that caloric density did not seem to be important, as lungs of high fat diet fed mice were not protected from the effects of infection.

Effects were not replicated by treatment with 1,3-butanediol (BD), which increases levels of the chemical BHB circulating. Protective T cells were required to achieve the full effect of KD.
 
A range of beneficial effects of KD have been described previously. These observations raise a number of questions regarding potential mechanisms - could diet-induced changes in gut microbiome play a role in modulating response to the virus? Will the effects last? An intriguing study.

Last updated: 15 Nov 2019 11:07am
Declared conflicts of interest:
None declared.

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