TOKYO, June 21, 2021 /PRNewswire/ — Researchers at Keio University, Japan, offer new insights into the adaptive immune system of the small intestine for new perspectives on host-microorganism symbiosis and organoid-based regeneration of the small intestine for treating short bowel syndrome. These findings were published in the journals Science Advances and Nature, respectively.
The Keio Research Highlights website offers more details about this and other recent research being conducted by researchers at Keio University.
Mammalian systems have sophisticated mechanisms to control symbiosis with bacteria in the gut
Bacterial cells are enveloped by a protective coating made up of complex sugar molecules. Mammalian cells that are under bacterial attack have evolved over time to recognize these complex structures and trigger a combative response. In turn, bacteria have developed a clever mechanism to evade this response, where the sugars in their protective lining are linked closely to small molecules known as amino acids. Bacteria have learned to disguise these amino acids by changing their configuration slightly. Instead of using amino acids traditionally found in nature (L-amino acids), bacteria adopt mirror-image variants called D-amino acids (D-aa) into their envelopes. However, a team of molecular biologists led by Jumpei Sasabe at Keio University has recently shown that mammalian cells may also have a way to degrade D-aa in order to keep bacterial growth in check.
Mammalian systems are equipped with an enzyme called D-aa oxidase (DAO) that is responsible for detecting and degrading D-aa. To see how exactly DAO works, the team employed mice that had been genetically modified to disable DAO. Notably, these mice exhibited high levels of D-aa in their blood.
When the body detects bacteria, a defensive mechanism is initiated via several steps. White blood cells, named granulocytes and macrophages, take the bacteria into their cells (eat them, so to speak) and sterilize them. Since these innate immune systems work regardless of the type of bacteria, they are the frontline defence system. However, even this is not enough, the acquired immune system comes into play next. The main players are lymphocytes, a type of white blood cells that flow in the blood. B-lymphocytes produce antibodies (immunoglobulins) that fight bacteria and render them harmless. This is how we become "immunized" to germs. DAO regulates the latter process. The researchers used a series of experiments to investigate how the immune systems of mice with disabled DAO behaved when they detected D–aa released from bacteria in the gut. These mice showed exceedingly higher immunoglobulin A (IgA) levels compared to those with well–functioning DAO. They also had a greater number of transformative B-lymphocytes ready to produce IgA. Healthy DAO function was thus crucial in keeping D–aa–producing bacteria in check and controlling the subsequent immune response. Moreover, mice with impaired DAO function also showed signs of increased inflammation in the gut.
A certain number of bacteria reside permanently within the mammalian gut and aid with digestive function in exchange for a home. Maintaining this symbiotic relationship is important in preventing infections and keeping our gut health intact. This study shows that DAO is a key element in degrading D-aa thereby preventing excessive immune responses against symbiotic bacteria. "Our results reveal unexpected roles of D-aa catabolism by host DAO in the adaptive immune system of the small intestine and provide a new perspective on host-microbe symbiosis," conclude the researchers. A deeper understanding of this protective mechanism in mammalian species can also be useful in devising antibacterial strategies targeting D-aa.
Masataka Suzuki, Tomohisa Sujino, Sayako Chiba, Yoichi Harada, Motohito Goto, Riichi Takahashi, Masashi Mita, Kenji Hamase, Takanori Kanai, Mamoru Ito, Matthew Kaden Waldor, Masato Yasui, and Jumpei Sasabe. Host-microbe cross-talk governs amino acid chirality to regulate survival and differentiation of B cells. Science Advances, 2021, Vol. 7, no. 10, eabd6480
Regenerating the small intestine
An organoid-based regenerative technique holds promise as a treatment for short bowel syndrome
In the human body, most of the digestion and absorption of food takes place in the small intestine (small bowel). In certain pathological situations, for example when the small intestine becomes blocked or infected or when tumors develop within the organ, it may need to be partly or completely surgically removed. This operation is called a small-intestine resection. An extensive resection can result in nutrients no longer being properly absorbed into the body, a condition that is known as short bowel syndrome (SBS). Symptoms of SBS include diarrhoea, dehydration, and weight loss, and in 50% of SBS cases, patients require the permanent intravenous administration of nutrition. Today, the only treatment for these patients is organ transplantation but the survival rate is low because of a high probability of the organ being rejected (as well as a shortage of donors). Alternative treatment options are much needed.
One such alternative approach currently being explored is based on advances in regenerative medicine—the term refers to the development of methods for regrowing tissue with specific functions or even organs. A breakthrough in this line of research with implications for SBS has now been reported by Shinya Sugimoto from Keio University and his colleagues, who have succeeded in generating a small-intestine-like organ that mimics the food-absorbing capabilities of the small intestine.
The scientists first created organoids from the tissue of the small intestine—the organoids are essentially cultured clusters of small-intestine stem cells. They speculated that when transplanting organoids to the large intestine (also known as the colon, which is located after the small intestine), a ‘small intestinalized colon (SIC)’ might form that is able to perform (some of) the functions of the small intestine. Experiments on mice showed that indeed, transplanted organoids can reconstitute small-intestine tissue and absorption capabilities. Importantly, the researchers confirmed the formation of villi—small, finger-like protrusions occurring everywhere in the small intestine and playing a key role in the nutrient absorption process.
To test the therapeutic potential of a SIC, the researchers performed experiments on rats. Parts of the rats’ small intestines were removed, leading to SBS, after which SICs were created using the rats’ large intestines. The scientists observed that intestinal failure in the SBS rats was reduced significantly. The results suggest that the SIC can perform the function of the small intestine and, importantly, that it can remodel its so-called lymphovascular structure. The latter refers to the highly complex structure of vessels carrying blood and other liquids around within the small intestine.
The findings of Sugimoto and his colleagues hold promise for treating SBS, as even a short residual small intestine (as the result of a resection operation) is still a rich enough source for creating organoids and therefore a SIC. In the words of the researchers, "These data provide a proof of principle for the use of intestinal organoids for regenerative purposes, and offer a feasible strategy for SBS treatment."
Shinya Sugimoto, Eiji Kobayashi, Masayuki Fujii, Yuki Ohta, Kazuya Arai, Mami Matano, Keiko Ishikawa, Kentaro Miyamoto, Kohta Toshimitsu, Sirirat Takahashi, Kosaku Nanki, Yoji Hakamata, Takanori Kanai, Toshiro Sato, An organoid-based organ-repurposing approach to treat short bowel syndrome, Nature 592, 99–104 (2021).
Keio Research Highlights
About Keio University
Keio University is a private, comprehensive university with six major campuses in the Greater Tokyo area along with a number of affiliated academic institutions. Keio prides itself on educational and research excellence in a wide range of fields and its state-of-the-art university hospital.
Keio was founded in 1858, and it is Japan’s first modern institution of higher learning. Over the last century and a half, it has evolved into and continues to maintain its status as a leading university in Japan through its ongoing commitment to producing leaders of the future. Founder Yukichi Fukuzawa, a highly respected educator and one of the most important intellectuals of modern Japan, aspired for Keio to be a pioneer of new discoveries and contribute to society through.
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