November 10, 2021

expert reaction to mice fed on high-sugar diets and psychiatric disorders

A study published in Science Advances looks at high-sugar diets in mice during adolescence and psychiatric disorders.

Prof Ciara McCabe, Professor of Neuroscience, Psychopharmacology and Mental Health at the University of Reading, said:

“This is an interesting study on the interaction between risk factors for psychosis behaviours and sugar on the rodent brain and behaviour, however caution is needed when extrapolating evidence from rodents to humans, especially when causal relationships between high sugar diets and psychosis in humans remains unclear.”

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“This is a study based on detailed experiments in mice, with some measurements on the brains of deceased humans. So how, if at all, can it tell us something about possible effects of a high-sugar diet on adolescent humans, in terms of possibly contributing to the development of major mental illness (schizophrenia and bipolar disorder), when the researchers didn’t look at all at sugar consumption in humans? And, you might reasonable ask, why am I, as a statistician and not an expert in the physiology and brain science of either mice or people, commenting on this study?

“I’ll deal with the last point first. One thing that applied statisticians have to be good at is picking out, from reports of experiments and other studies, the extent to which the reported results actually support the conclusions that are being drawn from them. So I won’t be commenting on whether the researchers used appropriate methods to measure the things that they did measure in the mice – you’d have to ask a biologist about that. I can say that I didn’t see any important problems in the statistical analyses that were carried out – it might seem that the numbers of mice used in some of the comparisons are rather small, but the kinds of mice used in studies like this are genetically very homogenous, are kept as far as possible under strictly controlled conditions that are the same for all of them, and hence differ very little, so there isn’t much variability that needs to be dealt with statistically (and this also minimizes the number of mice that need to be used in the experiments, which is a good thing for mice).

“But how can the study make conclusions, even suggestive ones, about a possible effect of a sugary diet on the mental health of young humans? Often in a study like this it would be enough simply to say, look, there’s bound to be considerable doubt about a conclusion on humans, just because we can’t be sure that what goes on in human bodies and brains matches closely enough to what goes on in mouse bodies and brains. That’s true here, but there’s an extra element in this study compared to what usually goes on in lab mouse and rat studies, which is that the researchers do incorporate some data from human tissues – so I feel I need to explain in a bit more detail, to make the point that, in my view, the inclusion of the human data doesn’t really help in establishing that the mouse study can tell us anything about people.

“The first thing to point out is that what’s going on in the mice, as proposed by the researchers, is quite complicated. They looked at four different types of mice. Some were fed on a starch diet, and some on a diet with a lot of sucrose (the usual type of sugar in table sugar, which is also used as a sweetener in many human foods and drinks). Some were, in genetic terms, ‘wild-type’ so that they had what you might call a normal genetic makeup. Others had a mutation in just one copy of one gene, called Glo1, which reduced their capacity to deal with some of the products of sugars which are potentially toxic. So some of the starch-fed and some of the sugar-fed mice were wild-type, and others in each feeding group had the mutation. The researchers found that mice that had the Glo1 mutation, and were on the sugar diet, behaved differently in several ways from the other mice (on the starch diet, or on the sugar diet but without the mutation). They reported that these behavioural changes were related to possible psychosis, though they do not describe how a psychosis in a mouse might map onto a serious mental illness in humans.

“The researchers went on to look at changes in tiny brain blood vessels of the various groups of mice, and found that there were changes, again generally only in the mice on the sugar diet who also had the mutation. They investigated possible mechanisms in the mouse brains that might lead to the changes in the blood vessels. They also discovered that giving the mice aspirin, which has effects on blood vessels, generally reduced the behavioural changes in the mice with the mutation on the sugar diet, and also reduced the blood vessel changes. Their proposed biological mechanism for how all this works is in Figure 6D of their research paper, and it’s quite complicated.

“After all that, they looked at samples from the brains of humans who had died, and found changes in the small brain blood vessels of the humans who had been diagnosed with either schizophrenia or bipolar disorder, compared to the position in the brains of humans who had not had such a diagnosis. The researchers considered that the changes in the human blood vessels were comparable to the changes they saw in the mice they studied. But they didn’t know anything about the sugar consumption of the people whose brains they studied.

