Research is steadily painting a picture revealing the significance the human gut microbiome plays in health and disease. From gastrointestinal tract disorders to the beginnings and treatment of Parkinson’s disease and beyond, the gut microbiome is a treasure trove of clues for researchers. We speak to three women in science – a biomedical scientist, a microbiologist and a bioscience engineer – about organs-on-chips and restoring an imbalanced microbiome.
Our gut microbiome is made up of trillions of bacteria, fungi, and other microbes. Its composition can be influenced by many different factors: the environment, diet, age, physical activity, medication, and more. A clear understanding of the consequences an unbalanced microbiome can have on the human body – and how the balance can be restored – will unlock a plethora of knowledge about health and disease.
Moving away from animal models toward organs on a chip
Scientists need representative models of the gut to study the human microbiome. Animal models are helpful, but researchers are working hard to replace them with “organ-on-chips” and “multi-organ-on-chips”, essentially small devices that mimic parts of one or more organs or how they interact.
One such example is the Human Microbial Crosstalk (HuMiX) model, a gut-on-a-chip developed and used by researchers at the Luxembourg Centre for Systems Biology (LCSB) at the University of Luxembourg with support from several FNR grants.
“With gut-on-chips, we have the possibility to understand how the microbiome influences our gut health and our immune system as well as the nervous system,” explains microbiologist Catherine Sedrani, who uses HuMiX in her research, and is evolving it to include the nervous system.
“We still need a physiologically representative model of the human gut, including the nervous system and a more complex microbiome – a model which has not existed to date. For sustainability reasons, it is also important to move away from animal models, and insteaddevelop a model as similar as possible to the human gut,” Catherine adds.
The main challenges lie in modelling the gut and all its complexity in vitro, as well as finding a way to culture the microbiome. For many species, researchers are still finding ways to culture them. Catherine succeeded in co-culturing enteric neurons, differentiated from stem cells together with epithelial cells and one bacterial species in the HuMiX gut model.
Restoring the microbial community
It has been established that there are links between what happens in the gut and Parkinson’s disease – there is, for example, evidence suggesting the disease initiation in the gut, in the form of inflammation of enteric neurons (neurons in the gut) and changes in the composition and function of the microbial community in the gut. These gastrointestinal symptoms manifest years, even decades before the motor symptoms that characterise the disease. Examples of changes are that the gut microbiome of Parkinson’s disease patients has a higher level of mucus foraging bacteria, and less fibre-degrading bacteria – issues that could be addressed by science-backed preventive or disease-modulating products or diets.
“We aim to develop a mixture of probiotic bacteria and prebiotic compounds that can modulate the microbiota in PD patients and has a protective effect on the intestinal epithelium,” explains bioscience engineer Dr. ir. Charlotte De Rudder, who is working on developing a synbiotic to restore the microbiome. The mixture of probiotic bacteria and prebiotics is aimed at modulating the gut microbiota of PD patients and people at risk of developing the disease.
Connecting two organs-on-a-chip to improve treatment
Researchers are also looking to the gut for answers on how to improve treatment strategies for Parkinson’s disease (PD) patients. It has, for example, been shown that the drug Levodopa, used for PD treatment, is metabolised by gut bacteria, leading it to cause side effects. Thus, another drug is given in addition to Levodopa to limit its side effects.
With the goal to improve the understanding of how gut microbes and pharmaceutics interact, researchers in this area are also pushing forward the organ-on-a-chip technology.
“The main challenge in the field of organ-on-chip technologies is to recapitulate the human gastrointestinal physiology, including biomechanical cues, as well as the 3D structure and diversity of cells in order to render them as physiologically relevant as possible,” explains biomedical scientist Mara Lucchetti, who in her current project set up a gut-liver platform connecting the HuMiX model to a liver-on-a-chip system.”
“I aim to develop a system that mimics the interplay between the gut and the liver to model gut microbial interactions with pharmaceutical drugs to improve treatment strategies. This technology could ultimately lead to the stepwise replacement of animal experiments and eventually speed up and improve the development of drugs,” Mara adds.
Mara Lucchetti, Catherine Sedrani, and Charlotte De Rudder are researchers in the Systems Ecology Group at the LCSB (University of Luxembourg), led by Prof Dr Paul Wilmes, which uses a Systems Biology approach to study mixed microbial communities in unprecedented detail. Discover more about each of these three scientists in our interviews below.
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Catherine Sedrani, Microbiologist and 4th year PhD candidate
Research focus: Understanding the interplay between the bacteria in our gut and the nervous system.
On her research focus
“My research is about further developing and adding complexity to an already existing gut model – the Human Microbial Crosstalk (short HuMiX) model, by including the nervous system. This resulting model will allow us to investigate how the bacteria in our gut interact with the nervous system.
“It is also important to get a better understanding of the gut microbiome-nervous system axis, which will subsequently allow us to understand the gut-brain axis better.
“This will help us understand the impact that the gut microbiome can have on our nervous system/brain and to what extent it can lead to neurological diseases.”
On her research highlights
“I successfully co-cultured enteric neurons differentiated from stem cells together with epithelial cells and a bacterial species in the HuMiX model. The next step will be to include a more representative human gut microbiome in order to have a better portrayal of the actual human gut.”
On her interest in the human gut microbiome
“Since early years, I have always been curious about how the human body works. During my bachelor degree I discovered my huge interest for the human gut microbiome and how these tiny organisms can have such a big impact on our body. This led to my decision to go into research and understand more about the gut microbiome and its potential.”
