Gut feeling
‘Go with your gut’, ‘trust your gut’, and other variations of the phrase illustrate the importance of the gut for our well-being. Whether we are referring to trusting our intuition or, literally, to the feeling of our guts, including our intestines, small and large, the fact remains; guts are important. The principal role of the small intestine is to absorb nutrients (1), while the waste left is passed on to the large intestine. A sophisticated relationship between the structure and function of the small intestine ensures the smooth progression of the digestive process, therefore providing us with the energy our bodies need for their daily activities!
Pillars of digestion
The epithelium of the small intestine is the largest surface of the body, larger even than the skin, and consists of 80% enterocytes. The intestinal epithelium is lined with enterocytes and maximizes its surface area by forming invaginations and protrusions called villi. By doing so, the small intestine optimizes the nutrient absorption process. The enterocytes are column-shaped cells composed of two domains, the apical and the basolateral, explaining why they are often referred to as polarized cells (1). The polarization results from the distinct structure and organelle distribution between the two domains; the apical faces the intestinal lumen and has small folds, called microvilli, that increase the membrane surface of the enterocyte exposed to the intestine environment (lumen) by 100-fold. The opposed basolateral domain faces the neighboring cells and is rich in mitochondria. Two types of junctions, classed by their different molecular composition as tight or adherent junctions, separate adjacent enterocytes, preventing the diffusion of molecules across them and safeguarding the mechanical integrity of the gut epithelium (1, 2).
Absorbing the good stuff
The primary role of enterocytes is to filter the nutrients present in the lumen of the small intestine, that result from digestion by pancreatic enzymes. Notably, the surface of the enterocyte microvilli also secretes enzymes (such as amylases) that contribute to the terminal digestion of polysaccharides. In turn, the nutrients are absorbed, crossing the enterocyte membrane by different methods: some can diffuse passively, whereas others are actively transported, explaining the need for a large number of energy-providing mitochondria in the basolateral domain. In the case of glucose, one of the major energy-carrying molecules, transport happens through a sodium gradient across the enterocyte membrane, as well as by active transport (2). The difference in the concentration of sodium between the exterior and the interior of the enterocyte (also referred to as gradient) allows glucose to enter the enterocyte, although the glucose concentration inside the cell is higher than that of the exterior environment. A transporter called GLUT2, on the opposite side of the cell, takes care of the active export of glucose from enterocytes. The balance between these two mechanisms ensures that glucose travels from the intestinal lumen, via the enterocytes, and reaches the blood vessels (2, 3).
More mature enterocytes are located closer to the epithelium and have more sodium pumps, therefore facilitating the creation of a sodium gradient that enables molecule absorption. It is worth noting that digestion is not a 100% efficient process. Small amounts of undigested nutrients, such as proteins, can be endocytosed by enterocytes to be then degraded in the lysosomes (4, 5). This is a way for enterocytes to prevent undigested, and therefore antigenic, proteins from reaching the basolateral membrane and generating an immune reaction. Increased transcytosis of food antigens has indeed been observed in animal models for food allergies (5). It is mediated by an enterocyte surface receptor named CD23, which binds and regulates the levels of IgE, an antibody linked to allergic reactions.
Shaping gut immunity
As the first barrier between the intestinal lumen and the rest of our body, enterocytes not only need to allow the absorption of nutrients, but also respond to molecules that may be potentially harmful and, most importantly, block pathogens from infiltrating the blood circulation (4). While resident microbes are beneficial for the intestine, they can become pathological if they were to cross the epithelial barrier and find their way to other tissues. In that respect, it is crucial that enterocytes keep out non-resident pathogens that can be introduced by food. As a first layer of defense, enterocytes have the glycocalyx, a highly charged mucus layer composed by glycoproteins called mucins, that coats the microvilli surface and forms a physical and electrical barrier that pathogens find difficult to cross (4, 6). Moreover, enterocyte microvilli secrete phosphatases, a family of enzymes (7), as well as antimicrobial peptides (8) that contribute to the defense of the intestinal epithelium against pathogens.
Given the charged environment of the gut in potential activators of the immune response, enterocytes have to tread lightly between maintaining immune tolerance versus setting of the immune response. This fine balance depends on a set of pathogen sensing receptors, and their respective signaling cascade, and on whether a pathogen is encountered on the apical surface of enterocytes or has managed to penetrate through the enterocyte junctions (4, 9). In other words, enterocytes are fine tuned to keep immune reactivity minimal towards gut microbes, but mobilize the immune response, through the release of chemokines and cytokines, in case a pathogen reaches the basolateral membrane (9). Since enterocytes cannot afford to repair every ‘injury’ incurred by a toxic molecule, they are, instead, constantly renewed by new enterocytes produced from adult stem cells at an area called the Lieberkühn crypt, from where they migrate to the villi. The old or damaged enterocytes undergo cell death, aka apoptosis. Altogether, this renewal cycle lasts between two and five days.
Leaky gut
But what happens when the intestinal barrier established by the enterocytes does not ‘hold’? Leaky gut syndrome, also known as increased intestinal permeability, is a hypothesis that is not officially recognised by the medical community as a condition, yet has been on the radar of researchers for a number of years. Our intestines are not 100% impermeable, otherwise this would be problematic too. Excessive intestinal permeability has been associated with conditions such as Crohn’s disease, irritable bowel syndrome and inflammatory bowel disease, among others (10). Intestinal permeability can be measured by the crossover of inert molecules through the intestinal barrier, an increase of which implies the undesired entry of pathogenic factors (toxins, microorganisms etc) into our blood circulation (10, 11). While a ‘leaky gut’ has been observed in the above diseases, it is not clear whether it is the cause or rather the result of the inflammation that goes with them. A higher microbe content has been measured in the blood stream of individuals suffering from bowel disease (10, 11), however more rigorous investigation is needed to establish a solid link between suboptimal enterocyte function and bowel disease.
