Do the liver and gut help produce peripheral T3?

Peripheral triiodothyronine (T3) levels are maintained by a highly coordinated, multi-organ network. While the thyroid gland directly secretes a portion of circulating T3, the majority is generated through peripheral pathways involving the liver, skeletal muscle, and the gut microbiome.

Hepatic and systemic deiodination

• Enzymatic conversion: Approximately 80% of circulating T3 is derived from the peripheral outer-ring deiodination of thyroxine (T4).
• Hepatic contribution: The liver expresses type 1 deiodinase (D1), which converts T4 to active T3 and clears inactive reverse T3 (rT3), contributing 20% to 30% of extrathyroidal T3.
• Skeletal muscle activity: Complementing hepatic function, skeletal muscle utilizes type 2 deiodinase (D2) to act as another dominant extrathyroidal source of systemic T3.

Microbiota-mediated enterohepatic recycling

• Conjugation and excretion: The liver metabolizes thyroid hormones into inactive, water-soluble conjugates, specifically T3-sulfate (T3S) and T3-glucuronide (T3G), which are excreted via bile into the intestinal lumen.
• Microbial deconjugation: Anaerobic gut microbiota express key deconjugation enzymes, including sulfatases and $\beta$-glucuronidases. These enzymes hydrolyze the inactive conjugates, regenerating free, biologically active T3.
• Reabsorption: This liberated T3 is reabsorbed across the intestinal mucosa back into the portal circulation. Animal models demonstrate that clearing gut microbiota virtually abolishes this conjugate hydrolysis and subsequent T3 reabsorption.

Bottom line

• The liver and gut microbiota are critical, cooperative regulators of thyroid homeostasis. The liver drives direct T4-to-T3 conversion via D1 (supported by skeletal muscle D2), while the gut microbiota run an essential enterohepatic recycling loop by deconjugating inactive thyroid metabolites back into active, absorbable T3.