Article: Up To 95% Of Serotonin Is Made In The Gut

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Aug 14, 2025Chronic Stress

Up To 95% Of Serotonin Is Made In The Gut

So, Does It Even Matter For Your Mood?

Originally Posted By: Shawn Wells - "The Most Trusted Voice In Supplements"

I’m a dietitian. I’m a biochemist. And I didn’t fully understand this until I read a post that stopped me in my tracks.

The post correctly says:

Gut-made serotonin doesn’t cross the blood-brain barrier.
Therefore, it doesn’t impact mood, stress, or emotional health.

At first, I was shocked. But the more I looked into it, the more nuance I found and the more I realized how important it is to question binary thinking in biology.

While gut serotonin itself doesn't cross into the brain, that doesn’t mean the gut-brain axis is irrelevant to serotonin signaling or emotional regulation. Far from it.

Here’s what the science actually shows:

Gut microbes can synthesize neurotransmitters like GABA, dopamine, and yes, serotonin.
While these molecules don’t enter the brain directly, they signal through the vagus nerve, immune system, and endocrine pathways, altering brain chemistry and mood. (Cryan & Dinan, Nat Rev Neurosci, 2012)
Tryptophan metabolism is regulated in the gut. The availability of tryptophan for serotonin synthesis in the brain depends on factors like inflammation, stress, and gut microbial activity. (Agus et al., Cell Host Microbe, 2018) (Gao et al., Cell Reports, 2020)
Inflammation diverts tryptophan down the kynurenine pathway instead of serotonin, a key factor in depression. (O’Mahony et al., Front Psychiatry, 2015)
Gut integrity and nutrient absorption (B6, magnesium, folate) influence the cofactors required to synthesize serotonin in the brain. (Dakshinamurti et al., Neurochem Res, 1983)
Vagal signaling from the gut modulates brain activity in areas like the amygdala and hippocampus. In fact, certain strains of Lactobacillus and Bifidobacterium have been shown to reduce stress hormones and modulate GABA and serotonin receptor expression in the brain. (Bravo et al., PNAS, 2011) (Tillisch et al., Gastroenterology, 2013)

So yes, I was initially surprised. But after diving into the literature, my conclusion is this:

Gut-derived serotonin may not cross the BBB, but the gut’s influence on serotonin signaling is real, powerful, and multilayered.
This has deep implications for how we treat depression, anxiety, and chronic stress and how we formulate supplements, therapeutics, and functional foods to support mental health from the inside out.
The gut doesn’t need to send serotonin into the brain to affect the brain. It just needs to send the right signals.
If you're formulating, researching, or biohacking, don't ignore the gut and respect the whole system.