When Gut Microbes Go Rogue: Dr. Mahesh Desai on Fiber-Starved Bacteria
Mohit Nikalje
Gut is one of the most underestimated but highly important organs in our body. Even ancient medicine systems, including Ayurveda and Traditional Chinese Medicine, placed strong emphasis on maintaining a healthy gut for overall well-being. Hippocrates—the father of medicine—stated over 2,000 years ago, “All disease begins in the gut.”
While their insights were based on keen observations, modern science is now revealing more about the factors that influence our gut health—especially the role of the gut microbiome.
It is well established that our gut microbiome aids in digestion and produces essential vitamins. New research from Dr. Mahesh Desai’s lab at the Luxembourg Institute of Health is now shedding light on its additional roles in immunity development and disease prevention.
But is our gut microbiome—a community of trillions of microbes—offering all these services for free? Probably not. These microbes are like daily wagers working in a factory, breaking down large food particles into smaller pieces. They largely rely on dietary fibers present in fruits and vegetables as their primary food source. But what happens if we don’t eat enough of them? Will these loyal workers, left without an essential diet, go on strike?
It turns out that these loyal workers not only go on strike when deprived of food, but may even resort to violence—attacking the very factory walls they work in.
Microbes That Strike Back
Image representing the breach of mucosal barrier
“When our diet lacks fiber, the microbiota develops a tendency to seek alternative sources of energy. And we have shown that one of these alternatives is the mucus lining in the colon,” says Mahesh.
Continuing with our worker analogy, imagine the mucosal layer as the compound wall of the factory. It acts as a barrier, preventing microbes and harmful byproducts like toxins from entering our body. As a mark of rebellion, the first thing to break down is part of this protective wall, as the microbes begin to feed on the mucus layer.
It was during his PhD at the International Max Planck Research School in Marburg, Germany, that he developed a passion for gut microbiota research while studying insect guts.
Weakening of the mucosal layer allows harmful pathogens to enter the body. For example, a 2016 study from Desai’s lab, published in the journal Cell, showed that this breach in the mucosal barrier enables pathogenic bacteria like Citrobacter rodentium to cause lethal colitis (inflammation of the colon), potentially leading to Inflammatory Bowel Disease (IBD) and even colon cancer.
However, this critical insight came from a mouse model system, which laid the groundwork for human studies in recent years. Due to the sheer complexity of the human gut microbiome, it becomes nearly impossible to study the role of each individual microbe. This is where gnotobiotic mouse model systems come into play, making such detailed investigations possible.
These mice are raised in controlled laboratory conditions, facilitating only a limited and carefully selected set of microbes to colonize their gut. This simplified and defined microbial community is known as a synthetic microbiome. It is established by introducing selected microbes—typically through food or water—into the mice at around 5 to 6 weeks of age, using a process called gavaging.
Desai’s lab has developed a synthetic microbiome involving 14 well-characterized bacterial species. “This 14-member microbiota contains bacteria originally isolated from the human gut, and the beauty of this microbiota is that it is fully characterized. We know what it is capable of growing on, what kinds of polysaccharides it requires. These bacteria have had their genomes sequenced, so we have all the possible information one can have about them,” says Mahesh.
Because we understand the types of fiber these bacteria require, we can manipulate their growth. By excluding specific types of nutrients, certain bacteria can be eliminated from the gut—allowing scientists to define the role of particular bacteria in the gut. One of the crucial insights recently gained from his lab using this gnotobiotic system was that removing dietary fiber from the maternal diet can adversely impact the development of the offspring’s gut microbiome.
Mother's Diet Shapes Baby's Gut
This study, published in the journal EMBO Molecular Medicine, showed that when dietary fibers were removed from the diet of mother mice, the breastfed infants failed to develop beneficial bacteria like Akkermansia muciniphila. That is because, in addition to providing nutrition, a mother’s milk also supports the development of a vibrant microbial community in the infant’s gut.
Fiber-rich mother’s diet influences the early establishment of key gut bacteria in infants. Source: EMBO Mol Med 2023
“When there is no fiber in the mother’s diet, this bacterium doesn’t stick early on in babies, which could be because the milk composition is slightly changed,” says Mahesh
Additionally, infants lack a developed mucosal layer that could serve as an alternative energy source. As a result, A. muciniphila typically develops only after the weaning period, when babies transition from liquid to solid food. Such a delay in the development of beneficial bacteria in the infant gut can have a profound impact on their overall health. The establishment of a diverse and functional microbiome early in life is important not only for effective digestion but also for the development of a strong immune system.
Alongside aiding digestion, the gut microbiome also serves as a training ground for the infant’s naive immune system. These microbes teach immune cells to identify microbes and distinguish between beneficial and harmful ones. This early-life training helps the immune system mature and lays the foundation for lifelong immune resilience.
“One of the questions we would like to understand is how this affects later life, because this means that early on you have a screwed up immune system, so you likely become prone to developing different diseases and allergies later on in life,” explains Mahesh.
Challenges and way forward
Similarly, gnotobiotic systems combined with synthetic microbiomes can help answer many important questions, but maintaining these models is an immensely challenging task.
“People often ask whether this work in mouse systems is translatable to humans, but more importantly, I believe having the right model is what truly matters—because a model is just a lie that helps you see the truth,” says Mahesh, reiterating a quote from a noted American oncologist, Howard Skipper.
The foremost challenge is the infrastructure used for housing these mice. It must be germ-free to limit the microbes interacting with mice effectively. To ensure this germ-free environment, laboratories are equipped with Biosafety Level 2 facilities where the filters maintain positive pressure.
"Working with gnotobiotic animals is incredibly delicate—almost like solving a geometry problem. Everything must be meticulously planned to keep the animals completely germ-free. Maintaining sterility is challenging, both technically and ethically. Entering a gnotobiotic facility is like stepping into a COVID isolation unit: you have to fully suit up, pass through an air shower, and follow strict protocols to prevent contamination," explains Mahesh.
Apart from the role of dietary fibers in our gut health, the Desai lab also explores how the gut microbiome has an impact on food allergies, inflammatory bowel disease, and multiple sclerosis. His strategic position at the Luxembourg Institute of Health proves invaluable, facilitating seamless collaborations with hospitals for crucial clinical studies and fostering partnerships with pharmaceutical companies.
Furthermore, Dr. Desai's lab actively engages with other leading European centers, collectively advancing our understanding of the multifaceted interactions within the gut microbial ecosystem and their profound influence on human health.