The Neuropsychiatric Role of Bile Acids in IBD
Accessing Brain health and mental health leverage in IBD
The extraintestinal symptoms in IBD are usually brushed to the side; not because gastroenterologists don’t care, but rather the mindset of the medical model is to reduce hospitalization, reduce steroid use, preserve intestinal tissue, and prevent surgery.
What is left to the side is often the things that cause morbidity in IBD, such as mental health, brain health, ARFIB, skin disorders, joint pain, and secondary IBS-dysbiosis conditions.
As part of the IBD team, we need professionals who assess these aspects. A team consisting of a GI-psychologist, dermatologist, registered dietitian, and a naturopathic physician (ND) will provide comprehensive care alongside the gastroenterologist.
I say ahem…tongue in cheek…as ND’s like myself are not included in the club. Often, there’s a sense that we are quacks or witch doctors and that we have no place in the “club.” Some of these thoughts are valid, and some are just pure intellectual arrogance. When we put aside judgment and listen to each other, the patient benefits, as there is a reason smart and empowered patients benefit from working with ND’s.
Let’s take bile acids, for example.
Who has an interest in seeing how bile acids may impact brain health and mental health in IBD patients?
I do!
I'm the nerd who wants to share this information with my patients to help them live their best lives and avoid the brain and mental health issues often linked with IBD. I aim to send them back to their gastroenterologists with improved daily functioning, better quality of life, and overall well-being while managing IBD.
I was reading an excellent article :
Boldyreva LV, Evtushenko AA, Lvova MN, Morozova KN, Kiseleva EV. Underneath the Gut–Brain Axis in IBD—Evidence of the Non-Obvious. International Journal of Molecular Sciences. 2024; 25(22):12125. https://doi.org/10.3390/ijms252212125
And its description and explanation of bile acids was clarifying. This is often a confusing topic but I believe it will be a key leverage point for IBD (and other diseases) for years to come.
In IBD, the gut doesn’t just inflame it remodels the brain. One of the most overlooked mediators in this gut–brain remodeling is the bile acid (BA) pool, which acts far beyond digestion.
Bile Acids Are Neuroactive Compounds
Bile acids cross the blood–brain barrier (BBB) and bind to nuclear (FXR) and membrane (TGR5, S1PR2) receptors in neurons, astrocytes, and microglia. This gives them direct access to modulate mood, neuroinflammation, cognition, and behavior.
Let’s look at the function of the receptors:
FXR (Farnesoid X Receptor):
Found in the hippocampus and cerebellum
When overactivated (e.g., by elevated Chenodeoxycholic Acid—a primary bile acid or atypical bile acid acids (BA) conjugates seen in Crohn’s disease), FXR suppresses Brain Derived Neurotrophic Factor (BDNF), alters serotonin and glutamate metabolism, and drives depressive-like behavior in rodent models
TGR5 (GPBAR1):
Expressed on neurons, astrocytes, and microglia
Activation (e.g., by secondary BAs like Deoxycholic Acid, Lithocholic Acid, Tauroursodeoxycholic Acid) reduces microglial activation, inhibits NF-κB, and promotes TGF-β signaling ; net anti-inflammatory and neuroprotective
S1PR2 (Sphingosine-1-Phosphate Receptor 2):
Activated by taurocholic acid in the brain
Drives neuroinflammation via CCL2, microglial activation, and BBB breakdown
IBD Skews the Bile Acid Pool Toward Neurotoxicity
Reduced levels of secondary BAs (DCA, LCA) lead to weakened TGR5 signaling, tipping the brain toward neuroinflammation.
Increased primary BAs (CDCA, CA) excessive FXR activation, linked to anhedonia, anxiety, and cognitive dulling
Elevated conjugated BAs (e.g., taurolithocholic acid, phenylalanine- and tyrosine-conjugated BAs) are strongly correlated with depression and anxiety scores in Crohn’s disease patients.
In research, patients with Crohn’s and co-occurring anxiety showed a depletion of Faecalibacterium prausnitzii, reduced secondary BA production, and elevated tauro-conjugated BA levels—alongside increased serum FXR activity.
Mechanism: How Dysbiosis Skews Bile Acids and Brain Function
IBD-associated dysbiosis leads to:
Decreased Clostridium cluster XIVa, which leads to decreased secondary bile acid conversion (to 7α-dehydroxylation). The net result is lower secondary BA production (DCA, LCA)
Dysbiosis leads to decreased microbial Bile Salt Hydrolase enzyme which leads to decreased BA deconjugation. Bile salt hydrolase ) enzymes, produced by commensal microbes like Lactobacillus, Bifidobacterium, and Clostridium, are essential for deconjugating primary bile acids, a critical step for producing neuroactive secondary bile acids.
This process result in accumulation of neuroactive BA conjugates
This shifts BA signaling from neuroprotective to neurotoxic.
Bi-Directional Loop: BAs Affect Mood → Mood Affects Gut
Stress reduces bile flow and alters hepatic BA synthesis (via cortisol’s effect on FXR)
Depression and anxiety increase intestinal permeability, worsen dysbiosis, and create a feedback loop of GBA disruption.
