Researchers at the University of Chicago have discovered that a hormone known as peptide YY (PYY), which is produced by gut endocrine cells and known to be involved in controlling appetite by signaling satiety, also appears to play an important role in maintaining the balance of fungi in the digestive system.
The team’s studies in human and mouse tissue found that specialized immune cells, called Paneth cells (PCs), in the small intestine express a form of PYY that prevents the fungus Candida albicans from turning into its more virulent form, allowing commensal yeast forms of C. albicans to flourish while keeping its more dangerous forms in check.
“So little is known about what regulates these fungi in our in our microbiome,” said Eugene B. Chang, MD, Martin Boyer Professor of Medicine at UChicago and senior author of the team’s published study in Science. “We know that they’re there, but we have no idea what keeps them in a state that provides health benefit to us. We now think that this peptide we discovered is actually important for maintaining fungal commensalism in the gut.”
The findings indicate that while PYY could be useful as a tool to combat fungal infections, its newly discovered function may also play a role in digestive diseases. Patients with Crohn’s disease of the ileum, the last portion of the small intestine, often have dysfunctional Paneth cells. Chang said it’s possible that this dysfunction, and lack of PYY, could create an environment for fungi to overgrow and trigger the onset of disease.
The team reported on the findings in a paper titled “Peptide YY: A Paneth cell antimicrobial peptide that maintains Candida gut commensalism.”
Gut microbes form “region-specific stable and resilient communities that are essential for processes such as immune and metabolic development and overall intestinal homeostasis,” the authors wrote. And while gut bacteria have been investigated extensively, less is known about gut fungi, they noted. The mammalian gut also secretes a family of multifunctional peptides that affect appetite, intestinal secretions, and motility, and regulate the microbiota.
Chang and his team didn’t initially set to explore the fungal side of the gut microbiome, or “mycobiome.” Joseph Pierre, PhD, a former postdoctoral scholar in Chang’s lab, and now an assistant professor of nutritional sciences at the University of Wisconsin-Madison, was studying the enteroendocrine cells (EECs) in mice that produce PYY, when he noticed that PYY was also present in Paneth cells. These are important immune system defenders in the gut of mammals, secreting several antimicrobial compounds to prevent dangerous bacteria from flourishing. “This finding was notable as PCs are gut mucosal epithelial cells found in most mammals, which secrete AMPs against pathogens and regulate the local gut microbiota,” the investigators stated.
This initially made little sense, because PYY was until then recognized as an appetite-related hormone. Further experiments also showed that PYY didn’t have significant antibacterial properties against the bacteria tested. But when the investigators ran a computer search for other classes of peptides with a similar structure, they discovered a molecule called magainin 2, which was similar to PYY, and which is found on the skin of the African clawed frog. “PC expression of PYY indicated it might have an antimicrobial function, the investigators explained in their paper. “The predicted structure of PYY resembles the alpha-helical, amphipathic AMP, magainin-2, produced in the skin of Xenopus laevis.”
The magainin-2 peptide protects the frogs from infection by both bacteria and fungi, so Chang’s team thought to test PYY’s antifungal properties. And in doing this they found that PYY is an effective antifungal agent, and specifically against C. albicans, a yeast which typically grows in small amounts in the mouth, on the skin, and in the intestines. The basic yeast form of C. albicans is commensal, in that it coexists peacefully in the body, but given the right conditions it transforms into what are called hyphae that branch out to form biofilms. “The yeast Candida albicans is found in 70% of humans but can transition into an opportunistic pathogen,” the team noted. When too much grows it can then cause thrush, an infection in the mouth and throat, as well as vaginal yeast infections, or more serious generalized infections in the body.
When Chang’s team tested PYY against both forms of the fungus, it effectively prevented growth and killed the more dangerous hyphae while sparing the commensal Candida yeast. And as the scientists further explained in their paper, “… we show that PC-PYY drives transcriptional programming in C. albicans hyphae consistent with cell death and down-regulation of virulence, whereas commensal yeast respond by downregulating pathways that promote the yeast-to-hypha transition.” Chang added, “This is a unique example of an ‘innate’ antimicrobial peptide secreted by Paneth cells that specifically kills the virulent form of this fungi and has no effect on the on the commensal form.”
The PYY peptides found in the Paneth cells and in the endocrine cells were slightly different. The full, unmodified version of PYY in the Paneth cells is a molecule with 36 amino acids, and when secreted into the gut acts as an effective antifungal peptide. But when endocrine cells produce PYY, an enzyme clips off two amino acids to turn it into a hormone that can travel through the bloodstream and signal to the brain that you’re not hungry. “PC-PYY is strictly the unmodified, full length PYY(1-36)whereas the circulating endocrine form, PYY(3-36), is formed by removal of two N-terminal amino acids by dipeptidyl peptidase IV (DPP-IV),” the authors wrote.
Just like discovering its function from a frog, Chang hopes more research on this peptide will turn up more surprises. “This is an example of the wisdom and beauty of nature that has repurposed a molecule, so it has two different functions,” he said. “That’s really cool, because this is an efficient way of making the most out of things you already have.”