A new project at the Quadram Institute into how bacteria process dietary xenobiotic compounds aims to decode the role of a group of bacterial enzymes.

With support from the Marie Skłodowska-Curie Actions programme, Dr Lauriane Plouhinec will take up a fellowship working with Professor Nathalie Juge’s group to understand how gut bacteria process dietary xenobiotics, small molecules found in foods, some of which can have toxic effects.

By studying how these xenobiotics are metabolised by bacterial enzymes from the gut microbiota, they hope to understand how this process may influence our health, either positively or negatively.

The human gut microbiota is a complex ecosystem of bacteria and other microbes. Everyone’s microbiota composition is individual and shaped by diet and lifestyle, and it plays a major role in maintaining health.

It influences health by breaking down dietary fibre and other complex carbohydrates that evade digestion in the upper gut and reach the colon intact. Here, gut microbes ferment these complex molecules, releasing energy, nutrients and beneficial compounds, such as short chain fatty acids. These can interact with cells of the gut lining and the immune system in beneficial ways.

The bacterial enzymes that carry out this fermentation process are known collectively as Carbohydrate-Active enZymes, or CAZymes. The fibre fermentation processes in the colon, and the bacterial CAZymes behind it, have been well studied to understand how they influence health.

But there’s another group of chemical compounds resistant to digestion in foods, that reach the colon and get metabolised by gut microbes. These are dietary xenobiotics; small, sometimes toxic molecules that occur naturally in plants and animal foods.

Dietary xenobiotics often have a sugar molecule incorporated into their structure in a process called glycosylation. Some gut bacteria possess the CAZyme tools to deglycosylate these compounds. This change to the chemical structures can enhance or diminish their toxicity, or lead to changes in the gut microbiota composition, and in turn the overall response to diet.

It’s estimated that we’re exposed to over 25,000 dietary xenobiotics in our lifetime. Yet, we still know surprisingly little about how these compounds are broken down at the molecular level, which CAZymes are responsible, and how their metabolism influences human health.

To address this knowledge gap, the Marie Skłodowska-Curie Actions programme is supporting the XENOZYME project to decode the role of dietary xenobiotic-active CAZymes in the human gut, through a prestigious Marie Skłodowska-Curie Actions Postdoctoral Fellowship.

Now in its 30^th year, the Marie Skłodowska-Curie Actions programme is seen as a beacon of excellence in collaborative European research.

Their highly competitive Fellowships allow the very best scientists in Europe to carry out research activities in other laboratories overseas, fostering international and interdisciplinary collaborations and excellence in research.

This year’s annual MSCA Postdoctoral Fellowships call attracted considerable interest from the global research community with over 17,000 proposals submitted, with less than 1 in 10 being successful.

The award of this fellowship is testament to the outstanding science, facilities and expertise in the Quadram Institute as a place to deliver world class research and nurture talent.

The Quadram Institute is one of eight institutes strategically supported by the UKRI Biotechnology and Biological Sciences research Council as a National Capability, to lead strategic partnerships nationally and internationally and train the next generation of researchers. Dr Plouhinec will join the Quadram Institute following a PhD studentship at Aix-Marseille Université, where she has been working with world-leading team of CAZyme experts and collaborating with pioneers of the CAZy database (https://www.cazy.org/). The project will allow her to bring that expertise to the Quadram Institute and receive training and access to the Quadram’s facilities for studying the gut microbiome and its interactions with diet and the host.

Dr Plouhinec will join the research group of Prof. Nathalie Juge, who have a long-standing focus on glycans and how these mediate interactions between microbes and their hosts.

Prof. Juge has led research uncovering the role of glycosylation in the adaptation of Ruminococcus gnavus to the gut. These bacteria are common members of the gut microbiota, whose abundance is strongly influenced by diet and lifestyle. Their presence has been associated with health condition, particularly inflammatory bowel disease. Prof. Juge’s work has shown how Ruminococcus gnavus possess and arsenal of strain-specific CAZymes that degrade glycosylated proteins in the mucus lining the human gut, which is key to their prevalence in health and disease.

The XENOZYME project will now investigate preliminary evidence from the Juge Lab that Ruminococcus gnavus can also deglycosylate dietary xenobiotics. The aims are to discover the bacterial enzymes responsible for metabolising xenobiotics, understand how they work, and investigate how their activity affects host health.

This project use biological models that simulate the gut environment in the laboratory, including fermentation models, organoids, and gut-on-chip systems.. These techniques accurately mimic conditions in the gut by growing together the cells and tissues that make up the gut lining. The project will benefit from access to human tissues and microbiomes derived from faecal samples.

These experiments will confirm the biological relevance of the CAZymes’ interactions with xenobiotics and how they may shape the microbiota or interact with human cells and tissues in the gut.

Ultimately, this research could lead to new biomarkers for health conditions or even provide new targets for therapeutics.

“I feel proud to have this opportunity to explore CAZyme diversity and function in the human gut microbiota within such an inspiring research environment” said Dr Plouhinec

“Developing my own research project with the support, guidance and mentorship of Prof. Nathalie Juge and working alongside experts in the field at a leading research institute such as the Quadram is an amazing experience as an early career researcher.”

“I’m grateful to Prof. Juge for trusting me with this adventure, for the wealth of training opportunities available at Quadram and to the MSCA programme for supporting this project. I hope this work will contribute to public health by advancing our understanding of the role of the gut microbiota in health and disease.”

“We are very excited to welcome Lauriane in our Lab at Quadram”, said Prof. Juge. “Understanding the role of gut microbial CAZymes in dietary xenobiotic metabolism will provide a handle on how to develop personalised medicine and nutrition strategies to keep us healthy”.

This project has received funding from the European Union’s Horizon Europe research and innovation programme under the Marie Skłodowska-Curie grant agreement No 101280731