The ‘poo machine’ reveals the link between gut bacteria and health

^{Text: Pauline van Schayck | photo: WUR.}

^{This article appeared in Wageningen World 2|2025, the magazine of Wageningen University & Research..}

The laboratory still smells like a sewer even when the poo machine is switched off. When it is switched on, the jars the size of biscuit tins bubble away. They simulate the various parts of the intestines, complete with the associated bacteria. Those microorganisms make up the most influential group populating the intestinal microbiome: the collection of bacteria, fungi, yeasts and viruses. The poo machine, which is actually called SHIME, has been in the lab of Jurriaan Mes, senior Nutrition & Health researcher at Wageningen Food & Biobased Research, for five years now and he has got used to the smell.

The solution of bacteria and food particles in each jar is pumped through to the next jar after a set time. The conditions – the acidity, temperature, presence of certain enzymes and so on – correspond successively to the situation in the stomach, the small intestine and three sections of the large intestine. The artificial intestines are fed from an apparatus that simulates the chewing and digestion of food in the mouth.

Scientists are using the artificial intestines to study how nutrition affects the composition of the organisms inhabiting the gut. That is because it is becoming increasingly clear that this composition in turn influences the development of diseases, recovery and general well-being in humans and animals. It might therefore be possible to boost the health of humans and animals by steering the microbiome in the right direction.

Mes controls the artificial intestines via the computer. ‘You can change the speed at which the food particles pass through the apparatus, you can alter the conditions or you can make it simulate the intestines of a baby.’ A key difference with real intestines is that the artificial intestines don’t have intestinal cells that absorb the nutrients from the mixture. ‘We take what remains of the food particles in the various pots and feed this to intestinal cells in another part of our lab. That is where we study the uptake into the bloodstream,’ explains Mes.

To be able to use the poo machine for research, it first needs to have the right gut bacteria. Mes: ‘If we take the microbiome from some excrement and put it in the machine, its composition will gradually shift under the influence of the conditions.’ For example, certain bacteria grow better than others in the small intestine with its particular combination of acidity, temperature and enzymes. The composition of bacteria in that particular pot therefore increasingly looks like the microbiome typically found in that part of the intestines. The availability of new DNA techniques is making it easier to work out exactly what organisms are living in an individual’s intestines. According to Mes, it is even possible to identify all the genes and all the proteins in a microbiome within one day. ‘Initially, we were only able to look at groups of bacteria at a broad level, but now we know which bacteria are involved and what substances they make.’

Even so, the interrelationships between the billions of microbiome inhabitants remain complex. ‘What happens in this population is called cross-feeding,’ explains Mes. ‘One bacterium nibbles something off a nutrient and the next continues with that piece, turning it into something new. In other words, it’s all about combinations of bacteria. If your diet changes, for example because you start eating and drinking more dairy products, the microbiome will change accordingly within one to three weeks,’ says Mes. It adapts to cope with the food in the new diet, but the changes also affect your metabolism. The metabolites, as the products of the chemical reactions in the bacteria are known, are used by other bacteria and by cells in the intestines and elsewhere. This, it transpires, has all kinds of connections with your health and well-being.

‘We now have a fairly clear idea of which bacteria cause the complaints in intestinal infections, but the situation is much more complex in the case of irritable bowel syndrome or brain diseases,’ says Mes. ‘They are not caused by one single bacterial species. It can be a combination of multiple species that jointly produce certain metabolites.’ It is also possible for substances created in the intestines to activate the immune system. These substances may end up in the brain. Mes: ‘This is sometimes called the gut-brain axis. There is often a lack of hard evidence, but it is increasingly accepted that there are links between the microbiome and the development of brain diseases. Alzheimer’s and Parkinson’s are probably linked to the digestive system, and autism, ADHD, depression and even stress could perhaps be influenced by our intestines.’

