Dietary phytosterols may ameliorate dyslipidemia partly through modulation of the gut microbiota-bile acid-FXR axis, with microbiota-associated BSH-THDCA-FXR signaling representing one plausible contributing pathway.
Key Findings
Results
Phytosterol exposure in humans was associated with distinct lipid phenotypes, gut microbial features, and circulating bile acid profiles.
Human observational and intervention studies were integrated with mechanistic experiments to examine phytosterol-gut-liver metabolic interactions.
Associations were identified between phytosterol exposure and lipid phenotypes, gut microbial composition, and circulating bile acid profiles in human subjects.
The study used a combination of human observational data, human intervention studies, hyperlipidemic rat models, fecal microbiota transplantation (FMT), and in vitro cellular models.
Results
Phytosterol treatment in hyperlipidemic rats altered gut microbial composition and reduced ileal luminal bile salt hydrolase (BSH) activity.
Phytosterol treatment changed the relative abundance of putative BSH-producing taxa in the gut microbiota.
Reduced ileal luminal BSH activity was observed accompanying these microbial compositional changes.
These alterations occurred in the context of a hyperlipidemic rat model.
Results
Phytosterol treatment induced bile acid remodeling, including increased concentrations of taurohyodeoxycholic acid (THDCA) in liver tissue and ileal contents.
Bile acid remodeling was observed in rats treated with phytosterols.
Specifically, THDCA concentrations were elevated in both liver tissue and ileal contents.
These changes in bile acid profile coincided with the alterations in gut microbial BSH activity.
Results
THDCA antagonized intestinal farnesoid X receptor (FXR) signaling in vitro.
In vitro cellular assays demonstrated that THDCA acts as an FXR antagonist in intestinal cells.
This finding mechanistically links the observed increase in THDCA to downstream modulation of FXR-dependent signaling.
FXR antagonism by THDCA represents one plausible contributing pathway by which phytosterols influence lipid homeostasis.
Results
Phytosterol treatment in vivo attenuated ileal FXR-fibroblast growth factor 15 (FGF15) signaling and altered hepatic bile acid synthesis enzyme expression.
Ileal FXR-FGF15 signaling was attenuated following phytosterol treatment in rats.
Hepatic CYP7A1 protein expression was decreased while CYP7B1 protein expression was increased.
This pattern of enzyme expression is described as "consistent with a shift from the classical toward the alternative bile acid synthesis pathway."
These in vivo findings are consistent with THDCA-mediated FXR antagonism observed in vitro.
Results
Fecal microbiota transplantation (FMT) experiments supported a contributory role of the gut microbiota in the lipid-modulating effects of phytosterols.
FMT experiments were performed as complementary mechanistic studies.
Results further supported that gut microbiota contributes to the lipid-lowering effects observed with phytosterol treatment.
FMT findings are described as providing convergent evidence alongside the in vitro and in vivo mechanistic studies.
Conclusions
The study provides convergent preclinical mechanistic and exploratory human evidence for a diet-microbe-host pathway linking phytosterol intake to dyslipidemia amelioration.
The proposed pathway involves dietary phytosterols modulating gut microbiota, which reduces BSH activity, leading to increased THDCA, which antagonizes intestinal FXR, attenuating FGF15 signaling, and shifting hepatic bile acid synthesis toward the alternative pathway.
The authors note that the findings 'suggest' and identify a 'plausible contributing pathway,' indicating mechanistic evidence is supportive but not fully conclusive.
Evidence was described as 'convergent preclinical mechanistic and exploratory human evidence.'
What This Means
This research suggests that plant sterols (phytosterols), which are naturally found in plant-based foods and are known to help lower cholesterol, may work partly through their effects on gut bacteria. The study combined observations from human participants with laboratory experiments in rats and cell cultures. The researchers found that phytosterols appear to change the mix of bacteria living in the gut, particularly reducing the activity of certain bacterial enzymes called bile salt hydrolases (BSH). This reduction in BSH activity leads to higher levels of a specific bile acid called taurohyodeoxycholic acid (THDCA) in the gut and liver.
The significance of THDCA is that it appears to block a molecular receptor called FXR (farnesoid X receptor) in the intestine. FXR normally acts as a signal that slows down the liver's production of bile acids from cholesterol. By blocking FXR, THDCA reduces this inhibitory signal, which changes how the liver processes cholesterol and produces bile acids — specifically shifting production toward an alternative pathway. Experiments where gut bacteria from phytosterol-treated animals were transplanted into other animals helped confirm that the gut microbiota itself plays an important role in these effects.
This research matters because it identifies a specific biological chain of events — from diet to gut bacteria to bile acid signaling to liver cholesterol metabolism — that could help explain how phytosterols lower blood lipid levels. This research suggests that the gut microbiome is an important intermediary in how dietary plant sterols affect cardiovascular risk factors, and this pathway could potentially be a target for future dietary or therapeutic strategies aimed at managing high cholesterol and related conditions.
Xia J, Pan D, Wu T, Feng Z, Tian Y, He Z, et al.. (2026). Phytosterol-induced modulation of gut microbial bile salt hydrolases ameliorates hyperlipidemia via taurohyodeoxycholic acid-mediated FXR antagonism.. Gut microbes. https://doi.org/10.1080/19490976.2026.2731687