Smart Innovation Understanding Gut Microbes-Human Diseases via a ‘Micro-Gut’

Scientists have developed a realistic ‘micro-gut’ model that can help them to study the relationship between gut microbes and human diseases. The 3D scalable ‘gut-on-a-chip’ model enables real-time visualisation of the interactions of gut microbes and the human intestine.

Queestown/Singapore – In a breakthrough for the advanced study of gut health, NUS scientists have developed a 3D microscopic version of the human intestines condensed into a small chip about half the size of a five-cent coin. This new cell culturing platform, known as the Gut-Microbiome on a chip (GMoC), provides a realistic in vitro microgut model that allows researchers to examine the interactions of gut microbes and their collective impact on gut health. The chip offers a scalable, reproducible, and efficient method to dissect the roles of gut microbes and their community, which is of key interest for the preventive healthcare and pharmaceuticals industry.

“The GMoC system represents a significant advancement in our ability to investigate the effect of the gut microbial community on gut health and diseases,” said Professor Lim Chwee Teck, Director of the NUS Institute for Health Innovation and Technology (iHealthtech). Prof Lim is also from the Department of Biomedical Engineering at the College of Design and Engineering, NUS. “By establishing a physiologically-relevant gut model capable of culturing communities of gut microbes, we can gain deeper insights into the role and complex mechanisms of these micro-organisms in maintaining gut health and preventing disease.”

The findings were published in the journal Advanced Science on 27 February 2024.

Understanding the complex interplay of gut microbes and health

Our intestines contain trillions of bacteria, fungi, and viruses which play a crucial role in our overall well-being. These communities of microorganisms – also known collectively as the gut flora or gastrointestinal microbiome – can either help or harm us.

However, the exact mechanisms by which these gut microbes prevent or cause gastrointestinal illnesses remain unclear. While researchers have identified individual differences in the gut microbiomes of healthy people and those with diseases, the complexity of the interactions amongst the trillions of microorganisms residing in our intestines makes it difficult to isolate the exact modes of action by which these microbes protect us or induce disease.

The innovative 3D ‘microgut’ platform developed by NUS researchers provides a more realistic presentation of the gut microbial community compared to existing models. It simulates biological conditions (like food movement and oxygen levels) as in the human gut, mimics key structural and physiological features of the gut lining, allows for diverse communities of microbes to be cultivated, and is designed for easy and real-time investigation.

Mimicking the human gut

The GMoC system provides a realistic in vitro (outside the body) model of the human gut, featuring a 3D version of the gut epithelium that mimics key architectural and functional aspects of the intestinal tract, such as the intestinal villi (tiny finger-like projections for absorption of nutrients), co-inhabitation of microbes and intestinal cells, and the dynamic conditions simulating movement of food.

Replicating the structure of the intestinal villi is important because the specific location of different microbial species within a 3D substrate influences how they organize and function, and it also has a distinctive impact on the gut’s response to various stimuli.

In addition to structural features, the team’s ‘microgut’ platform also demonstrated key attributes of a functioning and physiologically-relevant intestinal epithelium. The ‘microgut’ can also produce mucin, which serves as a line of defence against microbial invasion and contributes to the establishment of the gut-bacteria interface.

The GMoC system is therefore a more complete in vitro model because it replicates, architecturally, the cells lining the human intestine, and offers a more physiologically-relevant model compared to existing static in vitro systems.

Real-time visualization of inter-microbial interactions

Poised to be a versatile research tool, the innovative GMoC system enables scientists to study the inter-microbial interactions and gut-microbial community interactions in greater resolution and in real-time.

By studying how different bacterial species compete for limited resources such as nutrients and physical space for growth in the gut, and examining how this competition helps prevent harmful bacteria from overgrowing and disrupting the balanced gut microbiota in the gut, scientists can facilitate the development of targeted microbiome-based interventions and strategies for modulating gut microbiota.

The unique design of GMoC ensures scalability while enabling multiple tests to be performed on a single chip.

Future plans

The research team is focused on further developing the device, aiming to enhance its complexity to better replicate the human intestines. This includes incorporating complex mechanical cues, enhancing cellular complexity, and creating oxygen gradients within the GMoC system.

On the biological front, the team also aims to use the device to further investigate the assembly, interactions, and behavior of diverse microbial communities under various stimuli including nutrients and antibiotics. This will contribute to our overall understanding of how these interactions impact gut health. In terms of commercialization, the team is looking to bring the device to market by reducing the manufacturing costs and standardizing the production process.

The GMoC chip offers a crucial advancement to the field by providing a realistic, in vitro platform for the investigation of the multifaceted roles of gut microorganisms in a highly scalable way. This will help scientists to better understand the mechanisms of microbe-induced disease pathogenesis, identify novel therapeutic targets, and develop treatments capable of modulating gut microbiome to improve health and clinical outcomes.

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