A comprehensive and first-of-its-kind genetic atlas of the human small intestine reveals the secrets of food absorption and protection against infections
Tourists in a foreign city will find it difficult to navigate with only a topographical map, however detailed it may be. Therefore, tourist maps will often also show prominent landmarks and sites of interest. The mysterious territory of the human small intestine was mapped in anatomy books as early as the 16th century: the average length of this digestive tube is about 6 meters and it is lined with millions of villi - tiny finger-like protrusions that increase its surface area 30 times and are separated by crypts. . However, until now, it was not clear what those prominent landmarks and sites of interest were in the branched structure of the Kochuchs and Sisims. In a new study Published today in the scientific journal Nature For the first time, Weizmann Institute of Science scientists and the surgical team experts at the Sheba Medical Center present a detailed mapping of the various areas of activity of the human small intestine and reveal what makes it a miracle of efficient food absorption and protection against infections.
At every point in the small intestine, from the folds close to the intestinal wall to the tips of the cilia protruding into the alimentary canal, there are completely different environmental conditions. While the part close to the intestinal wall enjoys a rich supply of blood and oxygen, at the ends of the gills the environment is poor in oxygen and saturated with nutrients and bacteria. In 2018, the research group of Prof. His Itzkowitz From the department of molecular biology of the cell at the institute, that The basal cells of the small intestine of mice adapt themselves to the changing environment and perform defined roles according to their relative position on the bases.
"Up until that point, we only worked with mice", recalls Dr. Yotam Harnik from Prof. Itzkovitz's laboratory, how the project to create a genetic atlas of the human small intestine got started. "At one of the lunches on the lawn at the institute, I talked with Dr. Oren Yaakovovski, a general surgery specialist from Sheba who started the PhD program in our laboratory six months earlier. Oren asked me why we don't take human intestinal tissue from the operating rooms; One of the problems was the difficulty in locating a surgical procedure in which a significant part of a person's intestine is removed, even though the intestine itself is healthy."
"We started researching human intestinal tissue using samples from pancreatectomy operations (Wiffle operations)," says Dr. Yakovovski. "In this procedure, the entire duodenum is also cut up to the junction area with the continuation of the small intestine. One of the advantages of this procedure in the research aspect is that the intestinal tissue, which is removed for anatomical reasons, is considered healthy and therefore can be used to study the normal intestine. The cooperation with the general surgery set-up at Sheba allowed us to make sure that the sample goes into the freezer in its entirety and quickly." At the same time, in those days, advanced technology arrived at the institute that allows to efficiently map the spatial genetic expression in the tissue and to analyze with a resolution of 50 microns which genes are expressed in each region and to what extent.
Sustained release lipids
The atlas compiled by the institute's scientists, under the leadership of Dr. Harnik and Dr. Yakovovsky from Prof. Itzkovitz's laboratory and in collaboration with Dr. Ruben Hoflin from Dr. Itai Tirosh's laboratory, sheds light on several mysteries in the functioning of the intestine. Already in the 50s, it was discovered that there is a delay of up to two days in the absorption of fats from food into the blood, which prevents a spike in blood fat levels immediately after a meal, but the mechanism of its action was not known. The Atlas of the Human Intestine reveals that the digestion of basic human fat is carried out as in a kind of production line: the cells at the base of the ileum pack the fat from the food into fat droplets, and only after many hours, when those cells advance along the ileum and reach its end, do they load the fat onto "transport trucks" - particles A giant that carries it through the lymphatic system to the blood vessels and from there to storage in the body. The control of the iron balance in the body is also done in a "moving film": its absorption occurs in the gills and at the bottom of the gills and only when the cells reach the edge, and depending on the iron levels in the body, it is determined whether they will secrete their iron store into the blood or fall with it to their death in the intestinal cavity.
The Atlas also revealed that the absorption and production of digestive enzymes for the other major food components – amino acids, short proteins and sugars – occurs only towards the tips of the cilia, while the bases of those fingers specialize in the absorption of vitamins and minerals. As for the immune protection provided by the small intestine, the scientists identified that cells at the tips of the gills know how to secrete antimicrobial proteins that directly harm the bacteria as well as signal particularly aggressive cells of the immune system to arrive at the site. Thus, the tips of the hair follicles in humans were found to be rich in immune cells, including cells that promote inflammation.
when the road forks
In anatomy books, the villi of the healthy small intestine are usually described as looking like straight fingers, however, while compiling the atlas, the scientists identified intestinal villi that split from other villi - structures that until now had only been described in cancerous tumors. The scientists hypothesize that these bifurcations are intended to further increase the surface area of the intestine and improve absorption. The findings were obtained with the help of a new method that allows the spatial structure of a tissue to be recorded in 3D without damaging its integrity.
"The atlas we created will make it possible to answer basic research questions and later also clinical questions," says Prof. Itzkovitz. "Now, by mapping the healthy intestine, we can begin to better understand how the intestine changes in disease states, with age, when taking medication or under a certain diet regimen. This research, like a series of additional studies that we are conducting these days in cooperation with the array for general surgery at Sheba, are made possible thanks to the understanding of the importance of basic science among the senior members of the array, led by Dr. Ado Nahmani. In this framework, physician-researchers at the institute translate questions that arise in the clinic into studies that may provide them with answers."
Dr. Nachmani, director of the General Surgery Unit at Sheba, adds: "The collaboration between the Weizmann Institute and the General Surgery Unit at Sheba yields a series of studies on fascinating topics related to the physiology and the most basic functional anatomy of human tissues. The connection between the two worlds - basic research and clinical medicine - is a wonderful achievement, which is reflected in this work published inNature. We are working to strengthen this relationship and hope that more surgical interns will spend significant periods of research at the institute. We are convinced that this will have a profound effect on both sides."
Roy Novoselski, Dr. Keren Behar Halpern, Dr. Tal Barkai and Dr. Adi Aguzi from the department of molecular cell biology at the institute also participated in the study; Dr. Yael Korem-Kohanim from Yale University School of Medicine in New Haven, Connecticut; Ofra Golani, Dr. Yosef Addi, Dr. Mirav Kadami and Dr. Hadas Keren Shaul from the Department of Life Sciences Research Infrastructures; Dr. Tal Kidar Haran from the Hadassah University Medical Center; Dr. Yishai Levin and Dr. Alon Savidor from the Nancy and Stephen Grand Israeli National Center for Personalized Medicine at the institute; Dr. Niv Pankovich, Dr. Ron Perry and Dr. Chen Meir from the Sheba Medical Center and Prof. Dror Shuval from the Schneider Pediatric Center in Israel.
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