Gut sulfide metabolism modulates behavior and brain bioenergetics

Area of Science:

• Host-microbiome interactions
• Metabolomics
• Nutritional science

Background:

• The host-microbiome interface involves significant metabolite exchange, influenced by diet.
• Hydrogen sulfide (H2S) is a key metabolite at this interface, produced by both host and microbial metabolism.
• Mitochondrial sulfide quinone oxidoreductase (SQOR) detoxifies H2S, and its deficiency causes Leigh disease.

Purpose of the Study:

• To investigate if impaired H2S clearance in the gut contributes to disease.
• To determine if dietary sulfur content modulates H2S metabolism and related pathologies.
• To explore the impact of intestinal SQOR deficiency and methionine intake on host physiology and the microbiome.

Main Methods:

• Utilized murine models with intestinal epithelial cell-specific SQOR deficiency.
• Administered antibiotics to assess microbial contribution to H2S metabolism.
• Modulated dietary methionine intake (2.5-fold increase) to mimic animal vs. plant protein differences.
• Analyzed colon bioenergetics, gut architecture, microbiome composition, serum biomarkers (thiosulfate, ketone bodies), locomotor activity, and brain MRI.

Main Results:

• Intestinal SQOR deficiency alone perturbed colon bioenergetics, reversible by antibiotics, highlighting microbial H2S's role.
• High methionine intake synergized with SQOR deficiency, worsening colon architecture and altering the microbiome.
• Systemic sulfide metabolism was affected, indicated by increased serum thiosulfate and ketone bodies.
• Mice showed reduced exploratory activity, ventricular volume, and aquaporin 1 levels in the brain.

Conclusions:

• Dietary sulfur intake and gut sulfide metabolism dynamically interact at the host-microbe interface, influencing gut health.
• Intestinal microbial H2S significantly contributes to host physiology.
• Lower dietary methionine intake shows potential for modulating H2S-related pathologies.