GUT TRANSIT TIME IS ASSOCIATED WITH MUCOSAL HOMEOSTASIS AND HOST-MICROBE CO-METABOLISM IN IBS

Background
Gut microbial perturbation has been implicated in the development of irritable bowel syndrome (IBS), but the underlying mechanisms are poorly understood. In a large multi-omic study, we investigated how aspects of gut physiology and IBS-associated symptoms are linked to host-microbe homeostasis and co-metabolism.

Methods
Whole-metagenome deep sequencing was performed on fecal samples from prospectively included participants with functional bowel disorders (n=179), mainly IBS (n=164), and healthy individuals (n=31). Results were mapped to gut physiological parameters (oro-anal transit time assessed by radiopaque markers, luminal pH measured by a wireless motility capsule), detailed characterization of intestinal (GSRS) and extraintestinal symptoms (PHQ-12), colon mucosal responses (RNA-sequencing of biopsy tissue), and serum metabolomic profiles (liquid chromatography-mass spectrometry). General linear models were used to identify associations of these variables with the gut microbiome.

Results
Oro-anal transit time was the most important explanatory variable for the variation of both fecal metagenomes and serum metabolomes in this cohort (permutational ANOVA, p<0.001 for both). Slower transit was associated with higher relative abundance of Methanobrevibacter and Akkermansia, and a reduction in butyrate-producers from the Roseburia and Faecalibacterium genera, independent of concomitant IBS. Moreover, slower transit was linked to higher distal colon pH (p = 0.0002) and elevated serum levels of toxic host-microbe co-metabolites of aromatic amino acids, collectively suggesting increased protein degradation by the gut microbiota. RNA-sequencing of sigmoid biopsy tissue further revealed enrichment of pathways related to inflammation and interferon signaling in individuals with slower, compared to faster, transit. Abdominal pain was linked to increased mucosal expression of the substance P receptor gene TACR1 (FDR-corrected p-value = 0.005), and to expansion of Collinsella species. After correction for transit time, IBS was independently associated with increases of Bacteroides species, and enrichment of microbial genes related to oxidative phosphorylation, responses to oxidative stress and the degradation of host-derived sialic acids; together, indicating increased capacity for mucosal colonization.

Conclusion
Oro-anal transit time and abdominal pain were linked to specific gut microbiome signatures and mucosal responses. Notably, transit time was strongly associated with both fecal metagenomes and serum metabolomic profiles, reflecting microbial metabolic shifts of relevance for intestinal and extraintestinal health. Considering IBS-associated symptoms and alterations of gut physiology independently, rather than as a composite, yields additional important insights into underlying shifts in host-microbe homeostasis.