Recognizing and appreciating the labs working in this space:
- Raz Lab, UC San Diego, School of Medicine, Division of Rheumatology, Autoimmunity and Inflammation, San Diego, California, USA, https://sites.medschool.ucsd.edu/som/medicine/divisions/rai/research/raz-lab/Pages/default.aspx
- Tyska Lab, Vanderbilt University, School of Medicine, Department of Cell and Developmental Biology, Nashville, Tennessee, USA, https://lab.vanderbilt.edu/tyska-lab/, X: @TyskaLabActual
- Gunnar C Hansson, University of Gothenburg, Department of Medical Biochemistry, Gothenburg Sweden, https://www.linkedin.com/in/gunnar-c-hansson-3bb53833/
- Nick Barker Lab, Epithelial Stem Cells and Cancer, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research, Singapore, https://www.nickbarkerlab.com/
- Shalev Itzkovitz Lab, Weizmann Institute of Science, Department of Molecular Cell Biology, Rehovot, Israel, https://shalevlab.weizmann.ac.il/, X: @SItzkovitz
- Jean Lab, Université de Sherbrooke, Faculty of Medicine and Health Sciences, Department of Immunology and Cell Biology, Québec, Canada https://www.sjeanlab.com, X: @JeanlabUdes
- Gao Lab, Rutgers University, Newark, New Jersey, USA https://sites.rutgers.edu/gao-lab/
- Haeusler Lab, Columbia University, Department of Medicine, Department of Pathology and Cell Biology, Naomi Berrie Diabetes Center, New York, USA https://www.rhaeuslerlab.com/, X: @RebeccaHaeusler
- Michael Camilleri, Mayo Clinic, Rochester Minnesota, USA, https://www.mayo.edu/research/faculty/camilleri-michael-m-d-d-sc/bio-00026245
- Boulant Laboratory, Department of Molecular Genetics and Microbiology, University of Florida, College of Medicine, Gainesville, Florida, USA, https://boulantlab.com/research/, X: @BoulantLab
References
- Snoeck, Veerle et al. “The role of enterocytes in the intestinal barrier function and antigen uptake.” Microbes and infection vol. 7,7–8 (2005): 997–1004. doi:10.1016/j.micinf.2005.04.003
- Gromova, Lyudmila V et al. “Mechanisms of Glucose Absorption in the Small Intestine in Health and Metabolic Diseases and Their Role in Appetite Regulation.” Nutrients vol. 13,7 2474. 20 Jul. 2021, doi:10.3390/nu13072474
- Chen, Lihong et al. “Regulation of Intestinal Glucose Absorption by Ion Channels and Transporters.” Nutrients vol. 8,1 43. 14 Jan. 2016, doi:10.3390/nu8010043
- Miron, N, and V Cristea. “Enterocytes: active cells in tolerance to food and microbial antigens in the gut.” Clinical and experimental immunology vol. 167,3 (2012): 405–12. doi:10.1111/j.1365–2249.2011.04523.x
- Laiping So, A et al. “Antigen uptake and trafficking in human intestinal epithelial cells.” Digestive diseases and sciences vol. 45,7 (2000): 1451–61. doi:10.1023/a:1005536927137
- Pelaseyed, Thaher et al. “The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system.” Immunological reviews vol. 260,1 (2014): 8–20. doi:10.1111/imr.12182
- Shifrin, David A Jr et al. “Enterocyte microvillus-derived vesicles detoxify bacterial products and regulate epithelial-microbial interactions.” Current biology : CB vol. 22,7 (2012): 627–31. doi:10.1016/j.cub.2012.02.022
- Wells, Jerry M et al. “Epithelial crosstalk at the microbiota-mucosal interface.” Proceedings of the National Academy of Sciences of the United States of America vol. 108 Suppl 1,Suppl 1 (2011): 4607–14. doi:10.1073/pnas.1000092107
- Lee, Jongdae et al. “Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells.” Nature cell biology vol. 8,12 (2006): 1327–36. doi:10.1038/ncb1500
- Camilleri, Michael. “Leaky gut: mechanisms, measurement and clinical implications in humans.” Gut vol. 68,8 (2019): 1516–1526. doi:10.1136/gutjnl-2019–31842
- Bischoff, Stephan C et al. “Intestinal permeability — a new target for disease prevention and therapy.” BMC gastroenterology vol. 14 189. 18 Nov. 2014, doi:10.1186/s12876–014–0189–7
About the author:
DR. SEMELI PLATSAKI
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Semeli is a biochemist at heart, holding a degree in Chemistry and a PhD in protein biochemistry. After working as a researcher studying the structure-function relationship of protein in a range of biological contexts, from bacterial metalloproteins to synaptic signaling, Semeli moved on to a role in Scientific communication and project management in the European Virus Archive, a collection of virus and virus-derived resources available to researchers worldwide. Semeli is passionate about the creative mix of art, words and science, one of the best ways to make Science impactful.
About the artist:
RENSKE HOSTE
Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories
Renske is a professional medical artist who spends most of her time working on anatomy and pathology in 2D and 3D. She joined as a creator of the League of Extraordinary Cell Types to challenge herself to combine science with her love for art and all things nature and growing. When not working full-time or as a freelancer, Renske loves growing things in her garden, kicking butt doing Krav Maga, or being knee-deep in various creative projects.
About the animator:
DR. EMANUELE PETRETTO
Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.
Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.
About the series:
The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
