Research shows that a protein called SMRT controls how bile acids are distributed in your body, and when this system fails, bile acids accumulate in your blood instead of reaching your intestines. This disruption damages your gut barrier, increases harmful bacteria, and triggers severe intestinal inflammation and cancer risk—especially on high-fat diets. According to research reviewed by Gram, activating a bile acid receptor with a drug called XL335 reversed these problems in mice, suggesting a potential new treatment for inflammatory bowel disease.
According to research reviewed by Gram, scientists discovered that a protein called SMRT acts like a master controller for bile acids—substances your liver makes to help digest fat. When this control system breaks down, bile acids don’t get distributed properly, which damages your intestinal barrier and increases harmful bacteria. In mouse studies, this imbalance led to worse intestinal inflammation and increased cancer risk, especially on a high-fat diet. The good news: researchers found that activating a specific receptor with a drug called XL335 could restore gut health and protect against these problems. This discovery could lead to new treatments for people with inflammatory bowel disease and other gut disorders.
Key Statistics
A 2026 research article in Experimental & Molecular Medicine found that mice with disrupted SMRT protein function developed increased bile acids in serum and urine while showing decreased levels in the liver and intestines, leading to compromised intestinal barrier integrity and increased bacterial burden.
In the same study, treatment with the synthetic FXR agonist XL335 rescued mice with SMRT defects during acute colitis, demonstrating that activating the bile acid receptor pathway can reverse intestinal damage and inflammation caused by abnormal bile acid distribution.
The research showed that reduced intestinal bile acids decreased farnesoid X receptor (FXR) activity, which directly compromised intestinal barrier function and increased susceptibility to both acute colitis and colitis-associated cancer in laboratory mice.
The Quick Take
- What they studied: How a protein called SMRT controls bile acid levels in the body and whether this affects gut health and intestinal inflammation
- Who participated: Laboratory mice genetically modified to have a defective SMRT protein, tested on normal diets and high-fat diets, with some exposed to colitis (gut inflammation) models
- Key finding: Mice without proper SMRT function had too much bile acid in their blood and urine but not enough in their intestines, which damaged their gut barrier, increased harmful bacteria, and made intestinal inflammation worse
- What it means for you: This research suggests that maintaining proper bile acid balance is critical for gut health, and targeting this system with drugs like XL335 might help treat inflammatory bowel disease and prevent colitis-related cancer. However, these are early findings from animal studies and haven’t been tested in humans yet
The Research Details
Researchers created special laboratory mice with a genetic change that disrupted the SMRT protein’s ability to regulate bile acid production. They then studied what happened to these mice under different conditions: normal eating, high-fat diet, and when exposed to models of intestinal inflammation (colitis). The scientists measured bile acid levels in blood, urine, liver, and intestines, examined how the intestinal barrier functioned, counted bacteria in the gut, and tracked inflammation markers and disease outcomes.
The researchers also tested whether giving the mice a drug called XL335 (which activates a bile acid receptor) could fix the problems caused by the SMRT defect. This allowed them to understand both what goes wrong when SMRT doesn’t work and whether they could reverse the damage.
This type of study is valuable because it lets scientists understand the exact biological mechanisms involved and test potential treatments in a controlled setting before moving to human trials.
Understanding how bile acids are controlled is important because bile acids do much more than help digest fat—they also act as signaling molecules that communicate with your intestines and immune system. When this communication breaks down, it can lead to intestinal barrier damage, bacterial overgrowth, and inflammation. This research shows a specific mechanism that could explain why high-fat diets increase the risk of inflammatory bowel disease and colorectal cancer.
This is original research published in a peer-reviewed scientific journal, which means other experts reviewed it before publication. The study used genetically modified mice to isolate specific biological mechanisms, which is a rigorous approach. However, the findings are from animal studies and haven’t been confirmed in humans yet. The sample size of mice isn’t specified in the abstract, which is a limitation for assessing statistical power. The research does show dose-response relationships and tests potential treatments, which strengthens the findings.
What the Results Show
When SMRT protein function was disrupted in mice, the animals showed abnormal bile acid distribution: too much in the blood and urine, but too little in the intestines and liver. This happened especially when mice ate a high-fat diet. The reduced bile acid in the intestines meant that a receptor called FXR (which bile acids normally activate) didn’t work properly.
Without proper FXR activation, the intestinal barrier—which normally acts like a protective wall—became damaged and leaky. This allowed more bacteria to cross into the body and triggered increased inflammation in the intestines. The mice became much more susceptible to colitis (severe intestinal inflammation) and developed more colitis-related cancer.
When researchers gave these mice XL335 (a drug that directly activates the FXR receptor), it restored intestinal barrier function, reduced bacterial overgrowth, decreased inflammation, and improved survival during acute colitis. This suggests that the bile acid-FXR pathway is the key mechanism linking SMRT function to gut health.
