The research, led by Lingming Kong, Fengyu Shi, Hongru Kong and Haonan Xie, with Gang Chen as senior author, was carried out by teams at Wenzhou Medical University and collaborating institutions in China and the United States. The investigators focused on elderly-onset acute pancreatitis, abbreviated EOAP, and asked a deceptively simple question: does the gut microbiome of an aged organism process food differently in ways that make pancreatic injury worse? Their answer, built from mouse experiments and human clinical samples, is a carefully documented yes. The work identifies a specific microbial group, a specific metabolite and a specific cellular mechanism that together appear to convert an age-related shift in gut ecology into genuine pancreatic damage.

The starting point was a comparative analysis of metabolites. When the researchers profiled the metabolic output of the gut in aged mice and in elderly patients suffering from acute pancreatitis, two molecules stood out: phenaceturic acid, known as PAC, and phenylacetylglutamine, known as PG. Both are downstream products of phenylalanine metabolism. Phenylalanine is an essential aromatic amino acid that humans obtain from dietary protein, and gut bacteria routinely ferment it into a family of phenyl-containing compounds that are absorbed into the bloodstream and eventually excreted. In the aged animals and the elderly patients, the levels of these two phenylalanine-derived metabolites were markedly elevated compared with younger counterparts, suggesting that aging fundamentally rewires how the gut handles this amino acid.

Who was producing the extra metabolites? Metagenomic analysis of the gut communities pointed to a familiar and somewhat notorious culprit: bacteria belonging to the Escherichia-Shigella group. This cluster, which includes organisms closely related to Escherichia coli and Shigella species, was significantly more abundant in the aged mice and elderly patients. The correlation between Escherichia-Shigella expansion and elevated PAC and PG levels provided the first mechanistic thread: an age-associated bloom of particular bacteria appears to drive increased microbial processing of phenylalanine, flooding the host with metabolites that a younger gut produces in smaller quantities.

Correlation alone, however, is never enough to establish causation, and the team moved decisively to test it. Using fecal microbiota transplantation, they transferred gut communities from aged donor mice into young recipient mice. The young animals, which normally tolerate experimental pancreatic injury with a moderate inflammatory response, developed a strikingly aggravated phenotype after receiving the aged microbiota. Their pancreatitis became more severe, mirroring the pattern seen in naturally aged animals. This transfer experiment is conceptually powerful because it isolates the microbiome as a sufficient carrier of the age-related risk: the recipients’ own genomes and chronological age were unchanged, yet their disease outcome was transformed by the microbial community they received.

With the microbial contribution established, the researchers turned to the cellular level to understand how phenaceturic acid actually damages the pancreas. The pancreas’s exocrine tissue is built from acinar cells, specialized factories that produce and secrete digestive enzymes. These cells are packed with mitochondria, the organelles that generate the energy required for massive protein synthesis and export. The team found that PAC compromises mitochondrial integrity in these acinar cells. Damaged mitochondria are not merely idle; they leak reactive oxygen species, release pro-death signaling molecules and trigger quality-control responses that can themselves become destructive when overwhelmed.

One of those quality-control responses, mitophagy, sits at the center of the proposed mechanism. Mitophagy is the cellular process by which defective mitochondria are selectively engulfed and degraded, normally a protective housekeeping function that keeps the mitochondrial network healthy. The study’s findings indicate that in the context of EOAP, PAC-driven mitochondrial damage pushes mitophagy into overdrive, and rather than rescuing the cells, this excessive mitophagy coincides with enhanced cell death. The acinar cells undergo apoptosis, the programmed death pathway, at elevated rates. Widespread acinar cell death is a hallmark of severe pancreatitis because dying cells release their contents, including digestive enzymes and damage-associated molecular patterns, which amplify the inflammatory cascade and recruit further immune activation.

The chain of evidence therefore reads as follows: aging reshapes the gut microbiome, allowing Escherichia-Shigella to expand; these bacteria convert more dietary phenylalanine into phenaceturic acid and phenylacetylglutamine; elevated PAC circulates to the pancreas, where it undermines mitochondrial integrity in acinar cells; runaway mitophagy and apoptosis follow; and the resulting cell death intensifies inflammation, making the overall disease more severe. Each link in this chain was supported by the study’s combination of human sample analysis, mouse modeling, microbial transplantation and mechanistic cell biology, forming one of the more complete causal narratives in the microbiome-pancreatitis literature.

