Exploring mucosal cytopathology through the lens of the microbiome in Sjögren’s syndrome

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease, primarily affecting the salivary and lacrimal glands through lymphocytic infiltration and resulting in dryness of the eyes and mouth.^[1] In more recent times, SS has been recognized as a mucosal disease with complex features, including epithelial remodeling, immune dysregulation, and extraglandular manifestations.^[2] Within this evolving framework, recent advances in microbiome research are opening new perspectives for understanding mucosal pathology. Indeed, the possibility that host–microbiota interactions may influence epithelial health and local immune activity raises important questions for cytopathology. What has often been interpreted as non-specific morphological change may, in some cases, indicate disruption in mucosal microbial and immune balance.

The intestinal microbiome is already known to play a role in SS. Indeed, fecal microbiota transplantation from SS patients into germ-free mice results in the loss of regulatory T cells, depletion of goblet cells, and disruption of the corneal barrier. These findings suggest that microbial changes originating in the gut can have downstream effects on remote mucosal sites, including the ocular and oral surfaces.^[3] Beyond the gut, growing evidence supports the relevance of the ocular surface microbiome. Several findings in the literature highlight a microbiota that may modulate immune responses. Indeed, clinical data show that the ocular surface microbiota in patients with primary SS are significantly altered. This reduces bacterial diversity and shifts in composition, such as increased Acinetobacter and decreased commensal taxa.^[2-4] These changes correlate with clinical signs of ocular surface damage, including lower goblet cell density, worse Schirmer test scores, and higher ocular staining. Such findings support the hypothesis that microbial imbalance contributes directly to local epithelial stress and immune activation in SS.^[4]

These observations lead to an important conceptual proposition: Mucosal epithelia may function as “sensors” of microbial activity. Indeed, epithelial morphology reflects not only inflammatory insult but also microbial context. In this model, changes seen in cytological samples – atrophy, metaplasia, or reactive atypia – can be read as biological responses to microbial imbalance. This perspective is particularly relevant for SS, where epithelial tissues are in close interaction with immune cells and microbial communities. We may now need to integrate microbial information into our morphological frameworks, as with cervical cytology in the context of human papillomavirus-mediated disease. This interpretive shift has several implications for cytopathology. First, it positions cytological techniques such as impression cytology and oral exfoliative cytology as potential tools for monitoring microbiome-related mucosal changes in SS. Second, it encourages re-evaluation of morphological findings that are frequently labeled as reactive or non-specific. Third, it raises the possibility of using epithelial patterns as biomarkers to stratify SS patients based on microbial risk profiles, possibly identifying subgroups with more active disease or greater potential for progression.

Data from recent both human and animal studies support this approach. Recent literature underscores the relevance of microbial dysbiosis across multiple mucosal compartments in SS, including the ocular surface.^[4,5] Alterations in microbial diversity and composition, such as the loss of commensal Corynebacterium and expansion of Gram-negative or environmental species, have been associated with goblet cell loss, epithelial stress, and heightened inflammation. These findings support a model in which microbial shifts act as upstream modulators of mucosal barrier dysfunction and epithelial remodeling in SS.^[5]

It would represent a novel and interesting approach if cytopathology, rather than labeling epithelial abnormalities in SS as non-specific, could instead view them as functional indicators of dysbiosis. For instance, a pattern of squamous metaplasia in the absence of overt inflammation might suggest epithelial adaptation to microbial shifts. Similarly, mild nuclear atypia could reflect cytokine-driven stress or altered epithelial turnover secondary to microbiota composition. Moreover, recent research continues to refine our understanding of how microbial imbalance may contribute to epithelial dysfunction in SS. For instance, a 2024 Mendelian randomization study^[6] identified specific gut microbial taxa, such as Eubacterium coprostanoligenes, as potentially protective through the modulation of chemokines like chemokine ligand 6 ( CXCL6). These results suggest a scenario where bacteria affect host immune function before epithelial change.

In parallel, recent integrated omic studies in murine models of SS show that avoiding gut dysbiosis leads not only to improved glandular function but also to shifts in host protein expression and metabolic pathways.^[7] These findings point to a more comprehensive feedback loop between mucosal surfaces and microbiota, in which epithelial cells both reflect and perhaps mediate the microbiota-immune interaction state. Clinical and experimental evidence currently suggests that SS patients have a unique microbial profile at the ocular surface, with an increase in environmental or Gram-negative taxa and a decrease in commensal species. Goblet cell loss, elevated ocular staining, and modified inflammatory profiles are all correlated with these alterations. The interpretation of epithelial results as physiologically meaningful is further supported by the idea that the ocular epithelium is formed by and responds to microbial stimuli.^[8]

This emerging evidence invites us to reconsider the role of cytopathology in the study of SS, no longer just as a passive morphological observation but as a possible key to the dynamic interpretation of the mucosa–microbiota interaction. In this new paradigm, the epithelium is not only a target but also an active witness of a changing microbial-immune balance.