Sodium Butyrate

Eye-opening research from experts at Cincinnati Children's suggests it's possible CINCINNATI, Jan. 30, 2024 /PRNewswire/ -- Imagine a day when people can enjoy snacking on foods designed to "re-calibrate" their microbiomes—that vast population of friendly bacteria living in our intestines—in order to promote a healthy immune system and decrease infections or chronic inflammation. Continue Reading What are tuft cells? This confocal microscope image shows that projections extending into the lumen of the intestine are lined by epithelial cells (magenta) that arise from stem cells located at the base of these projections. Tuft cells (yellow) are a unique type of epithelial cell that regulate immune responses in the intestine. Nuclei in the epithelial cells and underlying intestinal tissue are stained with DAPI (cyan). Credit: Taylor Rice, Cincinnati Children’s How the microbiome influences tuft cells - This graphic describes a pathway in stem cells that allows development of tuft cells in the intestine. This process is dampened based on the levels of butyrate generated by the microbiome and suggests that targeting this pathway potentially offers new ways to protect against worm infection and manage the type of inflammatory reactions caused by food allergies. Credit: Emily Eshleman, Cincinnati Children’s. Experts at Cincinnati Children's have made a significant leap toward better understanding how these resident microbes instruct intestinal health in a far-reaching study published Jan. 30, 2024, in the journal Immunity. The research, led by immunologists and microbiome experts, Theresa Alenghat, VMD, PhD and Emily Eshleman, PhD, reveals a novel way to control allergic types of immune responses by adjusting how our intestines produce tuft cells, a lesser-understood element of our immune system. While many people know that our intestines are fundamental to absorbing nutrients from the food we eat, fewer people realize that the 22-foot tube curled into our abdomens also serves as the largest component of our immune defense against invading pathogens. Scientists have studied the intestine for many years, but even now they are learning surprising details about how it works. "This study shows that the microbiota—and products made by the microbiota—can dynamically control immune responses in the gut," Alenghat says. The research examines a reaction called type 2 immunity that occurs with chronic inflammatory conditions such as allergy and asthma. "We found that specific products made by bacteria in our gut can affect the power of type 2 reactions by controlling how many tuft cells form in the intestine's mucosal lining," Eshleman says. Until now, it was not clear if nor how the gut microbiome impacts tuft cells. But now that key elements involved in this developmental pathway have been identified, these findings open doors to designing new diet and microbiome approaches for preventing or promoting type 2 inflammation. A tale of fatty acids, organoids, stem cells— and worms Studying what goes on in the intestine has long been a scientific challenge because the gut environment is incredibly dynamic. In addition to all sorts of bacteria, fungi and viruses coming into the system, along with all the types of food and drink we consume, the intestine is constantly rebuilding itself. Our bodies continuously replace the entire epithelial lining from intestinal stem cells every two to five days. This means that the types of cells lining the intestine can often change, making them challenging to study in depth. In this project, Alenghat and colleagues used a combination of mouse models and human intestinal organoids (tiny spheres of functional human tissue grown in a lab dish) to measure tuft cell responses in action. Their goals were to figure out what drives the process during health and in the presence of inflammatory triggers. This is where worms enter the picture. Millions of people worldwide pick up "helminth infections", such as hookworms, roundworms and whipworms. It turns out that these parasites trigger similar type 2 immune reactions as a food allergy does. So by introducing worm infections to mice, researchers can study regulation of these immune responses in a controlled fashion without causing potentially dangerous allergic reactions in people. What's a tuft cell? Scientists figured out that cells exist back in the 1600s. But tuft cells weren't discovered until relatively recently—the 1950s. Their link to type 2 inflammation was made only within the last 10 years. These cells, so named because they are topped with fuzzy tufts of hair-like structures, emerge in widely variable, constantly changing numbers along the lining of the intestine. Researchers hunting for cures for parasite infections learned that the intestine forms large numbers of tuft cells during worm infections and that tuft cells sustain an immune cycle that gets rid of the worms. "This is one of many important reasons why we need a healthy intestinal immune system," Alenghat says. The Cincinnati Children's team shed light on how the tuft cell production process works. These special cells are created by stem cells that hide deep in pockets of the intestine called crypts. When the right trigger signal comes along, such as a worm infection, the production of tuft cells soars. However, the new study shows that bacteria that normally live in the intestine can play an inhibiting role that prevents stem cells from making tuft cells in both mouse and human intestine. Certain microbes chewing on dietary fiber emit butyrate, a common form of short-chain fatty acid that is often sold in health food stores as a potentially helpful dietary supplement. "Gut bacteria that emit lots of butyrate inhibit the activity of a protein called HDAC3, which stem cells need for making tuft cells," Eshleman says. "So, too much butyrate can mean not enough tuft cells—and that can be bad news when a helminth infection comes along." Next steps Much more research is needed before treatments aimed at controlling tuft cell numbers or function could be ready for patients, Alenghat says. One