January 16, 2025

Redefining Bile Acids: Central Regulators of Metabolism and Immune Balance

By Emily Hernandez, ND

When you think of bile function, what springs to mind? Detoxification? Cholesterol? Nutrient Absorption? These are all valid and true, but new research is showing so much more. Read on for a summary of mind-blowing information recently published in the journal Nature, entitled “The changing metabolic landscape of bile acids – keys to metabolism and immune regulation.”

In this review, you will learn about:

The continual discovery of new bile acid structures that make up a vast systemic-wide network
Bile acid production outside of the liver, including in the gut, gallbladder, spleen, ovary, and brain
The role of the gut microbiome in modifying bile acids to produce new bile conjugates
Key functions of bile acids as signaling molecules specifically involved in immune regulation and metabolic functions
Clinical applications and strategies for optimizing the bile acid network to support systemic health

There’s a fundamental shift happening in our understanding of bile acid biology. Advancements in analytical techniques and microbiome research over the past few decades are highlighting their diverse roles as signaling molecules, metabolic regulators, and mediators of host-microbiome interactions. Traditionally viewed as simple detergents necessary for fat digestion and absorption, bile acids are now recognized as central regulators of metabolism, immune function, and gut microbial ecology.

Early research on bile acids emphasized their role in lipid digestion through their amphipathic (hydrophilic and hydrophobic) properties, which enable the emulsification of dietary fats and fat-soluble vitamins in the small intestine. However, this classical view was expanded with the discovery of secondary bile acids—microbial derivatives of host-synthesized primary bile acids—and their involvement in human health and disease. In fact, we now understand there to be hundreds, if not tens of thousands of different bile acid structures made by the gut microbiome.¹ Bile acids act as hormones with signaling properties beyond the digestive system that can influence the function of distant organelles, cells, tissues, and organs.

Once again, the microbiome rises as a key mediator of whole-body health!

Bile Acids – Not Exclusively Made in the Liver

Bile acids are synthesized from cholesterol and conjugated into glycine and taurine amidates in what was previously thought to be exclusively the liver. However, RNA transcripts for bile acid CoA amino acid N-acyltransferase responsible for amidation can be found in other organs, including the gallbladder, spleen, ovary, and brain – suggesting that bile acids can be biosynthesized in other organs. Additionally, we know that gut bacteria can synthesize glycine-conjugated C₂₄ cholic acid and deoxycholic acid, proving that glycine bile conjugates are not only derived from the host but are gut microbial metabolites as well.

Bile Acid Modifications Through the Digestive Tract

As bile acids travel through the digestive tract they undergo repeated modifications that result in immense diversifications. Although glycine and taurine are the most commonly described bile amidates in the gallbladder, other amidates may be present, including:

alanine
arginine
asparagine
glutamine
leucine/isoleucine
lysine
phenylalanine
tyrosine
tryptophan

Once bile acids enter the duodenum, microbial processing begins and continues throughout the entire length of the digestive tract to create secondary bile acids. Multiple drastic transformations can be made – so much so that original bile acid molecules are no longer recognized.

With the diversity of microorganisms that reside in the gut, the genetic potential to encode enzymes with bile acid-modifying capabilities from human-associated microorganisms is at least 1.5 to two million times larger than the potential associated with the human genome.¹

No single detection protocol currently exists that comprehensively captures the full diversity of metabolic changes bile acids undergo. However, information summarized from three metabolomic and lipidomic database resources identifies 692 different bile acids. They observed 97 unique mass shifts relative to the parent bile acids that included 20 core modifications and 110 carboxy tail modifications.^2,3,4,5

Types of Modifications

Bile acids are fundamentally derived from cholesterol, and their structure can be modified in various regions, including the bile acid core, carboxyl group, and hydroxyl groups. These modifications are made possible by the gut microbiome – including both commensal and opportunistic microbes – and are categorized as:

Re)Deconjugation
Hydroxylation
Dehydroxylation
7α-Dehydration
Ketone formation
Dehydrogenation
α-Oxidation
Hydroxyl group epimerization
Side-chain epimerization
Loss of the side chain
Opening of the B ring
Reduction
Opening of the A-ring
Alterations to the A-ring and B-ring junction

Even more interesting is bile acid modification in the digestive tract by the gut microbiota seems region-specific and dependent on factors such as age, diurnal timing, sex, and health status.

