Book update: It’s time to talk about bile

 

Hey, how come you’ve never once mentioned bile?

I don’t know. There are a lot of specific chemicals I haven’t mentioned.

Yeah, but I’ve actually heard of bile, so it must be kind of important, right?

Oh, sure, it’s really important. I just never mentioned it because it wouldn’t add anything new to your understanding at a conceptual level. But, actually, bile is a great example of how digestion, metabolism, inflammation, and gut bacteria are all intertwined. I’d be happy to tell you more about it if you’re interested.

Sure, why not?

The basics of bile are very simple. It’s made by your liver and stored in your gall bladder. When you start eating, it’s released into your intestines where it helps to break down fat during digestion. When you’re finished eating, it’s reabsorbed into your blood and sent back to your liver for recycling.

OK, I’m with you.

Good. Now, of course, there is a lot more to it than that.

Like what?

Let me start by telling you about an experiment (1). Researchers took two groups of mice and overfed them, just like in all of those other studies that I’ve told you about.

So the mice became overweight and had high blood glucose and all of the other problems that overweight people have?

Right. Well, one group did anyway. The other didn’t because the researchers gave them extra bile along with their food.

Wait, that doesn’t make any sense. You said that bile helps break down fat during digestion. So having more bile should have helped the mice to digest more of the fat that they ate, right?

That’s right.

OK, so then shouldn’t the mice that got the extra bile have gained more weight than the mice that didn’t?

Well, if bile’s only job was to help break down fat during digestion, you’d probably be right. But bile actually does a lot more than that. Let me keep going.

OK, go ahead.

So first the researchers checked whether or not the two groups of mice were actually eating the same amount of food, which they were. So that meant that the mice that got the extra bile were burning off more calories than the mice that didn’t.

OK, but why?

Well, in order to understand what was going on, the researchers took some cells and put them in a dish.

What kind of cells?

Actually, they used two kinds: fat cells and muscle cells. But it didn’t matter, the results were the same for both.

Oh, OK.

The first thing they tried was to simply put some bile in the dish with the cells to see if it changed how many calories the cells were burning. And, amazingly, it did!

What? Why?

Well, the researchers did a lot of other experiments and they found out that cells have bile detectors, and when those detectors are triggered they kick off a series of chemical reactions that cause more calories to be burned.

Wow. Can I ask a question?

Sure.

These mice got the extra bile right away and it prevented them from gaining weight. But what would happen if you gave extra bile to mice that were already overweight? Would they actually lose weight or would they just stop gaining it?

Good question. The researchers actually tried that. They took a third group of mice, overfed them for a few months until they were overweight, and then kept overfeeding them while also giving them extra bile.

And?

And within a few weeks they were back to normal weight.

Whoa! OK, so can we give people extra bile to help them lose weight?

Maybe. Researchers are just starting to look into that (2). In a small study last year, they gave extra bile to humans for a few days and they found that it did in fact cause them to burn more calories. But these kinds of experiments have to proceed very slowly.

Why?

Because bile is involved in a huge number of complex chemical processes that are very delicately balanced. It’s impossible to manipulate one of these processes without affecting all of them, and it’s impossible to predict the effects that any particular manipulation will have. So it has to be done very carefully.

If you say so.

I think you’ll agree when you understand more about what bile does. Let me tell you about another experiment (3).

Go ahead.

A different group of researchers looked at the effects of blocking the release of bile in mice completely.

Wait, let me guess. Extra bile made the mice lose weight, so without any bile at all they should gain even more weight than they would normally, right?

Maybe, but they didn’t even get that far because without bile things go completely haywire. Do you remember the leaky gut problem?

I think so. Normally, my intestinal wall cells are packed tightly together and protected by a mucus lining, which prevents my gut bacteria from getting into my blood. But if the mucus lining breaks down or there are gaps between my intestinal wall cells, my gut bacteria will get into my blood and, of course, my immune cells will attack them.

Right, and that’s bad because …

Oh, because the chemicals that are released by my immune cells will leak out into other parts of my body and cause all kinds of trouble.

Like what?

Like interfering with my insulin and leptin. That part I will never forget because it’s really at the root of all of the other problems that come with unhealthy eating. Diabetes, heart attacks, strokes – those are all caused by chemicals from immune cells.

Right, good. So when the researchers looked at the intestines of the mice after a few days without bile, they found serious leaky gut problems: the mucus lining was gone, there were huge gaps between the intestinal wall cells, and a lot of bacteria had gotten past the intestinal wall cells.

OK, that’s not good. But I don’t really see how a lack of bile could cause a leaky gut.

Well, it turns out that, like fat and muscle cells, the intestinal wall cells and immune cells in your gut also have bile detectors (4).

OK, but how does burning more calories in your intestinal wall cells and immune cells help protect against a leaky gut?

What? Oh, no, these detectors are different from those in fat and muscle cells. They don’t cause cells to burn more calories. When these detectors are triggered they cause the release of chemicals that are helpful for making mucus, holding intestinal wall cells together, and even killing certain bacteria.

I see. And I guess the researchers did the usual experiments with mutant mice that have their bile detectors deactivated?

Right. Those mice develop leaky guts even if you don’t block their bile.

Right. Because even if the bile is there, the intestinal wall cells and immune cells in those mice can’t see it, so they don’t release any of those helpful chemicals.

Exactly. But there’s even more to it: the mice with their bile blocked had gut bacteria that were different from the gut bacteria in normal mice.

Why? Oh, wait, you just said that bile causes the release of chemicals that kill certain kinds of bacteria. So without those chemicals, the bacteria that would normally be killed will be able to survive, right?

Right, that’s part of it. But bile also has direct effects on gut bacteria because some gut bacteria can process bile themselves (5).

