Gut microbes may play a bigger role in digestion than previously thought, according to a new study. Researchers found that gut bacteria may be actively recycling hormones that help keep the colon moving, and that antibiotics can disrupt this process.
The study, published in Nature Neuroscience, found that androgen signaling, specifically testosterone, to neurons in the enteric nervous system is required for normal intestinal transit in mice. This signaling depends on the microbiome to function.
The enteric nervous system is the network of neurons in the gut wall, sometimes called the second brain. Within it, a specific population of neurons called NOS1+ enteric neurons appear to be key players in regulating movement in the colon. A separate group of spinal afferent neurons also express androgen receptors and contribute to motility.
When researchers depleted the gut microbiome in mice using broad-spectrum antibiotics, androgen receptor expression in enteric neurons dropped, serum testosterone levels fell, and intestinal transit slowed. Restoring androgen signaling was partly sufficient to fix the motility deficits, suggesting the hormone pathway is a meaningful driver of the effect.
The biology behind this is surprising. Testosterone does not disappear after the body uses it. Instead, the liver deactivates it by attaching a glucuronide molecule and excretes it into the gut. Under normal circumstances, certain gut bacteria produce enzymes that help reactivate the testosterone so it can bind to androgen receptors in gut neurons.
This creates a recycling loop: the body excretes a deactivated hormone, gut bacteria reactivate it, and it goes back to work signaling the neurons that keep digestion moving. The researchers confirmed this mechanism directly. The bacteria were performing a specific biochemical function that the gut neurons depend on.
The study also found that NOS1+ enteric neurons increase androgen receptor expression after puberty, in parallel with shifts in fecal bacterial enzyme activity. This timing suggests the microbiome and the hormonal system are co-developing in a coordinated way.
Why antibiotics disrupt this process
Broad-spectrum antibiotics do not just reduce the number of beneficial bacteria. They can eliminate the specific bacterial populations responsible for producing important enzymes. Without those enzymes, the testosterone recycling loop breaks down. Androgen receptor expression in enteric neurons falls, serum testosterone drops, and the colon slows.
The researchers found that androgens were necessary for antibiotics to affect transit at all. When androgen signaling was already absent, antibiotics had less additional impact on motility. This suggests the antibiotic-induced disruption of digestion is at least partly mediated through this hormone pathway, not just through a general reduction in microbial diversity.
The gut-hormone connection
This research adds to evidence that the microbiome is an active participant in hormone metabolism. Gut bacteria have previously been identified that can synthesize or break down androgens in the context of conditions like prostate cancer and depression. This study adds evidence that microbial hormone reactivation also plays a role in healthy, everyday gut function.
While this study was conducted in mice, the researchers found that human colonic enteric neurons express androgen receptors in both males and females, and that human gut bacteria also produce the same enzymes capable of metabolizing androgen glucuronides.
The finding offers context for understanding why gut disruption after antibiotics can feel more significant than a simple reduction in probiotic bacteria. The disruption may include interference with specific microbial functions, like hormone reactivation, that influence gut motility through distinct pathways.
A thriving microbiome depends on a diet rich in fiber and fermented foods, which supports the bacterial populations that produce these enzymes. After a course of antibiotics, the microbiome can take weeks to months to return to baseline.
The broader takeaway is that the microbiome is doing far more than fermenting fiber and crowding out pathogens. It may be actively maintaining the hormonal environment that gut neurons need to function, a level of sophistication that science is only beginning to map.
