Gut sulfide metabolism modulates behavior and brain bioenergetics

Area of Science:

• Microbiology
• Metabolism
• Host-Microbiome Interactions

Background:

• The host-microbiome interface involves complex metabolite exchanges influenced by diet.
• Hydrogen sulfide (H ₂ S), a product of microbial and host metabolism, is abundant at this interface.
• The mitochondrial enzyme sulfide quinone oxidoreductase (SQOR) detoxifies H ₂ S, and its deficiency causes Leigh disease.

Purpose of the Study:

• To investigate the impact of intestinal SQOR deficiency on host bioenergetics.
• To determine how high dietary methionine intake interacts with intestinal SQOR deficiency.
• To explore the consequences for local and global energy metabolism, brain pathology, and behavior.

Main Methods:

• Created murine models with SQOR deficiency specifically in intestinal epithelial cells.
• Administered diets with varying methionine levels, mimicking plant vs. animal protein intake.
• Utilized antibiotics to assess microbial contribution, measured bioenergetics, analyzed colon architecture, microbiome composition, serum biomarkers, and performed brain MRI and behavioral tests.

Main Results:

• Intestinal SQOR deficiency alone perturbed colon bioenergetics, reversible by antibiotics, highlighting microbial H ₂ S's role.
• High methionine intake synergized with intestinal SQOR deficiency, adversely affecting colon architecture and microbiome.
• Combined deficiency and high methionine altered global sulfide metabolism (increased thiosulfate), perturbed energy metabolism (increased ketone bodies), and led to brain changes (reduced ventricular volume) and behavioral deficits.

Conclusions:

• Intestinal SQOR deficiency and dietary methionine interact dynamically at the host-microbe interface.
• This interaction significantly impacts gut health, systemic energy metabolism, and brain function.
• Lowering dietary methionine may be a strategy to mitigate pathology associated with impaired sulfide metabolism.