By Eimear Holton, NIAID Training Social Media/Web/Outreach Program Specialist
The “Rising Research” series aims to elevate the research conducted by NIAID intramural research fellows by stepping behind the bench to get to know the early-stage scientists who drive this research. In his recent Cell paper, NIAID research fellow Yikun Yao, Ph.D., describes how sialylation, a biologically important modification to the terminal end of glycans on glycoproteins, determines the integrity of the gut mucus barrier and its maintenance of gastrointestinal (GI) homeostasis.
As a capstone to his postdoctoral fellowship in the Molecular Development of the Immune System Section of the Laboratory of Immune System Biology, Yikun Yao, Ph.D., published the product of a 4-year-long project. He uncovered how a protein modification mechanism called sialylation is responsible for maintaining the mucus barrier integrity in the gut. This barrier acts as the host defense against bacterial invaders while also serving as a habitat and nutrient source for the gut microbiota. When the sialylation process is deficient, the balance of host and gut microbiota is disturbed and in turn causes discord in the intestinal barrier function and changes to the microbiota living there. Dr. Yao’s research shows that sialylation controls intestinal barrier function, inflammation, and the microbial composition of the GI ecosystem, all of which are influential in the development of a human immune disease known as inflammatory bowel disease (IBD).
In a clinically focused environment like Building 10, the Laboratory of Immune System Biology pays close attention to the clinical relevance of their research. Dr. Yao said his postdoctoral research has always focused on the relevance to the patient first. For this study, he worked with inherited inflammatory bowel disease (IBD) patient samples from all over the world. “This environment has been conducive to a great training environment. My principal investigator, Dr. Michael Lenardo provides a very interactive, exciting, and open laboratory to foster creativity and new molecular concepts in our projects. We collaborate with many outstanding internal or external labs, as well as many physicians around the world—a key element in our proximity to patients and in the exploration of the molecular pathogenesis of the diseases.”
Sialylation is the terminal addition of sialic acid (SA) to glycans, and it occurs on mature mucin proteins, the major proteins in the intestinal mucus layer. Sialyltransferase (ST6) is an enzyme that plays a key role in this process, and Dr. Yao found that it was highly expressed in the gut, specifically in the goblet cells, of healthy individuals. Dr. Yao and his colleagues conducted a series of experiments in both human samples and mice that showed how essential ST6 is for mucus stability and in preventing intestinal bacterial infiltration into the host epithelium and consequential inflammation in the gut—factors that contribute to IBD. Whole genomic sequencing of IBD patients from worldwide cohorts and candidate patient tissue sample analysis uncovered that mutations in ST6 cause IBD. Further consequences of mucus barrier defects were changes in the make-up of the gut microbiota and subsequent imbalance in intestinal epithelial cell (IEC) regeneration and repair of the IEC layer.
This research shines a light on previously unknown mechanisms that maintain mucus barrier integrity in the gut. Defects in the mucus lining contribute to IBD and can lead to increased susceptibility to chronic disease and colon cancer. By defining this mechanism of homeostasis, Dr. Yao has uncovered potential pathways for the development of new IBD therapeutics. Interventions aimed at protecting the mucus barrier through sialylated mucin or a Foxo3 inhibitor used for promoting IEC proliferation may lead to new classes of clinically relevant drugs to treat IBD. Further, there is potential to focus not only on mucus proteins in the intestines but also on the effects that defective sialylation could have on other proteins and in other mucous tissues. In future work, additional sialylated proteins could be investigated to clarify the contribution of sialylation to homeostasis in all mucous tissues.
“Genomic sequencing and advances in gene-editing technologies are allowing us to uncover new disease-causing genes and the underlying pathological mechanisms faster than before— hopefully these advances will be passed along to benefit patients just as fast,” commented Dr. Yao.
From here, Dr. Yao is looking forward to the future avenues where this research may take him. Dr. Yao is poised for the academic track as an independent investigator and has recently switched from postdoc to research fellow to continue his work in the Molecular Development of the Immune System Section.
When asked to impart words of wisdom to younger scientists just starting at NIH, Dr. Yao made it clear that it is important to make the most of your time at NIH because of the wealth of resources at your fingertips: “If you have a good idea, pursue it. You can make it a reality because the resources are always available here to support you. Don’t stop trying new things.”
Yao Y, Kim G, Shafer S, et al. Mucus sialylation determines intestinal host-commensal homeostasis. Cell. 2022;185(7):1172-1188.e28. doi:10.1016/j.cell.2022.02.013