The research revealed that SMRT controls bile acid homeostasis through two pathways: directly in the liver (by regulating CAR genes involved in bile acid export) and indirectly in the intestines (by affecting FXR activity). The study also showed that the intestinal barrier damage wasn’t just a side effect—it was a major driver of the increased inflammation and cancer risk. Additionally, the bacterial changes in the gut appeared to play a role in worsening inflammation, suggesting that the microbiome is part of this disease mechanism.
Previous research established that bile acids and their receptors (like FXR) are important for gut health, but this study provides a specific molecular mechanism showing how a co-regulatory protein (SMRT) controls this system. The findings align with clinical observations that high-fat diets increase inflammatory bowel disease risk and that bile acid metabolism is abnormal in people with these conditions. This research goes further by identifying a specific protein target and demonstrating that activating FXR can reverse the damage.
This research was conducted entirely in laboratory mice with genetic modifications, so the results may not directly apply to humans. The study doesn’t specify the exact number of mice used, making it harder to assess statistical reliability. The high-fat diet and colitis models are artificial conditions that don’t perfectly replicate human disease. The drug XL335 was only tested in mice, so its safety and effectiveness in humans is unknown. Additionally, the study doesn’t examine how individual genetic variations in humans might affect SMRT function or response to treatment.
The Bottom Line
Based on this research, maintaining healthy bile acid metabolism appears important for gut health, particularly when eating high-fat diets. While these findings are promising, they’re from animal studies. Current evidence-based recommendations include: eating a balanced diet with adequate fiber, limiting high-fat processed foods, maintaining a healthy weight, and managing stress—all of which support normal bile acid metabolism and gut barrier function. If you have inflammatory bowel disease or recurrent colitis, discuss these findings with your doctor, as FXR-activating drugs like XL335 may eventually become treatment options, but they’re not yet approved for human use.
These findings are most relevant to people with inflammatory bowel disease (Crohn’s disease or ulcerative colitis), those with recurrent colitis, people at risk for colorectal cancer, and anyone with chronic intestinal inflammation. The research is also important for gastroenterologists and researchers developing new treatments. People without gut disorders can benefit from understanding that maintaining proper bile acid balance through diet supports long-term intestinal health. However, this research shouldn’t change current medical treatment until human trials are completed.
In animal studies, the benefits of FXR activation appeared relatively quickly (within days to weeks during acute colitis). However, if this leads to human treatments, it typically takes 5-10 years from animal studies to FDA approval. For dietary changes that support bile acid metabolism, benefits to gut health may appear over weeks to months of consistent practice.
Frequently Asked Questions
What are bile acids and why do they matter for gut health?
Bile acids are substances your liver makes to digest fat, but they also send important signals to your intestines that maintain the gut barrier and control inflammation. When bile acids don’t reach your intestines properly, the barrier breaks down, harmful bacteria increase, and inflammation develops.
Can I improve my bile acid balance through diet?
While this research focuses on a specific protein (SMRT), eating a high-fiber diet, limiting high-fat processed foods, and maintaining a healthy weight all support normal bile acid metabolism. Fiber helps bile acids move through your digestive system properly and feeds beneficial bacteria.
Does this research mean I shouldn’t eat fat?
No. Healthy fats are essential for nutrition. The research specifically shows problems with high-fat diets in mice with a genetic defect. For people without this defect, moderate fat intake as part of a balanced diet is fine—focus on limiting processed high-fat foods rather than all fats.
When will XL335 be available as a treatment for inflammatory bowel disease?
XL335 is still in early research stages and hasn’t been tested in humans yet. It typically takes 5-10 years from animal studies to FDA approval. Talk to your gastroenterologist about current approved treatments and clinical trials if you have IBD.
Could this explain why high-fat diets increase colon cancer risk?
This research suggests one mechanism: high-fat diets can disrupt bile acid balance, which damages the intestinal barrier and increases inflammation—both risk factors for colorectal cancer. However, colon cancer has multiple causes, and this is one piece of a larger puzzle.
Want to Apply This Research?
- Track daily dietary fat intake (grams) and fiber intake (grams), along with weekly gut health markers like bloating, bowel regularity, and energy levels. Monitor whether high-fat days correlate with increased digestive symptoms.
- Set a daily reminder to eat at least one high-fiber food (beans, whole grains, vegetables) and limit processed high-fat foods to one serving per day. Log these choices in the app to build awareness of how diet affects your gut.
- Over 8-12 weeks, track the relationship between your fat and fiber intake and digestive symptoms. Use the app’s trend analysis to identify your personal threshold for high-fat foods and optimal fiber intake. Share this data with your healthcare provider to personalize recommendations.
This research describes findings from laboratory studies in genetically modified mice and has not been tested in humans. The drug XL335 is experimental and not approved for human use. If you have inflammatory bowel disease, colitis, or chronic intestinal symptoms, consult your healthcare provider before making dietary changes or considering any new treatments. This article is for educational purposes and should not replace professional medical advice. Always discuss new research findings with your doctor to determine how they might apply to your individual health situation.
This research translation is published by Gram Research, the science division of Gram, an AI-powered nutrition tracking app.
