A tale of the gut, microbial miscommunication, and preventing disease

The many microscopic organisms, or microbiome, that live in our gut play a big part in keeping us healthy, yet a breakdown in communication between them and the rest of the body can badly affect our health. The EU-funded META-BIOME project set out to understand the causes of this miscommunication. To understand this could allow for new treatments against many diseases, benefiting all citizens.

Our gut is home to one the highest densities of microbes, or microscopic organisms, found on Earth. Together, these microbes are called microbiome, and they play a huge role in our well-being, impacting everything from metabolism to physiology, nutrition and our immune system. In fact, any change to the gut’s microbiome can have significant consequences for our overall health.

“The gut microbiome is shaped and regulated by multiple factors, including our genomic composition, local intestinal niche, and nutrition,” explains Eran Elinav, a professor of Immunology at the Weizmann Institute of Science in Israel, and director of the German Cancer Research Center’s (DKFZ) Cancer & Microbiome Division. “Recent research indicates that a disruption to the gut’s microbiome can lead to such conditions as obesity, diabetes, inflammatory bowel disease, Crohn’s disease – even cancer.”

Through the EU-funded META-BIOME project, supported by the European Research Council (ERC), Elinav and his lab are working to better understand these disruptions. “Our goal is to figure out what causes our microbiome to essentially miscommunicate with the rest of our body,” he adds. “In doing so, we hope to open the door to new microbiome-targeting treatments that could better regulate the microbiome and, ultimately, prevent the development of chronic disease.”

A matter of miscommunication

At the heart of this research is a sensor that plays a pivotal role in regulating the composition of gut microbiome, the NLRP6 inflammasome. In prior research, Elinav’s lab used mice to demonstrate that when this sensor is absent, communication between the microbiome and the host is disrupted. “This lack of communication alters the microbiome’s composition, affects its ability to function properly, and induces a wide variety of diseases,” notes Elinav.

In the META-BIOME project, researchers expanded on these findings by looking at what causes this miscommunication. “What we discovered is that commensals, or good bacteria that provide essential nutrients, release small molecules that are sensed by the NLRP6 and communicated to the host,” remarks Elinav.

The host uses this information to ensure that the microbes get everything they need while also taking steps to ensure other microbes don’t compete with these important commensals. “The result is a healthy, well-functioning gut,” adds Elinav. “However, when the NLRP6 sensor is missing, this important information isn’t properly communicated, which is where problems begin to develop.”

A conceptual leap

Although this finding was groundbreaking in and of itself, representing one of the very first examples of a molecular mechanism explaining the driving forces that cause a disruption in the gut’s microbiome, the researchers didn’t stop there. They took this one step further and discovered that an altered microbiome not only increases the risk of disease in the individual mouse but can actually be transferred to mice who don’t exhibit any sensor deficiency.

To demonstrate this fascinating but poorly studied phenotypic transfer, Elinav and his team exploited the fact that mice in captivity feature ‘coprophagy’, or the tendency to eat each other’s faeces. It is through this feature that the microbiome and the traits it regulates are transferred between mice. Elinav notes that microbiome can also be transferred into germ-free mice, or those that are housed in specialised sterile isolators and lack any microbiomes in and around them.

Once the malfunctioning microbiome is transferred, the microbes secrete small molecules that suppress the NLRP6 sensor in the genetically intact recipient. This in turn simulates a functional state of NLRP6 deficiency in their new host, which allows the malfunctioning microbiome to outcompete healthy commensals and make the mouse more susceptible to disease.

“Although more research is needed, this finding suggests that, in some cases, non-communicable diseases such as obesity and diabetes could be transmissible between individuals through their microbiome,” says Elinav.

According to Elinav, this finding is a step change in our understanding of biology. “The META-BIOME project represents a conceptual leap in our understanding of the body’s relationship with our microbes,” he concludes. “Knowing how these microbes communicate with our bodies, and the factors that can cause this communication to breakdown, we can now begin to address the range of diseases caused by a misfunctioning microbiome.”