138: How Bile Controls Insulin, GLP-1, and Fat Burning with Dr. Ben Bikman

Bile doesn't just digest fat. It actually controls your metabolism. Most people think bile is just digestive fluid, but bile acids act like hormones. After you eat, they're reabsorbed and activate powerful receptors that tell your liver to reduce fat, lower glucose production, and improve insulin sensitivity. At the same time, they increase energy expenditure, stimulate GLP1 and reduce inflammation. They even activate a TH thyroid hormone inside muscle and brown fat, increasing mitochondrial activity and helping you burn more energy. In fact, one human study, a bile acid called TUDCA was tested and found to improve insulin sensitivity by about 30%. That's because bile isn't just part of digestion. It's part of your metabolic control system. This is lecture 138 of the Metabolic Classroom. Welcome back to the Metabolic Classroom. I'm Ben Bickman, metabolic scientist and professor of cell biology. Today's mini lecture aims to teach you about something you probably haven't thought much about. That is bile. If you've studied any biology, you likely think of bile as a yellowish fluid that helps you digest fat. And that's not wrong. You'd be right. That's certainly one of its jobs. But bile acids, the active components within bile, are now recognized as bonafide hormones. They are signaling molecules that talk to tissues throughout the body, influencing insulin sensitivity, mitochondrial function, thyroid hormone activation, fat cell behavior, and even inflammation. Today, we'll start with the basics. What bile is, where it comes from, and what it does in the gut. Then we're going to follow bile on a journey most people never hear about, back into the blood and from there into tissues where they exert remarkable metabolic effects. We'll also talk about what happens when people lose their gallbladder and whether bile acid supplements actually do anything useful. All right, let's start with just the basics on bile. Well, it's a fluid produced by the liver cells, the hepatocytes. That's the main cell type within the liver. An adult liver produces somewhere in the range of 400 to 800 milliliters of bile per day. It's roughly 95% water. But dissolved in that water are several key components. The most metabolically important of these components are the bile acids, sometimes called bile salts. These are synthesized from cholesterol. And I want to note that because bile acid synthesis is actually the primary route through which the body eliminates cholesterol, that cholesterol is then dumped out. So when you think about cholesterol being made in the body, and what is something that takes out cholesterol? Well, it's actually because the cholesterol gets diverted into becoming bile. Now of course, beyond bile acids, bile also contains phospholipids, so a different type of fat, some straight cholesterol and even bilirubin, which gives bile its characteristic color, that yellowish, slightly greenish color. The two primary bile acids produced by the human liver are cholic acid and chinodeoxycholic acid. Before secretion, these are conjugated, so they're bound up with either the amino acid, glycine or taurine, making them more water soluble and more effective in the gut. So it just allows the bile to just work a little better. Once it's formed, bile is secreted into tiny channels called bile canaliculi. These then, these are pathways like almost vessels, which then merge into larger bile ducts. From there, bile either flows directly into the duodenum, the early part of the small intestine, or it's diverted into the gallbladder for storage. In the gallbladder, the bile is concentrated roughly five to ten fold. When you eat a meal containing fat, a hormone called cholecystokinin or CCK signals the gallbladder to, to contract and release all of that concentrated bile into the intestine. Once it's in the gut, the bile acids will emulsify dietary fats. That's its most famous role. It acts as a biological detergent, breaking up the large fat globules into very tiny little droplets called me cells, which of course then dramatically increases the surface area of all the fat, which allows the liver or the, the fat breakdown enzymes, the lipases, to do their work. The lipases are that family of enzymes that are designed to digest or help the body break down fat. Without bile, it's no surprise fat digestion is going to be severely impaired and you'll lose some of the ability to properly absorb not only fat, but also some fat soluble vitamins like those being A, D, E and K. Now the story starts to get really interesting as we continue through the after the production of bile, bile acids don't just do their job in the gut and then disappear. Roughly 95% of bile acids secreted into the intestine are reabsorbed primarily in the, what's called the ileum. So the back part of, in fact the back part of the back part of the small intestine. Once absorbed, they enter the portal blood, which means that it's going from the gut straight to the liver and are re