For example, less healthy microbiomes often contain a lot of bacteria that make lipopolysaccharides. These large molecules (consisting of a lipid and a polysaccharide) are known as endotoxins. They are substances that can trigger a strong immune response. Studies with the artificial intestines show these molecules adhere easily to fat particles and are thereby carried through the intestinal wall into the bloodstream. ‘The fat particles are not broken down in the liver immediately, so they end up in the lymphatic system and the bloodstream. We also find them high up in the neck, close to the brain, where they may contribute to an increased risk of Alzheimer’s,’ says Mes.

Mental health

Mes and his colleagues are also involved in different kinds of studies on the association between the gut microbiome and health. One is a study of people with risk factors for Alzheimer's disease, such as high cholesterol, obesity and type 2 diabetes. They are investigating the influence of lifestyle on the composition of the microbiome, in partnership with other universities and research institutes.
Last summer saw the start of the three-year research project Food4Mood, in collaboration with VU University Amsterdam. It is looking at young adults with mild mental health issues such as sombre feelings and concentration problems. Some of the participants are on a plant-based diet high in dietary fibre, with the aim of testing the influence this has on well-being and gut health.
Their excrement gives a picture of the microbiome to a certain extent, but it mainly only tells you about the final section of the large intestine. It would be better to study the content throughout the intestines to get a complete, realistic picture of the gut microbiome. However, looking deep into the intestines is not easy: it requires a distressing internal examination with a metres-long tube.

Smart pill

An alternative solution is the sensor pill developed by the OnePlanet Research Centre – a collaborative venture between the company Imec, Radboud University, Radboud University Medical Centre and WUR. This smart pill, no bigger than a multivitamin tablet, can be swallowed and then travels through the body, including the intestines, performing measurements and gathering data. The pill sends the data to a separate device, outside the body.

Last summer, PhD candidate Roseanne Minderhoud and assistant professor Guido Hooiveld of the Human Nutrition and Health chair group published an article in the journal Nature Electronics on the first tests with the sensor pill in humans. It turns out that the tiny sensor can measure variables such as the acidity, temperature and redox balance (the equilibrium between oxidants such as free radicals and antioxidants that neutralize them). A disrupted redox balance is a sign of inflammation in the intestines.

‘The pill worked as we had hoped,’ says Minderhoud. ‘The pH value, for example, tells you how active the gut bacteria are. The more they ferment, the more acidic it gets.’ After trying out the sensor pill, the consortium is now testing a ‘sampling pill’. This mini device collects fluid containing bacteria and various other substances from the intestines. The reactions between those substances and the bacteria are halted immediately so that it is possible to determine what was going on in that specific part of the intestines when the pill finally leaves the body hours later.

Animal wellness

The sensor pill has also been used in studies of animals, including cows, pigs and chickens. The diseases the animal studies focus on are different to the diseases in the human studies. ‘Animals don’t live so long and the diseases associated with old age are therefore not seen in animals,’ explains Dirkjan Schokker, a researcher at Wageningen Bioveterinary Research. ‘Anyway, we can’t ask them how they are feeling.’ Schokker is looking for other indicators of the association between the microbiome and well-being, such as behaviour and susceptibility to infections. For example, pigs that are reared in a more stimulating environment have a different microbiome than pigs that have less to do. Schokker: ‘Greater exposure to natural products such as peat and behaviours such as rooting and play result in a more diverse mix of bacteria. The immune system “learns” the difference between harmless and harmful microbes. Piglets with a more stimulating environment subsequently became less sick or recovered faster from a respiratory tract infection. The underlying mechanism is not yet clear, but there is definitely an association.’

The first few weeks of an animal’s life are crucial as that is when the colonization of the previously ‘empty’ intestines starts. It is also a period when a lot happens in the lives of farm animals. ‘Piglets are weaned and taken away from the mother at four weeks, switching from milk to solids,’ says Schokker. ‘That has economic benefits, but it is stressful for the piglets in a period in which the microbiome is still developing. The piglets are particularly vulnerable to infections at that time. Research in Belgium shows that weaning later is better for the piglets’ microbiome and health. Calves too are subject to stress in their first few weeks: they are moved to a new place with a lot of other calves. Some then begin to cough a lot or get diarrhoea. It looks as if the microbiome plays a role here too, as the most resilient calves have diverse microbiomes.’

