Tryptophan metabolites are associated with gut-brain alterations in functional dyspepsia

  1. Matthias Ceulemans
  2. Lucas Wauters
  3. Nathalie Weltens
  4. Greet Vandermeulen
  5. Henriette de Loor
  6. Pieter Evenepoel
  7. Raul Y. Tito
  8. Arnau Vich Vila
  9. Muriel Derrien
  10. Boushra Dalile
  11. Jan Tack
  12. Kristin Verbeke
  13. Jeroen Raes
  14. Lukas Van Oudenhove
  15. Tim Vanuytsel
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Abstract

Background

Disturbances in the microbiota-gut-brain axis are thought to contribute to the pathophysiology of disorders of gut-brain interaction, including functional dyspepsia (FD), although comprehensive human data remain scarce.

Objective

We aimed to study the relationships among microbiota-produced metabolites including tryptophan metabolites and short-chain fatty acids (SCFA), and functional brain connectivity in FD, in relation to symptomatology.

Design

In 46 patients with Rome IV-diagnosed FD and 30 healthy controls (HC), targeted metabolomics using chromatography and mass spectrometry was conducted to quantify metabolites in blood, urine, and stool. Associations with gut microbiota and symptomatology were tested using fecal quantitative microbiota profiling and validated symptom questionnaires. Resting-state functional magnetic resonance imaging in 27 patients and 36 HC enabled analysis of functional connectivity in selected brain networks.

Results

Patients with FD exhibited distinct profiles of tryptophan metabolites and SCFA with higher urinary indole-3-acetate (IAA, P =0.018), lower serum kynurenine ( P =0.030) and lower plasma propionate ( P =0.0055) concentrations. FD-specific metabolite alterations were associated with more severe GI and psychological symptoms. The fecal microbiota profile was similar between FD and HC. Complementary analyses demonstrated significant alterations in resting-state brain connectivity of 44 predefined regions between FD and HC, while a connectivity-based classifier discriminated FD from HC (82.3% sensitivity, 66.7% specificity, P <0.0001). Differences in connectivity measures mediated the higher urinary IAA levels in FD.

Conclusion

Dysregulated functional brain connectivity supports an objective pathophysiology in FD. Alterations in specific tryptophan metabolite and SCFA levels were linked to symptomatology, highlighting their potential as biomarkers, and warranting further investigation on microbiota modulating therapies for FD.

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