secreted into bile. This recycling loop is called the enterohepatic circulation. We're going to come Back to that later. And it is remarkably efficient. The total bile acid pool is only about 2 to 4 grams, but it cycles 6 to 12 times per day. Only about 5% is lost in feces daily, replaced then by synthesizing a new bile from cholesterol. The key insight that has transformed bile acid biology is this. When bile acids are reabsorbed into the blood, they don't just quietly return to the liver. They interact with specific receptors, nuclear receptors inside the cells, as well as membrane bound receptors on the surface of the cells. And it does so in the gut and in the liver and and tissues throughout the body. It's through these receptors that bile acids exert their metabolic effects. And now, of course, I get to then, as a metabolic scientist, talk about a topic that is always dear to my heart. And let's focus on the two most important metabolic effects when it comes to bile acids. The first is fxr, the farnesoid X receptor. This is a nuclear receptor, so it's found within the nucleus. Identified as a bile acid receptor in 1999, this finding established that bile acids could directly regulate gene expression. FXR is most active in the liver and intestine, and the metabolic effects of its activation are substantial. In the liver, FXR tells the cell to dial down lipogenesis, the machinery that builds new fat molecules. The net effect is less fat accumulation in the liver. And as we've discussed previously on the podcast, a fatty liver is one of the most potent drivers of insulin resistan. It actually ends up being both cause and consequence of insulin resistance. And FXR activation also improves hepatic insulin signaling. It promotes glycogen synthesis and reduces the liver's tendency to overproduce glucose. That's, of course, one of the key problems as a person transitions from insulin resistance to outright type 2 diabetes. It's that the liver begins misbehaving and over producing glucose. Well, bile acids help solve that problem. In the intestine, FXR triggers production of FGF19, that stands for fibroblast growth factor 19. This hormone travels to the liver and delivers a clear metabolic message. Stop making so much glucose and stop making so much bile acid. So it ends up being a bit of a negative feedback. A 2011 paper in Cell Metabolism found that FGF 19 inhibits the livers the liver's glucose production pathway. Exactly what you want in someone struggling with high blood glucose, like in type 2 diabetes. Think of it this way. Every time bile acids are reabsorbed and activate fxr, it's like a metabolic reset of sorts, the liver starts to reduce its fat production. It reduces its glucose output and improves its insulin sensitivity. The built in metabolic housekeeping is a result of this. And it's triggered by something that is produced when you've eaten your last fatty meal, namely bile acids. All right, now the second receptor, fxr, is the first, just by way of perhaps importance or relevance. The next is a receptor called TGR5. This falls in the family of an enormous class of receptors called the G protein coupled receptors. It's the most common type of receptor that you'll find on all of the cells throughout the body. If FXR regulates gene expression, and we could say that TGR5 regulates insulin or regulates cell signaling events rather, I shouldn't have mentioned insulin there. That's not a part of this. I just can't help but mention insulin. So TGR5 is triggering a cell cascade. So a cell response and three tissues matter enormously when it comes to the TGR5 receptor. First, brown adipose tissue and skeletal muscle. A 2006 Nature paper revealed that bile acids increase energy expenditure by activating TGR5 in brown fat and muscle. The mechanism is elegant. TGR5 induces type 2 deiodinase, an enzyme that converts inactive thyroid hormone T4 into the active form T3, and it does so locally in that tissue. And more local T3 means more mitochondrial activity and more thermogenesis or the production of heat from those mitochondria. This is a direct bile acid driven mechanism for increasing metabolic rate. Second, intestinal L cells, these have become famous because they produce GLP1. And wouldn't you know it, TGR5 activation stimulates GLP1 secretion from those L cells. And again, just to make sure you're following me, the L cells are the cells that produce GLP1. And GLP1 receptor agonists are the now famous class of weight loss drugs. So bile acids through TGR5 are your body's own endogenous stimulators of GLP1 release. A built in mechanism for what these drugs are attempting to do pharmacologically. And I would say they do too much. And GLP1 is a good thing. We definitely want to leverage it in our favor. We just want to make sure we're not getting too much of thing lest it start to work against us or at least not work as well. Okay, now there's a third effect, and that is something that's happening at immune cells. A paper in 2011 showed that TGR5 activation in macrophages inhibits NF kappa B