With the ability to produce so many bile acid structures, this raises the question – “What are the roles of all these diverse bile acids, and how do they influence different aspects of our health?” Not to mention the humility necessary when making assumptions about what may be considered an opportunistic, or even pathogenic, species! What if some opportunistic microbes play an essential role in producing bile acid metabolites?

Bile Acids In Utero

The developing fetal GI tract is thought to be sterile, thus unable to create microbial bile acids. The fetus is only exposed to bile acids through de novo biosynthesis or passed through the umbilical cord.

Astonishingly, fetal and neonatal bile acids exhibit remarkable structural diversity, many of which are absent in adults, suggesting the fetal environment is not as sterile as we once thought. These bile acids play a crucial role in establishing the immune system, receptor development, shaping nutritional absorption, energy balance, and the inflammatory environment of the developing human before birth and during the first few years of life. When born, bile acids such as cholate and chenodeoxycholate are present in breast milk, helping to support fat digestion, aid in the infant's development, and help drive the maturation of their microbiome.⁶

Early-life disruptions in bile acid metabolism, such as those caused by antibiotics or formula feeding, may predispose individuals to metabolic and immune disorders later in life.

A New Paradigm: Key Functions of Bile Acids as Signaling Molecules

The recognition of bile acids as endocrine and paracrine regulators has revealed their ability to modulate diverse physiological processes. Bile acids are multifunctional molecules that play critical roles in maintaining metabolic balance and supporting immune regulation. Their versatility stems from their biochemical properties and interactions with host and microbial systems. Key functions include the following:

Metabolic Regulation

Nutrient Absorption
Emulsify dietary fats, facilitating the digestion and absorption of lipids and fat-soluble vitamins in the small intestine.

Energy Homeostasis
Signaling molecules that regulate energy expenditure and storage.

Bind to nuclear receptors like the farnesoid X receptor (FXR) and cell surface receptors such as transmembrane G-coupled protein receptor 5 (TGR5), involved in cholesterol synthesis, bile acid production, and lipid metabolism.

Ensure efficient energy production for mitochondrial function by regulating bioenergetics and maintaining the integrity of cellular energy supplies.

Appetite Control
FXR activation by bile acids linked to appetite suppression.

Microbial Interactions

Bile acids regulate gut microbial composition by acting as antimicrobial agents.

Gut microbes, in turn, transform bile acids through various enzymatic processes (e.g., deconjugation, dehydroxylation, and epimerization), creating secondary bile acids with distinct biological activities.

These microbial transformations contribute to regulating gut permeability, motility, and nutrient absorption.

Protein Digestion and Cellular Function

Facilitate the breakdown of dietary proteins by activating pancreatic enzymes, such as proteases.

Bind to and regulate proteins in key organelles like mitochondria, the Golgi apparatus, and the endoplasmic reticulum, supporting protein synthesis, cellular metabolism, and intracellular transport.

Immune Modulation

Inflammation Control
Influence inflammation by interacting with immune cells and receptors, such as FXR and TGR5, which regulate pro-inflammatory and anti-inflammatory pathways.
Some, such as lithocholic acid, have direct immunosuppressive effects on T-cells.

T-cell Differentiation
Microbial bile acids have been shown to modulate T-cell differentiation, including regulating regulatory T-cells (Tregs), which are critical for maintaining immune tolerance and preventing autoimmunity.

The Bile Acid Metabolic Network – Systemic Effects and Organ Communication

Recent studies highlight bile acids as integral components of a bile acid metabolic network that facilitates inter-organ communication. This network is not limited to bile acid signaling within the gut and liver. It extends to the pancreas, kidneys, and reproductive organs, where bile acids act as signaling molecules that influence local metabolic and immune processes. The systemic distribution of bile acid receptors and transporters across diverse tissues underscores their broad functional impact and role in maintaining systemic homeostasis and preventing disease.

The Microbiome-Bile Axis

The microbiome plays a significant role in modifying bile acids. Altered gut microbiota composition affects bile acid metabolism, leading to the production of toxic secondary bile acids or the depletion of beneficial bile acids. These changes have been associated with conditions like small intestinal bacterial overgrowth (SIBO), IBD, and metabolic syndrome.

The Gut–Liver Axis

Bile acids aid in lipid digestion in the intestine, then are reabsorbed in the ileum and transported back to the liver via the enterohepatic circulation. This recycling mechanism helps regulate bile acid synthesis and maintain lipid and cholesterol homeostasis.