‘But an animal’s genes also determine how the microbiome develops,’ explains Schokker. Selecting specific breeds of cows, pigs and chickens has let them zoom in on the other factors that affect the mix of bacteria, such as nutrition and the environment. ‘If we can discover what effect a certain feed composition has, for example, we can use that information to improve the well-being of these animals.’ That could, for instance, mean they do not need antibiotics as much in future.

Eventually, the researchers want to know the details of a particular relationship between the intestines and health. For example, which mixes of bacteria in which parts of the intestine cause damage to which parts of the brain via which substances? That could be the starting point for targeted changes to the gut microbiome.
About ten years ago, ‘faecal transplants’ looked as if they might be a promising solution to various disorders linked to gut bacteria. In these transplants, the microbiome from the faeces of a healthy person is inserted in the patient using a tube through the nose, an enema via the anus or a capsule that is swallowed. Mes: ‘That worked well for pathogenic bacteria that couldn’t easily be removed from the intestines but not for diseases where the relationship between the intestines and health is more complex.’

Mes and Schokker are looking for ways to influence the bacterial mix in a positive sense, and often for preventive purposes. It all starts with a healthy diet. ‘In general, for humans that means not much sugar and lots of vegetables, fruit, nuts, wholemeal products and fermented products such as yoghurt,’ lists Mes. ‘But I want to be able to give customized advice for specific groups of people, for example recommending they eat food with an antimicrobial effect such as garlic. We will be investigating this further over the next few years, using the artificial intestines and studies with test subjects.’ Schokker is investigating the relationship between the feed composition for farm animals and well-being, the environment and production. How does animal feed made from residual products from the food industry affect animals’ microbiomes, immune systems, health and well-being? And how much does the animal then produce in terms of milk, eggs or meat? In a recently completed study, pigs were fed the remains from confectionery bakers and the pulp of sugar beets. ‘Sugar beet pulp changes the pig’s microbiome a lot, with more microorganisms that specialize in complex sugars,’ says Schokker. ‘That didn’t really happen at all with the waste products from the bakery. We didn’t see any adverse effects for the pigs’ behaviour or well-being in either group. The next step will be to investigate whether the changes to the microbiome actually have benefits.’

Pre-, pro- and postbiotics

The microbiomes of both humans and animals can be altered by nutritional supplements. Probiotics – live bacteria – can become established alongside the existing gut bacteria if they reach the intestines in sufficient numbers. Probiotics in the form of pills and drinks have been around for a while and can help some people suffering from irritable bowel syndrome or diarrhoea after taking antibiotics, for instance.

Newer variants of these supplements are prebiotics and postbiotics. Prebiotics provide nutrients used by specific beneficial bacteria in the intestines. They either boost the growth of these bacterial populations or they let the bacteria produce substances that are good for health. Dietary fibre is the best-known prebiotic. ‘Some pieces of dietary fibre look like pieces from the cell walls of specific bacteria,’ says Mes. ‘That acts as a positive trigger for the microbiome, and therefore also the immune system.’ He will soon also start investigating the effects of postbiotics – compounds produced by bacteria or pieces of dead bacteria that stimulate the immune system in the intestines.

Meanwhile, Schokker is playing with the idea of designing a microbiome. ‘New-born animals, such as chicks, start off with empty intestines. We can give them a helping hand in the first stage of life. For example, perhaps we could make chicks more resilient to diseases by giving them ten beneficial bacteria.’ He is already able to design a microbiome with the aid of software and scientific knowledge. That could be administered as an aerosol after the birth, or even earlier by injecting the yolk. ‘Vaccines are already being injected into the egg, so the gut bacteria could be added,’ says Schokker. It doesn’t matter if that microbiome changes later. ‘Giving the animal a good start makes such a big difference in terms of the chances of survival and well-being. ’