The naked mole rat (NMR), Heterocephalus glaber, the longest-living rodent, provides a unique opportunity to explore how evolution has shaped adult stem cell (ASC) activity and tissue function with increasing lifespan. Using cumulative BrdU labelling and a quantitative imaging approach to track intestinal ASCs (Lgr5⁺) in their native in vivo state, we find an expanded pool of Lgr5⁺ cells in NMRs, and these cells specifically at the crypt base (Lgr5^+CBC) exhibit slower division rates compared to those in short-lived mice but have a similar turnover as human LGR5^+CBC cells. Instead of entering quiescence (G0), NMR Lgr5^+CBC cells reduce their division rates by prolonging arrest in the G1 and/or G2 phases of the cell cycle. Moreover, we also observe a higher proportion of differentiated cells in NMRs that confer enhanced protection and function to the intestinal mucosa which is able to detect any chemical imbalance in the luminal environment efficiently, triggering a robust pro-apoptotic, anti-proliferative response within the stem/progenitor cell zone.

In homeostasis, counterbalanced morphogen signalling gradients along the vertical axis of the intestinal mucosa regulate the fate and function of epithelial and stromal cell compartments. Here, we use a disease-positioned mouse and human tissue to explore the consequences of pathological BMP signalling dysregulation on epithelial-mesenchymal interaction. Aberrant pan-epithelial expression of the secreted BMP antagonist Grem1 results in ectopic crypt formation, with lineage tracing demonstrating the presence of Lgr5(−) stem/progenitor cells. Isolated epithelial cell Grem1 expression has no effect on individual cell fate, indicating an intercompartmental impact of mucosal-wide BMP antagonism. Treatment with an anti-Grem1 antibody abrogates the polyposis phenotype, and triangulation of specific pathway inhibitors defines a pathological sequence of events, with Wnt-ligand-dependent ectopic stem cell niches forming through stromal remodelling following BMP disruption. These data support an emerging co-evolutionary model of intestinal cell compartmentalisation based on bidirectional regulation of epithelial-mesenchymal cell fate and function.

Enteropathogenic bacteria are a major cause of morbidity and mortality globally. While mouse models have been indispensable in advancing our understanding of infectious enteric diseases, key differences in intestinal microbiota and immunobiology between mice and humans underscore the need for alternative mammalian models that better recapitulate human disease states. The naked mole rat (NMR), the longest‐lived rodent and a model of healthy ageing, presents a unique opportunity. It possesses an exceptionally robust intestinal barrier, an abundance of goblet cells, a thicker mucin layer, and reduced gut permeability compared to mice. Additionally, the NMR gut microbiome exhibits compositional and functional features shared with human centenarians and traditional‐lifestyle populations (e.g. Hadza hunter‐gatherers), including an enrichment of health‐associated taxa and metabolic pathways. Here, we leverage this model to show that systemic Citrobacter braakii infection is associated with colonic inflammation and epithelial injury that closely mimics human haemorrhagic colitis. Infected NMRs develop mucosal erosions, ulcerations, depletion of goblet cells, expansion of proliferative compartments, and active inflammation in the lamina propria. Without intervention, systemic inflammation associated with sepsis ensues and results in high mortality. Furthermore, we demonstrate the utility of this model for therapeutic testing by showing a strong effect of a probiotic cocktail comprising lactobacilli, bifidobacteria, streptococci, and enterococci. Treatment with this cocktail promoted mucosal healing, restored intestinal homeostasis, and exerted an anti‐inflammatory effect. Taken together, we establish the NMR as a translatable model for investigating disease mechanisms in infectious colitis, including disruptions in mucosal barrier permeability, gut microbial ecology, and local and systemic immune regulation, as well as for testing functional probiotic strains as potential therapeutics. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Enteropathogenic bacteria are a major cause of morbidity and mortality globally. Mouse models have been indispensable in advancing our understanding of infectious diseases caused by intestinal pathogens and in identifying physical, chemical and immunological barriers that limit these infections. However, there are significant differences between laboratory mice and human intestinal microbiota and immunobiology that underscore the need to develop other models that recapitulate the disease pathology and mucosal immune responses of human enteric diseases. Here we report how the pathogenic expansion of Citrobacter braakii in naked mole rats (NMRs) leads to colonic inflammation and epithelial injury that mimics pathological features of human hemorrhagic colitis. We observe mucosal erosions, ulcerations, depletion of goblet cells, extension of proliferative compartments to the surface of the glands, and active inflammation in the colonic lamina propria of infected NMRs. Without intervention, systemic inflammation associated with sepsis ensues in infected NMRs and results in high mortality. Interestingly, we demonstrate a strong therapeutic effect of probiotics comprising Lactobacillus, Bifidobacterium, Streptococcus salvarius subsp. thermophilus and Enterococcus faecium strains. Treatment with probiotics induces mucosal healing and restores intestinal homeostasis, including suppression of excessive proliferation of epithelial cells, replenishment of goblet cells and also has an anti-inflammatory effect. Taken together, we demonstrate that NMRs, beyond their use as an anti-ageing and disease-resistance model, can also be used to address disease mechanisms underlying infectious colitis, including disruptions in the mucosal barrier permeability, gut microbial ecology and in local and systemic immune regulation; and in testing functional probiotics strains as potential therapeutics.

Background: The colonic mucosa consists of cell populations derived from multiple lineages. Induced pluripotent stem cells (iPSCs) are capable of generating large numbers of differentiated cells from any lineage. Thus, iPSCs are highly versatile for derivation of intestinal cells for generation of colonic mucosal tissue for clinical and biological applications. Objective: We set out to create a human iPSC (hiPSC) multi-lineage co-differentiation platform capable of generating colonic mucosal tissue in vitro. Design: We used hiPSCs and designed a differentiation protocol consisting of small molecules and recombinant growth factors to generate multiple cell lineages. Cells were seeded onto collagen hydrogels (forming colonic patches - CoPs) and modulated with multiple growth factors important in intestinal biology. CoPs were transplanted into immunosuppressed mice. Generated cells and tissues were profiled with transcriptomic analysis. Results: hiPSC co-differentiation led to multiple intestinal epithelial, mesenchymal and endothelial cell populations. Seeded onto collagen scaffolds these cells created CoPs, which were transplanted into mouse subcutis. Engrafted CoPs developed into normal-looking colonic mucosa containing epithelial crypts (with enterocytes, goblet cells and neuroendocrine cells), multiple lamina propria-resident stromal populations and muscularis mucosae smooth muscle. They anastomosed to murine vasculature and maintained in-vitro for several weeks. We demonstrated that CoPs respond to known signalling pathways important in colonic mucosal biology and fibrogenesis, showing potential to provide a complex model of colonic pathobiology. Conclusion: This platform could offer an accurate model of intestinal pathobiology, supply cells for regenerative cell therapies to treat intestinal disease, and provide therapeutic autologous grafts to repair damaged colon.

With more than 230,000 estimated new cases in 2013, prostate cancer represents the most commonly diagnosed cancer in American men. While a subgroup of patients will develop an aggressive and lethal prostate cancer, most present with a low-risk form of the disease that requires little or no treatment. It is therefore crucial to distinguish patients whose tumors are likely to progress to aggressive disease from those whose tumors will remain indolent and for whom treatment may be more detrimental than beneficial.