On mentors with an impact
“By giving me the opportunity to pursue a PhD in the field I am most interested in, Prof. Wilmes definitely made a significant positive impact on me and my research career. The same is true for some post-docs, especially Dr. Susheel Busi, in my group, who never fail to motivate me and also making me appreciate the small successes. One has to celebrate the small things in life, which will eventually lead to bigger outcomes in my project and outside of it.”
On choosing Luxembourg for her research
“Being from Luxembourg, I was very excited to see the research grow in Luxembourg and stayed up to date with its evolution and progress over the years, while I was studying abroad. The gut microbiome got me fascinated early on during my studies, which drew me to Prof. Wilmes’ research. I was amazed by the gut-on-chip model, HuMiX, which he and his group have developed, and I decided to come back to Luxembourg and do research on the gut microbiome within Prof. Wilmes group at the University of Luxembourg.”
On where she sees herself in 5 years
“Working in the laboratory has been a passion of mine since I started studying and I enjoy my time in research. During my PhD, I discovered another passion of mine: Science Communication. I realised how much I like to talk about science to people outside of science and make them excited about it. One thing is sure, I want to stay in science.”
Charlotte De Rudder, Bioscience Engineer, Postdoc
Research focus: Understanding interactions between humans and microbes in health and disease, and through this understanding steering the gut microorganisms towards a state that is beneficial for human health.
On her research focus
“I am working on the development of a synbiotic, a mixture of probiotic bacteria and prebiotics, to modulate the gut microbiota of Parkinson’s Disease patients and people at risk of developing Parkinson’s Disease. In this project, we will further develop the HuMiX system to reflect relevant conditions in the PD patients gut environment, both on the level of the microbiome and the human cells.
“At the end of this project, we aim to have a novel synbiotic product, with disease-modifying anti-inflammatory and neuroprotective properties for Parkinson’s Disease patients, and with prophylactic potential for individuals with an increased risk of developing PD.”
On her interest for human health
“I have always been interested in environmental and human health, as well as in steering mechanisms and technical solutions to improve these. In my research project, I have the chance to combine my enthusiasm for microbiology and microbial ecology with my interest in human health; I can study how the microbiota impact human health, and how we can steer them towards beneficial health effects.”
On what she loves about being a scientist
“I love that I have the chance to learn new things every day, either by performing experiments in the lab, reading scientific papers, or through interaction with my colleagues. It’s also very refreshing that almost every day looks different; there are always new questions and challenges, and new ways to answer them through experiments. I love working in this very interactive and collaborative environment, and greatly enjoy discussing ideas with other scientists. Next to this, the research we do will benefit society, which is a great motivation.”
On mentors with an impact
“I have had the pleasure of being surrounded by many bright and inspirational people during my research career. They have impacted my research process, how I look at challenges, and opened my eyes for new approaches. My PhD promotors, dr. Marta Calatayud Arroyo (UGent) and professor dr. ir. Tom Van de Wiele (UGent) have had a great positive impact by sharing their expertise with me and guiding me on my way to become an independent researcher.”
On choosing Luxembourg for her research
“I decided to do my research in Luxembourg after being drawn in by a research article about a microfluidic device developed to study host-microbe interactions, published by professor Paul Wilmes’ group. I was very interested in using this model system for my own experiments, so I reached out to professor Wilmes and was invited to do a research stay in the Systems Ecology group for five months (FWO funded). This was a very positive experience, therefore I applied for a postdoc project in the same group. Next to that, Luxembourg is a pleasant country to live in, with many different types of landscape, a very international community, and has created a great environment for research.”
On where she sees herself in 5 years
“In the future, I would like to continue my career in research and development, either in an academic or in an industrial setting. There is great potential in microbiota-targeted therapies and preventive treatments, and I would like to develop new model systems to study host-microbe interaction and/or biotherapeutic products, and/or work in the translation of these products from bench to bedside.”
Mara Lucchetti, Biomedical scientist and 3rd year PhD candidate
Research focus: Understanding the interplay between the human gut microbiome and drug metabolism using Organ-on-chips (OoCs).
On her research focus
“With my research, I contribute to the advancement of multi-organ-on-chips that try to mimic the relationship between two organs. In my PhD thesis, I am aiming to develop a system that mimics the interplay between the gut and the liver to model gut microbial interactions with pharmaceutical drugs to improve treatment strategies.”
On the context of her research
“Research in the field of OoC technology has led to scientific advances in trying to find a physiologically relevant replacement for animal models. These scientific advances have shown that it is possible to mimic parts of an organ and to study cellular interactions in a more physiological, rapid and cost-efficient way.
“The main challenges in establishing an appropriate clinical model for drug metabolism are the complexity of cellular parameters of the gastrointestinal tract and the liver.”
On her research highlights
“In my first two years of PhD thesis, I could successfully set up a gut-liver-on-chip platform that connects the HuMiX (human microbial crosstalk) gut model to a liver-on-chip system. With this gut-liver platform, I would like to overcome current challenges in drug toxicity assessment assays as these organ-on-chip technologies are designed to be more physiologically relevant than conventional in vitro and in vivo models.”
On getting out of her comfort zone
“As I am a really curious and ambitious person with the goal to improve human health, it is exciting for me to do a job where I can be creative and fully explore my ideas with the aim to find solutions to answer important questions.”
On what she loves about science
“What I love about science is that it is rewarding; putting effort in researching can have positive impacts on human life.”
On mentors with an impact
“I have been taught by my previous mentor that research comes with failures and that these failures should not keep you from doing research.”
On choosing Luxembourg for her research
“The reason why I came back to my home town to do my research project is because I got aware of the HuMiX gut-on-chip model developed by Paul Wilmes’ lab and I was very eager to work with such a technology.”
On where she sees herself in 5 years
“In 5 years, I see myself still being involved in science. I am eager to gain more experience in my research field and pursue a career in science.”
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