Hormone cascade from the gut influences our sleep

‘Can a change in diet improve sleep?’

Professor Kim Rewitz leaves the question hanging while he gives a guided tour of his laboratory, which is part of the Department of Biology at the University of Copenhagen.

The lab is full of glass tubes, all buzzing with three to four millimetre Drosophila, otherwise known as fruit flies. These are experimental flies, genetically modified to switch off their ability to detect certain nutrients in their diet, or to produce a specific hormone in their gut.

The experiments Rewitz uses the flies for are generally aimed at gaining a better understanding of a highly complex signalling system known as the gut-brain axis. This axis is present in humans, but also in fruit flies, which in many respects have the same basic biology as mammals. This then, is why fruit flies are ideal to use as experimental animals in studies where scientists are investigating factors involved in disorders or diseases of the human organism – including dysfunctions assumed to derive from the gut-brain axis,’ explains Rewitz, who is studying this complex axis via an Ascending Investigator grant from the Lundbeck Foundation:

‘Basically, this axis is all about signalling between the gut and centres in the brain. As the largest hormone-producing organ in the human body, the gut is continuously releasing a whole cascade of hormones responsible for things like transmitting signals to the brain. These are signals that influence that sense of fullness after a meal (satiety), and also our sense of hunger, but they are also implicated in a number of other important functions. We know that because there is every indication that the gut-brain axis is also involved in regulating behaviour in mental health disorders, in learning ability, in memory and in sleep, for example. And through various experiments on fruit flies, such as by putting them on a sugar-rich or high-protein diet, we can study these areas in order to gain a better understanding of how the gut-brain axis influences processes that are essential for human health and well-being,’ Rewitz explains.
 

The role of diet

One of the aspects Professor Rewitz and his staff at the University of Copenhagen are investigating concerns how signals from gut bacteria and nutrients might influence signalling to the brain – in order to learn more about how diet and gut health might influence general physical and mental health.

It appears, for example, that various types of nutrients and some bacteria may affect the gut’s ability to communicate with the brain and other organs via the hormone cascade. And Rewitz confirms that it is not actually too far out to ask if a change in diet can improve sleep:

‘The answer is most likely yes, that may well be the case. That then begs the question of what’s best to eat, and in what amounts, and how such dietary advice might be individualised in order to achieve the desired effect? We don’t have any detailed recommendations on that yet, but the ultimate aim is to be able to offer dietary pointers because if we can improve people’s sleep, we will be improving quality of life for a great many individuals. Not least in people with mental health disorders, where sleep disturbances are very often part of the general disorder,’ Rewitz explains.
 

Flies flown in from abroad

The temperature in the laboratory is around 25 degrees Centigrade, and at that temperature it takes about 10 days for the fruit flies to reach their adult life stage. They may then live another few months until they reach the end of their life cycle, and when the fruit flies are not participating in one of Rewitz’s many dietary experiments, they are served a standard blend of cornflour, sugar and yeast.

The fruit flies are ordered by the Professor and his colleagues at the Department of Biology from various international producers, typically in the US, Australia or Japan. These are companies that specialise in producing fruit fly lines to meet scientists’ specifications, Rewitz explains:

‘We order model organisms – meaning fruit flies – in which it’s possible to switch off various genes in cells, tissues or the gut. These are fruit flies custom-modified for the experimental studies they will be used in’.

The effectiveness of such custom-bred fruit flies was demonstrated by Rewitz and his colleagues a few months ago in an article in the high-ranking scientific journal, Nature Metabolism

In this study, their fruit fly experiments allowed them to demonstrate the existence of a hormone-derived ‘sugar brake’. This is a biological mechanism – a hormone – that prevents the fruit flies from gorging on sugar at the expense of protein intake, for example, and the same may be the case in humans because we have a mammalian version of the same hormone.

One question the research team at the Department of Biology is currently seeking to answer by studying fruit flies is: how do food intake and the balance between dietary sugar-protein impact sleep? And to what extent is food intake regulated by specific gut hormones?

With the aim of answering that, Rewitz and his colleagues have stressed fruit flies by starving them or feeding them an alternately sugar-rich or protein-rich diet, while studying the flies’ sleep pattern.

‘Like humans, fruit flies sleep at night,’ explains Rewitz, adding: ‘We could see that their sleep was affected by switching them from a sugar-rich diet to a protein-rich diet. When we then put them on a diet that was more balanced overall, their sleep quality improved.’

Like humans, fruit flies sleep at night. We could see that their sleep was affected by switching them from a sugar-rich diet to a protein-rich diet.

The University of Copenhagen research team is also investigating a gut hormone, which, in the fruit fly study, was suspected of causing fragmented sleep. ‘And the interesting thing about this hormone is that we know that it’s regulated by food intake,’ says Rewitz, adding: ‘The only problem is that we’ve not yet identified which nutrients are pushing the buttons, as it were. A variant of this hormone exists in humans, and the hypothesis is that it may play a role in determining how deeply we sleep at night. That link is not unlikely, and definitely warrants further investigation.’

Another gut hormone that Rewitz and his team have decided to study in more detail is assumed to play a major role in the gut’s ability to detect protein in the food we eat. Equally, this hormone appears to be part of the explanation for, and link between, gut bacteria and their effect on animal health,’ the professor explains.

Determining if this also applies in humans can likewise be investigated through fruit fly studies, as humans have a version of the same hormone.

‘We’re seeking to learn more about this interesting hormone in collaboration with a team of international colleagues,’ says Rewitz:

‘Our preliminary findings indicate that the hormone is also involved in regulating appetite and sleep at a higher level, and that it may also be controlling the role played by food intake and gut bacteria in these processes. In collaboration with our international colleagues, we expect to be able to publish more scientific articles on our findings later this year.’

 

 

Hunger hormones and satiety hormones

• Going to bed on an empty stomach is not exactly conducive to a good night’s sleep. And the science behind that is well-established,’ says Rewitz, adding: ‘In all animals we see that fasting inhibits sleep, while satiety promotes sleep’.
• Hormones are involved in regulating both satiety and hunger, which is why the spotlight is on these hormones when we’re trying to determine how the gut-brain axis influences our sleep,’ explains Rewitz.
• A study currently being conducted by Rewitz in collaboration with international colleagues demonstrates that gut hormones may also influence life expectancy. The gut hormone under investigation in this study is assumed to play a major role in the gut system’s ability to detect protein.

 

The preliminary results of these fruit fly studies indicate that this hormone is involved in triggering sugar cravings after a high-protein meal. But if we inhibit this hormone, the fruit flies’ craving for sugar is reduced, even if they have been fed a very protein-rich diet. The experiments also show that they live longer.

‘In humans, that’s basically the equivalent of opting for a healthier diet. We’re now in the process of trying to understand the mechanism behind the life-extending effect, and how diet can influence lifespan via this gut hormone,’ says Professor Rewitz.