The clinical implications are considerable. Acute pancreatitis in the elderly is a growing burden as populations worldwide age, and current treatment remains largely supportive, with no approved drugs that specifically target the mechanisms of disease severity. If the findings hold up in further studies, they suggest several concrete intervention points. Microbial phenylalanine metabolism could be modulated with dietary strategies that alter protein intake or amino acid availability. The offending bacterial groups could be suppressed with targeted antimicrobials or outcompeted through microbiome-directed therapies. The metabolites themselves, PAC and PG, could serve as biomarkers, allowing clinicians to identify elderly patients at risk of severe disease before the inflammatory storm fully develops. And the downstream mitochondrial and apoptotic pathways offer pharmacological targets for drugs that stabilize mitochondrial function or restrain excessive cell death.

As with any translational study, important questions remain. The work was conducted in mouse models and human cohort samples, and the precise dose-response relationship between circulating PAC and pancreatic injury in humans will need prospective validation. It is also not yet clear whether reducing phenylalanine-derived metabolites after pancreatitis has already begun can improve outcomes, or whether the intervention window lies earlier, in maintaining a healthier microbiome throughout aging. What the study undeniably establishes is that the age-related severity of acute pancreatitis is not written solely in the pancreas or the immune system, but is partly manufactured in the gut by microbial chemistry. That reframing — treating a metabolic product of our resident bacteria as a driver of organ failure — is likely to resonate well beyond pancreatology, and it adds pancreatic disease to the expanding list of conditions, from neurodegeneration to cardiovascular disease, in which microbial metabolites of dietary amino acids are emerging as unexpected culprits.

Subject of Research: The role of gut microbiota-derived phenylalanine metabolites in exacerbating elderly-onset acute pancreatitis through mitochondrial dysfunction and cell death

Article Title: Gut microbiota-derived phenylalanine metabolites exacerbate elderly-onset acute pancreatitis by promoting mitophagy and enhancing cell death

Article References: Kong, L., Shi, F., Kong, H., Xie, H., Pan, Z., Liu, Z., Yu, D., Chen, W., Sun, H., Jin, Y., Wang, J., Ergashev, A., Li, T., Wang, Y., Zhang, J.-S., Fernandez-Zapico, M. E., Zhang, C., & Chen, G. (2026). Gut microbiota-derived phenylalanine metabolites exacerbate elderly-onset acute pancreatitis by promoting mitophagy and enhancing cell death. Microbiome. https://doi.org/10.1186/s40168-026-02518-2

Image Credits: AI Generated

DOI: 10.1186/s40168-026-02518-2

Keywords: elderly-onset acute pancreatitis, gut microbiota, phenylalanine metabolism, phenaceturic acid, phenylacetylglutamine, Escherichia-Shigella, mitophagy, apoptosis, mitochondrial dysfunction, acinar cells, fecal microbiota transplantation, Microbiome journal

The study, published on September 17 in the journal Nature Communications, describes how the researchers guided human pluripotent stem cells, or PSCs, through a sequence of developmental steps that mirror the way salivary glands form naturally during human embryonic development. Stelios Andreadis, PhD, SUNY Distinguished Professor in the Department of Chemical and Biological Engineering in the School of Engineering and Applied Sciences at the University at Buffalo, serves as co-principal investigator on the study alongside Olga Baker, PhD, DDS, a professor in the Department of Otolaryngology at the University of Missouri School of Medicine in Columbia. Andreadis also directs UB’s Center of Cell, Gene and Tissue Engineering and is a member of the UB Center of Excellence in Bioinformatics and Life Sciences.

The appeal of pluripotent stem cells as a starting material lies in their remarkable accessibility and versatility. Human pluripotent stem cells can be derived from easily obtainable adult somatic cells, such as skin or blood cells, and then reprogrammed into a state in which they retain the potential to become almost any cell type in the body. That reprogramming concept earned Shinya Yamanaka of Japan and the late British biologist John Gurdon the Nobel Prize in 2012, and in the years since, researchers have used the technique to generate vascular cells, brain cells and kidney cells for study and potential therapy. Salivary gland tissue, however, had remained an elusive target, largely because of the intricate architecture and multiple specialized cell types that a working gland requires.

The Buffalo team’s approach centers on coaxing the pluripotent stem cells into becoming salivary gland epithelial progenitor cells, abbreviated SGEPs. These progenitors then organize themselves spontaneously into tiny three-dimensional structures known as organoids, miniature versions of organs that recapitulate key features of native tissue in the laboratory. Organoids have become one of the most powerful tools in modern biomedical research because they allow scientists to study organ development, disease progression and drug responses in a dish, using human-derived tissue rather than simplified cell cultures. According to Andreadis, the findings suggest that salivary gland organoids may hold promise not only for studying salivary gland development, disease progression and drug screening, but also for the development of cell therapies aimed at regenerating the glands themselves.

