Do taurine and glycine provide answers to the mammalian gallbladder and kidney mysteries?

No, but they are interesting.

Back to incredibly esoteric biology topics!

The gallbladder is an oft-overlooked organ. It’s not nearly so vital as the heart, the lungs, or the brain. It can be removed without any serious health consequences if it malfunctions. Gallstones are the only common disease that affects it, and gallstones, although painful, are rarely serious.

If you learn anything about the gallbladder, you probably learn the one fact that the gallbladder “stores and concentrates bile”. It doesn’t produce it (that’s the liver’s job), but it helps keep bile until it’s needed. If you learn a second thing, it’s that bile helps digest fats. This is why people who have their gallbladders removed have a bad time when they eat fatty foods.

All of this presents a plausible reason why humans still have gallbladders, even if they’re not super necessary. They're nice to have, even if you don’t need to have them. But I’m not satisfied with a purely human-centric viewpoint. I want to expand your view to the rest of the animal kingdom.

After all, it’s not just humans with gallbladders. Lots of animals have gallbladders: dogs, cats, chickens, mice. And all of them have gallbladders for more or less the same reason that people do: to store and concentrate bile, which is used to digest fats. This is not so strange. What is strange is which animals don’t have gallbladders: horses, deer, alpacas, pigeons, some parrots, lampreys, and rats.

Now, maybe there’s a story you can tell about the animals that don’t have gallbladders in which they don’t eat fatty foods, so having a gallbladder is superfluous. That probably fits with horses, deer, and pigeons, although it’s frankly difficult to say that chickens or turkeys definitely eat more fatty food than pigeons. But, that story doesn’t make sense with rats.

Rats, like humans and mice, eat everything, including fatty foods. So why don’t they need gallbladders?

***

Cyclosporine is a fascinating drug that I’ve written about a lot (and done studies on). It’s an effective immunosuppressant and it preserves mitochondrial health in times of stress. This makes it a good choice for, among other things, preventing long term damage from traumatic brain injuries.

However, as I’ve written about before, it’s not a risk-free drug. One of the biggest risks from cyclosporine use is nephrotoxicity (kidney damage), both acute nephrotoxicity, from cyclosporine overdoses, and chronic nephrotoxicity, from the accumulation of cyclosporine over time. If you look up why cyclosporine causes nephrotoxicity on ChatGPT, like I just did, it tells you that it’s because of blood restriction and oxidative damage.

This is a fine explanation. It doesn’t, however, explain the interspecies differences in cyclosporine nephrotoxicity. Humans and pigs can get both acute and chronic nephrotoxicity from cyclosporine use. Dogs and rats can get acute nephrotoxicity, but not chronic, except under a low sodium diet. Cats can’t get either, as far as I can tell.

Low sodium there is some sort of clue, as extremely low sodium diets activate the renin-angiotensin system, as the kidneys strain to retain as much sodium as possible from fluids to make up for the lack of it from food. And cats are another clue, given their hyper efficient kidneys adapted to their ancestral desert lifestyle. Still, we don’t get much idea, mechanistically, of why humans and pigs have such a harder time with cyclosporine.

***

I spent a solid month or two trying to make sense of these interspecies differences. My plan was to tie them together through the taurine/glycine difference. Taurine and glycine are both nonessential amino acids for humans, meaning that they are not essential to be supplemented, not that they are nonessential for life.

In fact, they are essential for life, in the gallbladder, the kidneys, and elsewhere. In the gallbladder, taurine and/or glycine, depending on the species, are used to make bile acids more soluble. Taurine is better than glycine for this purpose, because it’s more soluble at a greater range of pHs.

In the kidneys, taurine and glycine prevent oxidative damage, keep osmoregularity, help detoxification, and participate in biochemical pathways. Taurine supplementation can prevent against cyclosporine-induced nephrotoxocity in rodent studies. Elsewhere, taurine and glycine play subtler but still important roles, which we mostly only know about from cases of deficiency. Cats with taurine-deficient diets, for instance, eventually go blind and develop cardiomyopathy.

There are seemingly random differences in how different species both acquire and use taurine and glycine, at least in their bile acids. Humans produce both endogenously, and use both for bile acids, with about a 70/30 glycine/taurine mix. Dogs produce both endogenously, although they benefit from taurine supplementation, and have roughly the reverse mix, 80/20 taurine/glycine.

Cats only produce glycine endogenously, and need taurine supplementation. They use only taurine in their bile acids. Rats and mice produce both endogenously, although they benefit from glycine supplementation. They only use glycine in their bile acids. Finally, pigs produce both endogenously, although they benefit from glycine supplementation. They have the same mix as humans, about 70/30 glycine/taurine.

You can see how there’s some glimmer of sense there. These are clear interspecies differences in taurine and glycine, and they tie together the gallbladder and kidneys. If I had found that taurine-dominant species had less nephrotoxicity with regards to cyclosporine, more need of a gallbladder, and more need of taurine supplementation, this would be a great hypothesis to explain the mysteries above. It’d also help explain why taurine supplementation seems to help with life extension (more on that in another post).

Unfortunately, that’s not what I found. The nephrotoxicity hypothesis falls apart with rats, given that rats don’t use taurine at all and still don’t have a huge problem with nephrotoxicity. The gallbladder hypothesis falls apart with mice having gallbladders and rats lacking them, given they both use glycine exclusively. And the supplementation hypothesis falls apart with pigs needing glycine supplementation and humans seemingly not needing it.

My hope is that the data is wrong somewhere, given that I like my hypothesis. As my dad puts it, it’s always a tragedy when a beautiful theory is destroyed by a gang of vicious facts. And it doesn’t seem impossible for this data to be wrong, given that this is a relative backwater of science. But I don’t have much hope.

For now, the gallbladders and kidneys will have to remain mysteries.