signaling and reduces pro inflammatory cytokine production. Given that chronic low grade inflammation is a hallmark of metabolic disease and a chronic cause, a cardinal cause of insulin resistance, I think the anti inflammatory effect is very relev when it comes to appreciating bile acids. Metabolic effects at the whole body. Now within the whole body there is a tissue that I'm always enamored by and that is fat tissue. Bile acids directly influence adipocyte or fat cell behavior. And this is an underappreciated part of the story. Both FXR and TGR5 are expressed in adipose tissue. FXR activation affects adipocyte differentiation, so the production of new fat cells as well as lipid metabolism, essentially influencing how fat cells mature and how they handle the fat they store. TGR5 activation in white adipose tissue has been associated with reduced inflammation and improved adipokine profiles, meaning that the fat cell is secreting a healthier ratio and levels of these fat cell hormones like leptin and adiponectin, something I've discussed previously. Now this matters enormously because in obesity and insulin resistance, adipose tissue doesn't just get bigger. These individual adipocytes, they become inflamed as something we've discussed and they become insulin resistant to try to prevent their growth. So as the fat cells swell beyond their healthy capacity, they become stressed. They they secrete the pro inflammatory signals to try to improve blood flow and then they become insulin resistant to try to prevent further growth. The combination of those things of course rapidly spreads the insulin resistance throughout the body. Bile acid signaling through both FXR and TGR 5 represents a pathway for restoring healthier fat cell function. It reduces inflammation. It improves the secretion of adipokines, namely by increasing adiponectin production and it supports a better lipid overall cycle and balance. And through the TGR5 mediated activation of thyroid hormone in brown fat and muscle, bile acids also drive mitochondrial biogenesis, the creation of new mitochondria. A 2006 study showed increased oxygen consumption and mitochondrial activity in brown adipose tissue following bile acid administration. Follow up work has found that bile acid's effects on mitochondrial function exists across multiple different tissues. So when we talk about insulin sensitivity, bile acids improve it through multiple converging mechanisms. It reduces liver fat via the FXR. It reduces hepatic glucose output via FGF19. It increases energy expenditure via TGR5 mediated thyroid hormone production. It increases GLP1 release, reduces inflammation and improves fat cell function by helping the size stay small. This is Just not one single thing. It's a coordinated, multi, pronged, myriad aspect approach. And there is fascinating clinical proof of concept here. Bile acid sequestrants, these are drugs that people can take. One of them is Coley Cevalim, Choleceville, that it will bind bile acids in the gut. So this is a class of drug that was reduced to help lower LDL cholesterol because the thought was you reduce the ability of the guts to absorb cholesterol and into the blood and that's going to help reduce ldl. Now that doesn't really work. But the clinicians noticed that patients also showed improved blood glucose control. And in 2008 the FDA approved colavesolam as an adjunct therapy for type 2 diabetes. For type 2 diabetes, by altering the bile acid pool composition, these drugs ended up accidentally shifting FXR and TGR5 signaling toward increased GLP1 secretion and improved glucose handling. It's a reminder that in metabolism, the details of signaling matter as much as the quantity. So by binding up the bile acids, it ended up resulting in the production of more. Alright, now underlying all of this discussion of bile may be a consideration or those who are concerned about their gallbladder. So let's get very practical and talk about that. With the cholecystectomy, the removal of the gallbladder, we have some considerations, not only because of the effects of bile acids on metabolism, but also because a cholecystectomy is one of the most commonly performed surgeries worldwide. So what happens to bile acid metabolism when that organ is gone? Without the gallbladder, bile flows continuously from the liver into the small intestine in a dilute, untimed fashion. You still make bile, because that's something that happens in the liver. But with the loss of the gallbladder, you lose the concentrated on demand delivery system. Now, the body compensates, the enterohepatic circulation speeds up, bile acids will cycle more frequently, and bile acid synthesis increases modestly. Work by Pomare and Heaton described this in some really classic studies. The total bile acid acid pool shrinks to roughly half its normal size, but the recycling rate increases to partially compensate. However, the compensation is imperfect. We see that within epidemiological studies that there's an association between gallbladder removal with an increased risk of