Generating the organoids in culture, however, is only half of the challenge. A replacement gland must survive inside a living body, integrate with surrounding tissue and mature into the full complement of functional cell types. To test whether the lab-grown structures could meet that bar, Baker’s research team in Missouri transplanted the organoids into the submandibular salivary glands of immunodeficient mice. The use of immunodeficient animals was a deliberate methodological choice: it allowed the human-derived tissue to be studied in vivo without the complication of immune rejection, giving the researchers a clear window into how the transplanted cells behave in a living glandular environment.

The results were striking. After more than 40 days inside the mice, the transplanted organoids had not merely survived; they had integrated into the existing salivary gland tissue of their hosts. Andreadis and the UB team performed the immunostaining and analyzed how well the grafts had incorporated and differentiated within the host tissue. Further analysis revealed that the organoids contained the cell types found in more mature glands, including acinar cells, which are the workhorses of saliva production; ductal cells, which form the channels that carry saliva from the gland into the mouth; and myoepithelial cells, specialized contractile cells that help squeeze saliva out of the glands and into the ductal network. The presence of all three lineages indicates that the organoids were recapitulating the essential cellular architecture of a functioning gland.

Perhaps most encouraging was the structural maturity the grafts achieved. Andreadis noted that the newly formed glands looked similar to native salivary glands and even developed lumens, the hollow interior spaces through which saliva would normally flow. Lumens are a hallmark of organized epithelial tissue and a prerequisite for any gland that hopes to secrete fluid in a directed way. Their appearance in the transplanted organoids suggests that the developmental program the researchers initiated in culture continued to unfold once the cells were placed in a living environment, driven by cues from the surrounding host tissue.

Laura Sherwood, a PhD candidate in biomedical engineering and a member of Andreadis’s research group, was first author on the paper together with Ronel Samuel, who completed his doctorate in 2024. Sherwood, who earned an award for this research at the 2025 Salivary Glands and Exocrine Biology Gordon Research Conference, summarized the significance of the transplantation experiments plainly. The experiments so far showed that the transplanted organoids have the potential to survive in vivo, she explained, and they integrated with the mouse gland and differentiated to include major salivary gland structures. That combination of survival, integration and differentiation, she noted, means the organoids could potentially become a renewable source of replacement cells for patients in the future.

Considerable work remains before such a therapy could reach the clinic, and the team is pursuing several parallel lines of refinement. One priority is to improve the differentiation process so that the cells composing the organoids become more mature and their developmental fate can be controlled with greater precision. The researchers are also working to determine the optimal stage of organoid development for transplantation and to improve the culture conditions in which the organoids grow. The ultimate functional goals are demanding: the engineered tissue must produce saliva in useful quantities, connect properly with the existing ducts that carry saliva into the mouth, and establish connections with the nerves that regulate salivary gland function. Each of these requirements represents a distinct biological hurdle, from vascularization and innervation to mechanical coupling with the recipient’s own ductal system.

Even with those challenges ahead, the implications of the work extend well beyond a single future therapy. Andreadis observed that while using these cells in humans is a long way off, the research suggests that one day scientists could repair salivary glands damaged by radiation therapy, restore saliva production in people with chronic dry mouth, study diseases of the salivary glands in the laboratory and test potential new drugs on human salivary tissue. For the patients whose quality of life is most eroded by xerostomia, particularly survivors of head and neck cancer and people living with Sjögren’s disease, the study offers something that has been missing from the field for decades: credible evidence that replacement salivary tissue can be built from a patient-accessible cell source and can take root in a living gland. Other participating researchers included graduate student Sai Harsha Bhamidipati in the UB Department of Chemical and Biomedical Engineering; Kihoon Nam, Frank Maslow and Travis Small with the University of Missouri; and Yali Zhang, Jianmin Wang and Song Liu with the Department of Biostatistics and Bioinformatics at Roswell Park Comprehensive Cancer Center. The researchers reported no conflict of interest.

Subject of Research: Derivation of transplantable salivary gland organoids from human pluripotent stem cells for treating dry mouth

Article Title: UB researchers grow salivary glands from pluripotent stem cells

Article References: UB researchers grow salivary glands from pluripotent stem cells. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: pluripotent stem cells, salivary glands, organoids, xerostomia, Sjögren's disease, regenerative medicine, tissue engineering, radiation therapy, acinar cells, Nature Communications, cell therapy, University at Buffalo