Reduced BDNF (via FXR activation) leads to impaired vagal tone, sleep quality, and motivation
What this means for practice:
Neuropsychiatric symptoms in IBD (fatigue, low mood, cognitive fog, insomnia, sensory hypersensitivity) may stem more from bile acid imbalance than cytokines alone. Lets not rush and put all of these patients on antidepressants! Although that might be a temporary supportive move.
BA-modulating therapies (e.g., TUDCA, ursodiol, FXR antagonists) may offer dual benefits for both the gut and the brain.
Dysbiosis protocols must prioritize secondary BA producers (e.g., F. prausnitzii, Eubacterium, Clostridium XIVa) to restore neuroprotective signaling.
Conjugated BA levels may be an early marker of psychiatric risk in IBD.
Lets get tracking Bile Acids! What to test or track:
Stool BA profiles (DCA, LCA, CDCA, CA, tauro-conjugates). Several companies like Vibrant and Diagnostic Health Solutions offer stool BA studies)
F. prausnitzii and Clostridium cluster XIVa levels (can be seen on 16srRNA stool microbiome testing)
Serum FXR/TGR5 target gene expression (e.g., SHP, BDNF, CCL2)- this is likely only available for research but may be more clinically applicable in the future.
Neurocognitive screening for fatigue, executive dysfunction, and depressive features
Therapeutic Leverage: Supporting Neuroprotective Bile Acid Signaling
Emerging evidence suggests that bile acid-modulating therapies may hold dual benefits in IBD dampening gut inflammation while simultaneously improving mood and cognition via neuroimmune signaling.
TUDCA (Tauroursodeoxycholic Acid) is a hydrophilic bile acid with strong neuroprotective, anti-apoptotic, and anti-inflammatory properties. It activates TGR5, suppresses ER stress, and reduces microglial activation. In rodent models of colitis and depression, TUDCA improves intestinal permeability and rescues hippocampal BDNF expression [(McMillin et al., 2016)].
FXR antagonists (e.g., glycine-β-muricholic acid, gβMCA, or synthetic inhibitors) have been shown in animal studies to reverse FXR overactivation, restoring BDNF signaling and attenuating depressive-like behavior [(Kiriyama & Nochi, 2019)]. While not yet used clinically for psychiatric indications, they represent a new class of gut-brain-targeting agents.
Restoring secondary BA production requires replenishing key taxa, especially Clostridium scindens, Clostridium leptum, Faecalibacterium prausnitzii, and Eubacterium hallii all of which express 7α-dehydroxylation enzymes. Prebiotic interventions like resistant starch, arabinoxylans, and inulin-type fructans have shown promise in promoting these taxa and enhancing DCA/LCA output [(Shao et al., 2021)].
Dietary strategies that emphasize polyphenol-rich plants, nut-derived fibers, and fermented foods appear to indirectly modulate BA metabolism by boosting microbial diversity and short-chain fatty acid production both upstream regulators of BA transformation pathways.
We’re used to looking at bile acids through the lens of digestion and absorption. But in IBD, they may be one of the most underrecognized modulators of mood, fatigue, cognition, and quality of life. By tracking and modifying bile acid signaling—especially the FXR/TGR5 balance—we can start to bridge the gut-brain gap and give our patients back more than just symptom control. We can help them feel whole again.
References:
Boldyreva LV, Evtushenko AA, Lvova MN, Morozova KN, Kiseleva EV. Underneath the Gut–Brain Axis in IBD—Evidence of the Non-Obvious. Int J Mol Sci. 2024;25(22):12125. doi:10.3390/ijms252212125
Kiriyama Y, Nochi H. The biosynthesis, signaling, and neurological functions of bile acids. Biomolecules. 2019;9(6):232. doi:10.3390/biom9060232
McMillin M, DeMorrow S. Effects of bile acids on neurological function and disease. FASEB J. 2016 Nov;30(11):3658-3668. doi: 10.1096/fj.201600275R. Epub 2016 Jul 28. PMID: 27468758; PMCID: PMC5067249
Fiorucci S, Biagioli M, Zampella A, Distrutti E. Bile acids activated receptors regulate innate immunity. Front Immunol. 2018;9:1853. doi:10.3389/fimmu.2018.01853
Duboc H, Rajca S, Rainteau D, et al. Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut. 2013;62(4):531–539. doi:10.1136/gutjnl-2012-302578
López-Siles M, Martínez-Medina M, Surís-Valls R, et al. Faecalibacterium prausnitzii: from microbiology to diagnostics and prognostics. ISME J. 2017;11(4):841–852. doi:10.1038/ismej.2016.176
Shao, J., Ge, T., Chen, S., Wang, G., Yang, Q., Huang, C., … & Chen, Z. (2021). Role of bile acids in liver diseases mediated by the gut microbiome. World Journal of Gastroenterology, 27(22), 3010-3021. https://doi.org/10.3748/wjg.v27.i22.3010
Vernia P, Di Ruscio M, Stefanelli G, et al. Gut-liver axis: interactions between bile acids and intestinal microbiota. World J Gastroenterol. 2020;26(40):6146–6163. doi:10.3748/wjg.v26.i40.6146