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Abstract

BackgroundThe regional physicochemical environment of the gut, particularly colonic pH, is a key determinant of microbial composition and metabolic activity. However, how these localised intraluminal physicochemical dynamics interface with systemic immunity in humans remains unknown. ObjectiveWe aimed to investigate the relationship between colonic pH, microbial metabolism, and immune tone. DesignIn a cross-sectional study of 54 healthy adults, we integrated four complementary datasets to enable a systems-level analysis of gut-immune interactions: in vivo real-time colonic pH and transit dynamics via the SmartPill wireless pH-motility capsule; microbial community structure via faecal metagenomic sequencing; microbial metabolic activity via plasma short-chain fatty acid (SCFA) quantification; and 121 circulating immune subsets via deep immunophenotyping of peripheral blood mononuclear cells (PBMCs). ResultsLower colonic pH was associated with circulating cytokine-producing CD8+ T cells. Conversely, higher pH correlated with an increase in circulating mature low-density neutrophils (LDNs) and a distinct shift towards PD1-expressing exhaustion-like CD8+ T cells. Metagenomic profiling identified species-level associations within the genus Eubacterium, linked to colonic pH and distinct peripheral immune profiles. ConclusionThese findings suggest that guts physicochemical microenvironment, driven by pH, may act alongside microbial activity and metabolism to jointly shape systemic immune tone in humans. This supports a functional intraluminal-peripheral axis, suggesting that targeting gut pH and fermentation dynamics could offer novel avenues for exploring immune-targeted interventions. What is already known on this topicO_LIColonic pH is a critical driver of microbial niche selection and metabolic activity in vitro, but how this localised physicochemical environment influences systemic immunity in humans remains unknown. C_LI What this study adds?O_LIBy pairing in vivo real-time wireless pH-capsule transit data with metagenomics, plasma SCFAs, and deep immunophenotyping, we demonstrate specific associations between colonic pH and the peripheral immune landscape, mapping gut-immune interactions in humans C_LIO_LILower colonic pH associates with robust, cytokine-producing CD8+ T cells, whereas a higher pH correlates with a shift toward PD1 exhaustion-like CD8+ T cell phenotypes and elevated systemic mature LDNs. C_LI How this study might affect research, practice or policyO_LIThese findings establish a novel physicochemical-gut-immune axis, suggesting that therapeutic manipulation of colonic pH (via diet, prebiotics, or targeted delivery systems) could serve as a strategy to modulate or support systemic immune tone in inflammatory or metabolic diseases. C_LI

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