important future line of study will be seeking more understanding of how the life-long interplay of factors that change the microbiome also "train" the immune system, in good ways and bad. "The microbiome colonization process begins at birth, which suggests that there's a very early window that can set the course for microbiome-cell interactions for years to come," Alenghat says. Looking ahead, the paper suggests three possible ways to influence tuft cell production and potentially control the inflammation that occurs during chronic inflammatory conditions. Dietary regimens that can control fiber intake, up or down, can influence HDAC3 activity and change the number of tuft cells. Microbe-produced metabolites might be used to calibrate stem cell responses in the gut. Also, introducing new colonies of gut bacteria might be useful if people lack enough of the right types of bacteria. Successful treatment regimens down the road would likely require highly personalized approaches to re-calibrate, or re-balance the dynamics within the microbiome in healthy ways. "It's basically a constant balancing act," Alenghat says. "One of the struggles our bodies have is balancing the protective vs. pathologic aspects of our immune systems." About the study: In addition to Eshleman and Alenghat, Cincinnati Children's co-authors included: Taylor Rice, Crystal Potter, Amanda Waddell, PhD, Seika Hashimoto-Hill, DVM, PhD, Vivienne Woo, PhD, Sydney Field, Laura Engleman, and Fred Finkelman, MD, all with the Division of Immunobiology; Hee-Woong Lim, PhD, Division of Biomedical Informatics; and Lee Denson, MD, Division of Gastroenterology, Hepatology, and Nutrition. Funding sources for this research include several grants to investigators from the National Institutes of Health (DK114123, DK116868, DK095004, DK119694, K01DK131390, F32AI147591 and K01DK135647), the Kenneth Rainin Foundation, and the Burroughs Wellcome Fund. This project also is supported by the Center for Stem Cell & Organoid Medicine at Cincinnati Children's and NIH grants to the Digestive Health Center (P30 DK078392) and the Molecular Hematology Center of Excellence (U54 DK126108). SOURCE Cincinnati Children's Hospital Medical Center

CHICAGO--( BUSINESS WIRE )--ClostraBio, a biotech company focused on developing novel therapeutic solutions for diseases of the gut, is excited to announce a major breakthrough in targeted metabolite delivery to transform intestinal health. This first-in-class, oral, targeted metabolite delivery platform enables butyrate to achieve its maximum therapeutic potential with an initial focus on helping patients who struggle with gastrointestinal issues like mild to moderate ulcerative colitis and food allergies. This groundbreaking development of an oral nanoparticle platform has the potential to revolutionize the treatment of gut-related diseases and marks a significant step forward in the field of gastrointestinal health ( source: University of Chicago release ). Until now, oral delivery of sodium butyrate had been a challenge due to not only its foul odor and taste, but because it metabolized too rapidly to maintain a pharmacologic effect in the small intestine and colon, the areas of the gut where it has a therapeutic effect. “We have created an innovative way to use polymeric nanoparticles to address delivery of butyrate to the lower gut to help patients with mild to moderate ulcerative colitis and food allergy,” said ClostraBio founder, Dr. Cathryn Nagler. “This new therapeutic has the potential to help patients by restoring normal barrier protective function over time.” In a recent study published in the journal Nature Biomedical Engineering , ClostraBio’s founders, Dr. Cathryn Nagler, Dr. Jeffrey Hubbell, and co-authors demonstrated that the use of polymeric nanoscale micelles can effectively restore intestinal homeostasis in mouse models of colitis and peanut allergy. Butyrate was selected for its ability to alleviate inflammatory diseases of the gut through multiple mechanisms. ClostraBio co-founder, Dr. Jeffrey Hubbell said, “In today’s options for gastrointestinal issues, targeted drug delivery has become key in pharmaceutical product development. Innovative, sustained-release technologies allow for increased performance of new and existing compounds.” In addition to this exciting news, ClostraBio is pleased to announce a key addition to its management team with the appointment of CEO, Ritu Shah, Managing Director at Portal Innovations and taking on leadership roles at Portal’s portfolio companies. “I’m honored to serve as the CEO at ClostraBio. The science and technology behind their metabolite delivery platform, along with Dr. Nagler and Dr. Hubbell’s long-term vision is what attracted me to the company,” said Shah. “After the successful delivery of the drug in mice as featured in Nature Biomedical Engineering, I’m excited to execute a go-to-market plan to help bring visibility of ClostraBio to the marketplace where more than 33 million Americans suffer from inflammatory bowel disease (IBD) and food allergies.” Shah joins ClostraBio with over two decades of experience in multiple leadership roles in drug development for pharma and biotech. She was recently Chief Operating Officer at Pyxis Oncology. To date, Shah helped take Pyxis public, while also completing mergers and acquisitions with four biotech and pharmaceutical companies. “At ClostraBio, our novel delivery platform is designed to transform the treatment of lower gut disease —starting with ulcerative colitis,” finished Shah. About ClostraBio ClostraBio is a late-preclinical stage biopharma company focused on targeted metabolite delivery to transform intestinal health in patients with inflammatory bowel disease (IBD) and food allergy. Founded on seminal science originating from Dr. Cathryn Nagler’s and Dr. Jeffrey Hubbell’s labs at the University of Chicago, the company is developing a novel nanoparticle platform that enables oral delivery of short-chain fatty acids (SCFAs) to targeted locations in the gastrointestinal tract. For more information about the company, please visit: http://clostrabio.com