What inspired you to work in gut microbiome research?
Nutrition at the molecular level fascinates me. I trained in molecular biology and biochemistry, and initially focused on dietary lipids and regulation of their absorption by the body. Several years ago, DNA-sequencing technologies took us into a whole new realm of microbiome research, and I became intrigued by the differences in gut microbial communities between healthy people and people with metabolic diseases, and whether these could be linked to differences in processing of foods by the body. How nutrients are absorbed, how they are metabolized directly after eating — these processes differ greatly between healthy people and, for example, people with diabetes. It became clear that various microbial communities in the gut are also involved in different responses to diet — even to individual foods in a person’s diet.
Why is glycemic control of interest?
Dysregulated blood glucose responses are associated with a higher risk of developing metabolic diseases such as diabetes. A seminal paper by Segal’s group in Israel demonstrated that you could improve the prediction of a person’s postprandial glucose response to different food types with considerable accuracy by including details of their faecal microbiome in a computer model. Previous predictions had only been based on a person’s diet, BMI and so on, and were only about 30–35% accurate. This clearly suggested that the gut microbiome somehow influences glycemic responses at an individual level. The team also showed that if different people eat two foodstuffs containing the same amount of carbohydrate — say bread and cake — some people will have high glucose levels in their blood after eating bread but not cake, or vice versa. No two individuals’ responses were the same, even when they consumed the same food. This was something we also observed in our human studies. This all begs the question: why?
Why focus on the small-intestine microbiome?
The small intestine is an underexplored microbial organ, largely because it is very difficult to access in humans. Most microbiome research to date is based on faecal samples, but these are taken from just one end of the intestinal pipe and only tell part of the story. We know that people respond differently to different food products, and that glucose responses change in individuals depending on what they eat. Because the small intestine is the region of the gut where nutrients, including glucose, are absorbed, it is likely that the small-intestine microbiota is involved. This indeed is shown in preclinical studies. For our Gut Health project, we will focus on the role of the small-intestine microbiota in glycemic control in humans and how this differs between and within individuals in response to different dietary inputs.
What drives the rapid changes in the composition of the small-intestine microbiome?
It is multifactorial — from a bacterium’s perspective, it has to grow. Bacterial species depend on the substrates, the food available in their environment — these are largely sourced from an individual’s diet. The small intestine is a very dynamic environment; food passes through depending on the varying speed of a person’s digestion, and the pipe expands and contracts. Other components, such as digestive enzymes or bile acids, may be harmful and impair the growth of some bacteria. All these processes determine which microbes are able to thrive and grow there over time, but we know very little about glycemic control and the small-intestine microbiota. A few studies have shown a correlation between glucose and the colon’s microbiome, and animal studies have found that lipid absorption is manipulated by the small-intestine microbiota. But when it comes to carbohydrate absorption and associated glycemic control, this is new research.
What does your project propose to do?
We will screen for 70 participants that respond in very different ways to several standardized food products with the same amount of carbohydrates. We know from our previous work and published results which food products can produce such differential responses, and we hope to replicate our findings. The chosen foods could be bread, cake, cookies — it doesn’t matter as long as the portions have the same carbohydrate load. What we need is each person to react differently to the two chosen products so we can pinpoint what drives individualized glucose responses.
In a subset of participants, we will use catheters to take multiple samples from their small intestines in the minutes before and hours after consuming each of the food products. We will measure the composition of each person’s microbiome over time, the carbohydrates in the given food, and the person’s glucose responses, and we will do this several times to check for reproducibility. We will see whether there are differences in each person’s small-intestine microbiome composition in response to each food, and how this correlates with glucose levels in the individual’s blood. This will provide fundamental insights into the role of the small-intestine microbiome. It is a small, proof-of-concept study, but if it works, we will expand on our findings in the future.
How might host responses be influenced by the small-intestine microbiome?
Differential glycemic responses could be driven by the fact that certain small-intestine bacteria can metabolize one carbohydrate source better than another. It could also be that different bacteria have differential impacts on host responses. To explore this, we will use human intestinal cell culture models that will be exposed to the small-intestine content obtained through the catheter, and see what effect these samples have on markers of glucose uptake and metabolism in the host cells.
What conclusions might be drawn from this project?
This is about gathering valuable data on an under-researched microbial ecosystem, and improving our understanding of what drives variable glucose responses. In time, we aim to verify the role of the small-intestine microbiota as an additional factor in gut-host responses, and provide concrete evidence that diet drives small-intestine microbiota composition and influences overall health. We hope to identify new microbial targets that could be used to improve glycemic control and give better, evidence-based dietary advice. There’s so much misinformation out there in terms of nutrition; it’s vital that advice is based on rigorous scientific evidence.