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Dissecting microbiome and immune interactions in human intestinal (cancer) organoids

Periodic Reporting for period 4 - Organoid (Dissecting microbiome and immune interactions in human intestinal (cancer) organoids)

Reporting period: 2020-05-01 to 2020-10-31

Our discovery of stem cells of many (diseased) organs has allowed us, using a tissue-specific mix of (growth) factors, to develop a unique 3D culture system, called organoids or mini-organs in a dish) in which stem cells of these organs can be expanded and differentiated. The organoids retained their original organ identity, were genetically stable and could be expanded long term. This 3D culture system has also been successfully applied to diseased epithelia, including cancer. Organoid technology can therefore be used to model human organ development and various human pathologies ‘in a dish’.
In this ERC grant, I used the organoid technology to dissect interactions of the gut microbiome, viruses and parasites with healthy and diseased organoids and the immunoreactivity of specific immune cells with colorectal cancer (CRC) organoids.
The colon epithelium is constantly exposed to a great variety of gut bacteria, which help in digestion of food and regulation of immune responses. In contrast to these beneficial effects, some species of gut microbiota show associations to diseases such as colorectal cancer.
Our aim was to move these findings beyond mere associations and investigate the direct effects of potentially carcinogenic bacteria on human colonic epithelial cells using organoids.
Beyond bacteria, we have investigated whether human intestinal and lung organoids can be used as an experimental platform to study infection with a parasite (Cryptosporidium) and viruses (COVID19). Such models are ultimately required to understand several biological processes and for the generation of novel and/or improved drugs.
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells, distinguishing them from their healthy tissue. Many solid tumours harbour specific immune cells, yet these cells fail to mount an effective immune response, i.e. to kill off the tumor. Our aim was to understand why this is.
Our discovery of organ-specific stem cells has allowed us to develop a unique culture system in which the stem cells of these organs can grow into 3-dimensional (3D), ever-expanding epithelial organoids that retain their original organ identity. This 3D culture system has also been successfully applied to diseased epithelia, including cancer. Organoid technology can therefore be used to model human organ development and various human pathologies ‘in a dish’.
In this study, funded by the EU, we successfully used the organoid technology to dissect interactions of the gut microbiome, parasites, and viruses with healthy and diseased organoids and assess immunoreactivity with colorectal cancer (CRC) organoids.
More specifically, the colon epithelium is continuously exposed to a great variety of gut bacteria, which help in digestion of food and regulation of immune responses. In contrast to these beneficial effects, some gut microbiota species show associations to diseases such as colorectal cancer. We aimed to move these findings beyond mere associations and investigate the direct effects of potentially carcinogenic bacteria on human colonic epithelial cells using organoids. To test this hypothesis, we have set up a long-term co-culture system that allows human wild-type epithelium exposure to the bacteria for several passages. Our studies showed that some bacteria could indeed cause cancer. Moreover, we also showed that organoids are an excellent model to study parasite and virus infection, including COVID-19. This
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells, distinguishing them from their healthy tissue. Many solid tumors harbor specific immune cells, yet these cells fail to mount an effective immune response, i.e. to kill the tumor. We have successfully investigated the immunoreactivity responses using a co-culture of colon cancer organoid and specific immune cells.
In conclusion, this program has provided molecular detail to the effects of pathogens (microbiome, parasites and viruses (COVID-19)) and immune system on our gut, in health and disease.
This program has provided molecular detail to the effects of pathogens (microbiome, viruses and parasites) and immune system on our gut, in health and disease
organoid-immune cells coculture