You mean that they take in bile and convert it to something else, keeping a bit of energy for themselves in the process?

That’s right. So without bile, those bacteria can’t survive.

Are those bacteria important?

Yes, very. Usually, what these bacteria release after they take in bile is, in fact, still bile. It’s just different bile. There are a few different kinds of bile, all of which are similar, but the subtle differences between them end up being pretty important.

How?

Well, do you remember those bile detectors on fat and muscle cells that increase how many calories the cells burn?

Yes, we were talking about them literally one minute ago.  

OK, sorry! Anyway, those detectors won’t detect your normal bile, they’ll only detect the bile that’s been changed by your gut bacteria (6).

Oh. Wow. OK, I guess I should have known that gut bacteria would be deeply involved in this somehow.

Right. It really seems like they have a role in everything.

OK, so all of that stuff about extra bile helping to prevent weight gain or encourage weight loss only happens if the right gut bacteria are there to convert the bile into the kind that muscle and fat cells can detect.

Exactly (7).

OK, this is starting to get a bit complicated.

Good, that’s exactly the point. Like I said, bile is a great example of how digestion, metabolism, inflammation, and gut bacteria are all intertwined. Let me just tell you about one last experiment (8). Researchers took two groups of mice and put them on diets that were the same except for one difference: one group got saturated fats and the other group got unsaturated fats.

OK, but the total number of calories were the same?

Right. And so were the amounts of carbs and protein and everything else.

OK.

Good. So first of all, they found that the two groups of mice ended up with different bile.

Why? Oh, wait, I remember that you told me during our first conversation about those other experiments that showed that eating different fats will encourage the growth of different kinds of gut bacteria. So maybe those different kinds of gut bacteria will change bile in different ways?

Right, that’s part of it. But even without gut bacteria, eating different fats will cause your liver to release different kinds of bile.

Why?

Just because certain biles are better at breaking down certain fats. If you eat a lot of saturated fats, then your liver will release a lot of saturated fat biles. If you eat a lot of unsaturated fats, then your liver will release a lot of unsaturated fat biles.

Oh, OK, that makes sense.

Good. But, of course, the type of bile that is released by your liver does have a big impact on your gut bacteria because it determines exactly which type of bile bacteria will be able to survive in your gut. If you have a lot of saturated fat biles, then bacteria that process those biles will be able to survive, but bacteria that process unsaturated fat biles won’t.

Right. Got it.

Good. Now, it turns out that some of the bacteria that process saturated fats biles can cause problems.

Why?

Because when they take in saturated fat biles, what they release isn’t just another bile, it’s a chemical that can damage your intestines.

OK, so let me get this straight: a change in diet causes a change in bile, which then causes a change in gut bacteria, which then causes a leaky gut and inflammation.

Right. Do you want me to describe the experiments that the researchers used to figure all of this out?

No please don’t. I mean, I’m grateful for the explanations, but I think I’ve reached my limit for the day. I think I followed each of the experiments that you described, but I’ve lost sight of the big picture. Is bile good or bad?

It doesn’t really make sense to talk about bile as either good or bad. It’s just one of many chemicals that interact to control digestion, metabolism, inflammation, and gut bacteria. I could choose any one of these chemicals and tell you about how it has many different roles in many different systems just like bile. But the important point is that the interactions between these chemicals are really complicated, so when something changes in your gut, so when something changes in your gut, it’s really difficult to predict what will happen.

Right.

But now comes the part where I return to my usual refrain: if you just eat a reasonable mix of unprocessed foods, you’ll never have to worry about any of this stuff. Just give your body the foods it was designed to process and, bile and large, everything will be fine.

Oh my god …

 

1. Watanabe, M., Houten, S.M., Mataki, C., Christoffolete, M.A., Kim, B.W., Sato, H., Messaddeq, N., Harney, J.W., Ezaki, O., Kodama, T., et al. (2006). Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489.

2. Broeders, E.P.M., Nascimento, E.B.M., Havekes, B., Brans, B., Roumans, K.H.M., Tailleux, A., Schaart, G., Kouach, M., Charton, J., Deprez, B., et al. (2015). The Bile Acid Chenodeoxycholic Acid Increases Human Brown Adipose Tissue Activity. Cell Metabolism 22, 418–426.

3. Inagaki, T., Moschetta, A., Lee, Y.-K., Peng, L., Zhao, G., Downes, M., Yu, R.T., Shelton, J.M., Richardson, J.A., Repa, J.J., et al. (2006). Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc. Natl. Acad. Sci. U.S.A. 103, 3920–3925.

4. Vavassori, P., Mencarelli, A., Renga, B., Distrutti, E., and Fiorucci, S. (2009). The bile acid receptor FXR is a modulator of intestinal innate immunity. J. Immunol. 183, 6251–6261.

5. Sayin, S.I., Wahlström, A., Felin, J., Jäntti, S., Marschall, H.-U., Bamberg, K., Angelin, B., Hyötyläinen, T., Orešič, M., and Bäckhed, F. (2013). Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235.

6.Wahlström, A., Sayin, S.I., Marschall, H.-U., and Bäckhed, F. (2016). Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab.

7. Joyce, S.A., MacSharry, J., Casey, P.G., Kinsella, M., Murphy, E.F., Shanahan, F., Hill, C., and Gahan, C.G.M. (2014). Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc. Natl. Acad. Sci. U.S.A. 111, 7421–7426.

8. Devkota, S., Wang, Y., Musch, M.W., Leone, V., Fehlner-Peach, H., Nadimpalli, A., Antonopoulos, D.A., Jabri, B., and Chang, E.B. (2012). Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature 487, 104–108.