metabolic syndrome, fatty liver disease, as well as altered glucose homeostasis. So the gallbladder, as it turns out, isn't just a storage pouch for the bile. Because of that storage, we can really call it part of the metabolic signaling apparatus. Now, I Want to be careful here. Many people do perfectly well after gallbladder removal and the surgery is clearly necessary when gallstones cause symptoms. Now, ironically, one of the most common causes of gallstone formation is eating insufficient fat. But this isn't a lecture about gallstones, so I won't focus on that too much. Nevertheless, the emerging evidence suggests that we really do need to think of the gallbladder as a metabolic pacemaker of sorts, and its loss with its removal, it does have consequences that go beyond digestion. Now that brings us to another practical matter, which is supplements. There are two main categories when it comes to bile supplements. Ox bile, which is a bovine derived bile salts, as well as tudca, which stands for tauro. Remember, taurine is one of these amino acids that the bile can be bound to. Toro, ursodeoxycholic acid. T U D C A OX bile is marketed to people who've had their gallbladder removed. Not surprising. The rationale is straightforward. Supplement with bile salts at mealtime to replace what the gallbladder used to deliver on demand. Many people report improvements in bloating and fatty stools and discomfort after their high fat meals. The logic is physiologically sound, though large scale rigorous trials on ox bile are really pretty limited for someone with persistent fat malabsorption after cholecystectomy. I think it's very reasonable thing to consider and certainly to discuss with your clinician. Now, TUDCA is a more interesting story from a metabolic perspective. It's the taurine conjugate of ursodeoxycholic acid. And beyond its bile acid properties, its function. It, it functions as a chemical chaperone. It helps proteins fold correctly and alleviates something called endoplasmic reticulum or er, stress, which is thought to be a contributor to inflammation, inflammation and then to insulin resistance. The most compelling human evidence comes from a 2010 paper in diabetes. They gave obese insulin resistant men and women 1,750 milligrams, or in other words, 1.75 grams of tudca daily for four weeks in a randomized placebo controlled design. So gold standard hepatic and muscle insulin sensitivity improved by approximately 30%, comparable to moderate weight loss or even taking metformin. Muscle insulin signaling also improved. Interestingly, er, stress markers, that's the cause of inflammation I mentioned a moment ago, also improved. But so all of this when viewed in combination suggests that perhaps if it is a bile supplement, you need to get the right one. Further adding onto this, a 2022 study found that TUDCA treatment in aged mice attenuated hyperinsulinemia, improved glucose homeostasis, reduced adiposity and increased energy expenditure. So higher metabolic rate, less fat and improved insulin sensitivity. Similarly, in a mouse model, TUDCA improved beta cell mass and even reduced insulin degradation. This was actually explored in a type 1 diabetes study. So pretty interesting implications for type 1 diabetes. Now, of course, the question would be, well, should everyone just be taking tudca? Well, not necessarily. The human data are still limited and they're short term, but the mechanistic rationale is compelling. The safety profile is strong, and for individuals with insulin resistance, particularly those without a gallbladder, then I think it would be worth exploring the implementing some tudca. Now let's share some concluding thoughts as we wrap up Bile acids are among the most important metabolic signaling molecules in the body, among the most important, and I would say among the most overlooked. Through These distinct receptors, FXR and TGR5, they can regulate things from liver fat and glucose production, insulin sensitivity at tissues throughout the body, GLP1 production from the gut, as well as inflammation and even mitochondrial biogenesis, and uncoupling and thermogenesis in fat cells. The enterohepatic circulation ensures that these signals are constantly delivered, not just to the gut, but everywhere throughout the body as it gets reabsorbed. And because the gallbladder can hold on to a concentrated amount of bile acids, it ends up having some direct influence on metabolism by ensuring that the bile acid signals arrive at the right concentration at the right time. And when someone loses the gallbladder, there are some metabolic consequences that we perhaps don't yet fully appreciate. But thankfully, bile acid supplements and the natural physiological adaptation to accelerating the enterohepatic circulation can make up for it. Thank you for joining me for another mini lecture in the metabolic classroom. I hope this has expanded your understanding and appreciation of metabolism and maybe even helps you make some practical applications of it all. Remember, more knowledge, better health.