Dysregulation in this axis has been linked to liver diseases such as non-alcoholic fatty liver disease (NAFLD)⁷, non-alcoholic steatohepatitis (NASH), and cirrhosis, where altered bile acid signaling can exacerbate liver fat accumulation, inflammation, and fibrosis.⁸ Additionally, impaired bile acid homeostasis has been linked to metabolic syndrome, such as those with obesity and/or Type 2 Diabetes.⁹

Bile acids regulate glucose and lipid metabolism through the FXR and TGR5 pathways, impacting insulin sensitivity and energy expenditure. Modulating bile acid pools is a key therapeutic strategy for enhancing metabolic control.

Some current therapies include:

Ursodeoxycholic acid (UDCA) – a widely used bile acid derivative for treating cholestatic liver diseases and dissolving gallstones
Obeticholic acid (OCA) – an FXR agonist approved for treating primary biliary cholangitis and being investigated for NASH

The Gut-Brain Axis

Bile acids, such as chenodeoxycholic acid and cholic acid, act as antagonists for neurotransmitter receptors, including GABA and NMDA receptors.¹⁰ They influence excitatory and inhibitory signals in the brain and inflammatory responses. This interaction highlights their role in regulating mood, cognition, sleep, and neuroprotection.

Alterations in bile acid composition have been observed in neurological disorders such as Alzheimer’s disease, depression, and anxiety. The presence of bile acid receptors and biosynthetic enzymes in brain tissues supports the hypothesis that bile acids contribute to neuroimmune interactions and brain homeostasis¹¹. Bile acids such as tauroursodeoxycholic acid (TUDCA) have shown neuroprotective effects¹², offering potential as therapeutic agents.

The GutImmune Axis

Bile acids modulate immune responses by influencing T-cell differentiation and cytokine production, primarily through FXR and TGR5 signaling pathways¹³. They also regulate inflammation by activating anti-inflammatory pathways and suppressing pro-inflammatory signaling. Microbial bile acids, such as lithocholic acid, enhance the differentiation of regulatory T-cells (Tregs), promoting immune tolerance. All of these functions make them key players in systemic immune homeostasis.

Aberrant bile acid metabolism and microbial bile acid transformations contribute to gut inflammation in conditions like Crohn’s disease and ulcerative colitis¹⁴. Dysregulated bile acid pathways may also exacerbate autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus. Secondary bile acids, particularly deoxycholic acid (DCA) and lithocholic acid (LCA), have been implicated in promoting inflammation and DNA damage, contributing to colorectal carcinogenesis.¹⁵

Therapies targeting bile acid signaling aim to restore gut homeostasis and reduce inflammation and are being explored as a strategy for cancer prevention and therapy.

Communication with Distant Organs

Adipose Tissue and Metabolic Regulation: Bile acids contribute to systemic energy balance and may mitigate metabolic disorders such as obesity and type 2 diabetes by increasing insulin sensitivity.
Muscle and Bone Interactions: Through systemic circulation, bile acids impact muscle metabolism and bone health by regulating mitochondrial function and calcium homeostasis.
Cardiovascular System: Imbalances in secondary bile acids may contribute to hypercholesterolemia, atherosclerosis, and cardiovascular diseases by promoting inflammation. Modulating bile acid pathways may offer strategies for managing cardiovascular risk by enhancing cholesterol clearance.

Clinical Implications and Future Perspectives:

Exciting breakthroughs are expanding our understanding of bile acids as versatile messengers that bridge the gut, liver, and distant organs, orchestrating a range of physiological processes.

Recent discoveries are fueling the exploration of new therapies and diagnostic tools. For example, novel bile acid conjugates and derivatives such as tauroursodeoxycholic acid (TUDCA) are being developed to target metabolic, inflammatory, and neurological disorders. We now understand that altered bile acid profiles can serve as biomarkers for systemic diseases, aiding in diagnosis and treatment monitoring. Non-invasive bile acid testing in blood, urine, and feces could facilitate early detection and monitoring of disease progression. Further, profiling bile acid compositions and their interactions with the microbiome may enable personalized therapeutic approaches tailored to individual metabolic and immune profiles.

Thanks to perspectives such as those from “The changing metabolic landscape of bile acids – keys to metabolism and immune regulation,” we see how far we’ve come in learning about the ever-adapting bile acid world, even as we are humbled by how much more there is to discover. Enormous opportunity remains for researchers to uncover the biological patterns that drive bile acid modifications and absorption.

Resources:

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