Stanford Researchers Unveil Microscopic “Communities” in the Human Gut
A groundbreaking discovery by Stanford scientists has unveiled intricately organized cellular “neighborhoods” within the human intestine. This revelation comes as a result of cutting-edge imaging techniques that fuse microscopy and robotic technology. The captivating images generated by this method offer a remarkable glimpse into the world of cellular diversity residing within our digestive system.
Each hue within these images signifies specific molecules expressed by distinct cell types. These molecules, predominantly proteins, play pivotal roles in defining the identity and function of individual intestinal cells. Through a process akin to painting or tagging, these scientists assign distinct colors to specific cells, providing profound insights into the complex interactions and structures inherent to our intestines. In this context, every color corresponds to a particular molecule, offering valuable information regarding the presence and distribution of diverse cell types and structures.
While pondering an ideal neighborhood, one may envisage tree-lined streets or a tight-knit community that thrives on mutual support. Surprisingly, the human digestive system also exhibits its own set of neighborhoods, as revealed by a team of scientists spearheaded by Stanford Medicine researchers. These “neighborhoods” consist of various cell types collaborating to execute tasks like food digestion and protection against infections. An ultra-high-resolution map, created using cutting-edge technologies, showcases the functional magnificence and visual splendor of the human intestine.
Much like our earthly neighborhoods, cellular neighborhoods are composed of varying quantities of cell types, each endowed with specific functions. By combining advanced imaging and sequencing techniques, the researchers have successfully mapped these neighborhoods down to the level of individual cells.
Michael Snyder, Ph.D., a professor of genetics and co-senior author of this research, described this endeavor as akin to exploring a new planet, as the exact cell types and their organization were previously unknown.
This groundbreaking mapping effort, part of the Human BioMolecular Atlas Program initiated by the National Institutes of Health, involved scientists from multiple laboratories, both within Stanford Medicine and beyond. Their aim is to construct a comprehensive cellular map of the human body.
To map the intestine, they examined tissue samples from eight regions of the small and large intestine from nine deceased donors. Utilizing a technology called co-detection by indexing, or CODEX, they stained and washed the tissue repeatedly with fluorescent antibodies, allowing them to identify 20 distinct cellular neighborhoods based on the relative abundance of each cell type. Additionally, molecular analysis of RNA and chromosomal material from some samples provided even greater insight into each cell type’s characteristics.
Snyder, the Stanford W. Ascherman, MD, FACS Professor in Genetics, highlighted the significance of these maps as a reference for a healthy intestine. They can be used to compare various digestive diseases, ranging from irritable bowel disease to early-stage colon cancer.
The human intestine, measuring roughly 20 feet in length, absorbs nutrients, guards against invading microbes, and maintains a delicate balance of beneficial bacteria essential for digestion. To execute these functions, various cell types, including epithelial cells, connective tissue cells, nerve cells, and immune cells, are employed. The new maps precisely pinpoint the locations of each cell type and their associations with others.
Garry Nolan, Ph.D., a professor of pathology and co-leader of the research, emphasized that the functionality of cells is defined not by their individual presence but by how they are grouped together.
Additionally, the researchers explored how the organization of healthy tissue changes along the digestive tract, from the stomach to the rectum. This exploration revealed that the prevalence of certain cell neighborhoods, like those dominated by smooth muscle cells, increased towards the end of the colon, while neighborhoods primarily comprised of immune cells decreased.
The maps also unveiled intriguing clinical connections. Higher body mass index (BMI) was correlated with an increased number of M1 macrophages, immune cells linked to inflammation. This finding is significant because individuals with higher BMI levels are known to have a greater risk of gastrointestinal diseases associated with chronic inflammation.
Donors with a history of hypertension exhibited fewer CD8 T cells, a type of immune cell responsible for identifying and eliminating potential cancer cells, in a specific neighborhood within the intestinal epithelial cells. This observation is noteworthy, as it suggests a higher risk of colorectal cancer among individuals with hypertension.
The future of this research includes a concerted effort to diversify the sample pool by including individuals from various ethnic backgrounds and age groups. Additionally, the scientists plan to create a three-dimensional map of the intestine, which will provide insights into the networks of nerves and blood vessels in a healthy intestine. As John Hickey, Ph.D., the paper’s first author, aptly stated, “You can’t understand dysfunction until you understand what’s normal.” This work is poised to revolutionize our understanding of digestive health and associated diseases.
Reference: “Organization of the human intestine at single-cell resolution” by John W. Hickey, Winston R. Becker, Stephanie A. Nevins, Aaron Horning, Almudena Espin Perez, Chenchen Zhu, Bokai Zhu, Bei Wei, Roxanne Chiu, Derek C. Chen, Daniel L. Cotter, Edward D. Esplin, Annika K. Weimer, Chiara Caraccio, Vishal Venkataraaman, Christian M. Schürch, Sarah Black, Maria Brbić, Kaidi Cao, Shuxiao Chen, Weiruo Zhang, Emma Monte, Nancy R. Zhang, Zongming Ma, Jure Leskovec, Zhengyan Zhang, Shin Lin, Teri Longacre, Sylvia K. Plevritis, Yiing Lin, Garry P. Nolan, William J. Greenleaf and Michael Snyder, 19 July 2023, Nature.
DOI: 10.1038/s41586-023-05915-x
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Frequently Asked Questions (FAQs) about Gut Cellular Neighborhoods
What is the significance of mapping cellular neighborhoods in the human gut?
Mapping cellular neighborhoods in the human gut is significant because it provides insights into the intricate organization of cell types and their functions within the intestine. This knowledge serves as a reference for understanding digestive diseases and may lead to advancements in diagnosing and treating gastrointestinal disorders.
How was the mapping of gut cellular neighborhoods conducted?
The mapping was conducted using advanced imaging techniques, including microscopy and robotic technology, along with a process called co-detection by indexing (CODEX). Fluorescent antibodies were used to stain and wash the tissue repeatedly, allowing the identification of distinct cellular neighborhoods.
What are the practical applications of this research?
This research offers a foundational understanding of a healthy intestine, enabling comparisons with various digestive diseases, such as irritable bowel disease and colon cancer. It also revealed clinical connections, such as the link between higher BMI and inflammation, which can have implications for healthcare and disease prevention.
How might this research benefit healthcare and medical advancements?
The mapping of gut cellular neighborhoods can contribute to improved diagnoses and treatments for digestive disorders. It may aid in the development of targeted therapies and interventions based on a better understanding of cellular interactions in the intestine, ultimately enhancing digestive health and patient care.
More about Gut Cellular Neighborhoods
- Stanford Medicine’s Research Announcement
- Nature Journal Research Paper
- National Institutes of Health – Human BioMolecular Atlas Program