“So, given all this detail, can we say more about how this study, mainly on mice, can tell us anything, even potentially, about humans?

“I’ll take it as read that the differences in behaviour, between the different groups of mice, are real. But, first, do the mice that were affected, those who ate a lot of sugar and had a particular genetic mutation, actually correspond to any groups of humans? That’s beyond my expertise – there’s an obvious correspondence between a high sugar diet in mice and a high sugar diet in humans, but I don’t know how far they might work in a similar way, and I don’t know how the mouse genetics in these experiments might correspond to any real-life human genetics. It’s known that there are genetic components to the causation of various human mental illnesses, and I don’t know whether there is any known correspondence between those human genetics and the particular mutation in these mice – but there’s clearly a question to be investigated there before we can know whether the new study says anything about humans.

“Then, are the behavioural changes in the affected mice actually caused by the changes in their brain blood vessels? Well, the researchers did investigate in some detail the way that the sugar diet, in the mutated mice, might lead to the changes in blood vessels, but the evidence as to whether the changes in blood vessels actually cause the behaviour differences is a bit indirect, I’d say. I wonder whether there could be other mechanisms causing the behaviour differences, possibly. The blood vessel differences and the behaviour differences do look real enough, but I’m not so sure whether one causes the other, from the evidence here – though you’d have to ask a biologist to be sure. A key argument that the researchers put forward to support that this association is one of cause and effect is the experiment involving aspirin. Giving the mice aspirin reduced both the effect on the blood vessels and the effect on behaviour. But aspirin has effects other than on blood vessels, and I don’t think that the aspirin experiment rules out other possible patterns of cause and effect. So again, I’d say there’s a question to be answered here.

“I’m going into this detail on the mouse experiments to point out that the only thing in common between the results in mice and the results in human brains is in the data on blood vessels. There are perhaps doubts about whether the mice that showed the behavioural and blood vessel changes, those on the sugar diet with the Glo1 mutation, actually match humans enough. There perhaps remain some doubts as to whether the blood vessel changes definitely caused the behaviour changes, in mice. There are doubts, to me at least, on whether the behaviour changes in the affected mice do entirely correspond to serious mental illnesses in humans. All we have from this study, from human specimens, is a difference in blood vessels between those with the two major mental illnesses that were considered and those who had not had such a diagnosis. We don’t know how those blood vessel differences arose in the human brains – there was no way that these researchers could study that, because the people whose brains were involved had already died. We don’t know how much sugar the humans involved ate during their adolescence. Yes, it remains possible that the human blood vessel differences arose because of differences both in genetics and in how much sugar there was in the unfortunate people’s diets, but that’s only one possibility – even if we could be certain that that’s how it works in mice, and I’m not sure we could be, there are just too many gaps to be able to transfer that understanding to humans.

“Overall, then, my strong feeling is that the usual doubts about applying the results of lab animal studies to humans aren’t in any way overcome by the fact that these researchers do also include a small amount of data from humans. Yes, they describe a potential mechanism that would lead to an effect of sugary diets on human mental health, in individuals who are genetically at risk – but their study cannot establish that that is what actually happens in humans, even if it really does work that way in lab mice.”

Prof David Curtis, Honorary Professor, UCL Genetics Institute, said:

“The study provides no evidence at all that high-sugar diets increase risk of psychiatric disorders. It shows that mice who are fed high sugar diets may have subtly different behaviours from other mice.

“We know perfectly well that high sugar levels do not cause mental illness because if they did we would observe much higher rates of mental illness in people with poorly controlled diabetes.  High sugar diets are bad for one’s health in many ways but one of the things they do not do is cause mental illness.”

‘High-sucrose diets contribute to brain angiopathy with impaired glucose uptake and psychosis-related higher brain dysfunctions in mice’ by Shinobu Hirai et al. was published in Science Advances at 7pm UK time Wednesday 10 November 2021.

https://science.org/doi/10.1126/sciadv.abl6077

Declared interests

Prof Ciara McCabe: “Prof McCabe has worked on projects funded by EPC Natural Products Co., Ltd.”

Prof Kevin McConway: “I am a Trustee of the SMC and a member of its Advisory Committee.  My quote above is in my capacity as an independent professional statistician.”

Prof David Curtis: “I declare no conflict of interest.”