How Diet Can Treat Depression: The Metabolic Marvel of Bile Acids

Metabolic and nutritional psychiatry are exploding fields now, with millions of dollars being poured into trials being conducted at Harvard and Stanford and elsewhere on diet and mental health disorders, including depression. Why? Well, it should be obvious. Your diet impacts your metabolism, and healthy brain metabolism is the foundation for a healthy and happy mind. But it's only just now becoming apparent how powerful diet can be to treat, even cure, disorders like depression. So in this video, I'm going to do a deep dive into the bowels of new mechanistic data, but I promise to tie this back in to human clinical trials at the end. Trust me, you're gonna wanna watch this from beginning to end to fully appreciate the metabolically elegant dance among our diets and brains, and because there are some interesting surprises at some point throughout the video. So the paper that has me so excited was just published in Neuron, and it reviews how bile acids, molecules that are made by our bodies and released into our intestines to help break down fat, well, these bile acids can be endogenous antidepressants. Mind blown, right? Well, not yet. The first thing to understand is that bile acids aren't just released into our intestines but are also released into the blood and circulate throughout the body. This makes sense at a high level since these molecules are serving a function in responding to what we eat to help us break it down, specifically break down fat. They shape our microbiomes, and so if our bodies were smart, and they are, they would also couple bile acids to the regulation of whole body metabolism, including brain metabolism, which is exactly what our bodies do. Now, one key receptor for bile acids is called the Takeda G-protein coupled receptor, or TGR5 for short. And as an aside, if you're like me and wondering why it's called Takeda, I did look this up and the etymology of Takeda translates to warrior rice paddy in Japanese. That's all I got. Someone can tell me a little bit more in the comments. Anyway, getting back to business. Bile acids bind TGR5 all over the body to alter metabolism, including binding TGR5 in the brain. And researchers in this study found that stressors, including subjecting mice to chronic social defeat stress, which is dominance by an aggressor mice, and resistance strain, which is restraining mice in these little tubes. Sorry, mice. Basically stressing mice decreased levels of TGR5 in a brain region called the hypothalamus, specifically the lateral hypothalamus. And this was specific to mice who were susceptible to stress-induced depression, as you can see here. So the hypothalamus is the master regulator of the body's hormonal system and the body's stress response axis, the hypothalamic-pituitary-adrenal axis, or HPA axis. And they also found that in stress-induced depression mice, there was an association whereby lower levels of TGR5 in the hypothalamus associated with less social interaction, which is a sign of anhedonia, or a depression sign that's the inability to feel pleasure. So we're starting to develop this picture here in this study. Could it be that stressors lower TGR5 levels in the brain, and lower TGR5 signaling promotes depression? Let's now develop that picture a little bit more. Indeed, the researchers found that in depression-susceptible mice, stress increased levels of stress hormones like cortisol. You've heard of cortisol, right? And cortisol can bind to its receptor in the brain, the glucocorticoid receptor, and this can then go and bind DNA elements to downregulate expression of the TGR5 gene coding for the TGR5 protein, the receptor in the hypothalamus. So basically, stress promotes cortisol, cortisol decreases TGR5, and that promotes depression. But wait, something's missing. How? How do decreased TGR5 levels contribute to depression, if indeed they do so? Well, what the researchers find is that TGR5 signaling inhibits off or inhibitory GABAergic neurons, in the hypothalamus. So more TGR5 signaling basically shuts down these neurons, the neurons that researchers actually ended up finding promote depression. Conversely, less TGR5 signaling, as in the stress-induced mice, removes the shackles on the depression neurons, leading them to induce a depression-like phenotype. Now stepping back, how they demonstrate causality in this pathway at a high level is basically by blocking and activating various nodes in the pathway. Which they do quite elegantly using techniques I've covered previously in other videos like optogenetics, which is pretty cool. You should go check out this video, this timestamp for more on that. But the data, the primary data, they look like this. As you can see, they're pretty complicated. So I've made the executive decision not to figure bomb you nor get into the nitty gritty about disdendritic spine morphologies, even if there were a bunch of jokes I really wanted to drop on mushrooms. Anyway, I'm gonna kind of move over the nitty gritty in part to help with YouTube video retention. Yes, I did admit that. But also because I want to encourage you to read the paper yourself, and I wanted to get on to how these mechanistic data relate to human data, how they're more relevant to you. As I mentioned, there have recently been a slew of studies showing that carbohydrate restriction and ketogenic diets can improve mental health disorders including bipolar disorder, schizophrenia, and depression. Now, we know that ketogenic diets can treat depression and save lives, but how, how ketogenic diets and carbohydrate-restricted diets work remains a metabolic mystery. The exact mechanisms are likely multitudinous, but this mechanism highlighted in this paper may be one whereby high-fat, low-carb ketogenic diets increase levels of TGR5 signaling bile acids in humans. This has been shown. Better understanding of these mechanisms has several functions. First, I think it enables innovation of more targeted treatments. Some questions that arise in my mind: could it be that bile acid response to ketogenic diet actually predicts improvements in depression? Or could it be that different ketogenic diet compositions could lead to a more favorable bile acid profile and lead to more impactful clinical results on depression. These are possibilities. Additionally, providing biological plausibility in preclinical models, including mouse models, motivates investment in more research, research that needs to be done. And on this, I really want to add, doing rigorous human trials is difficult. This is in large part because of financial constraints and the lack of a clear business model for metabolic mental health. Pharma has no reason to want to fund these studies, but they need to be done. So they're getting done in large part because of funding from philanthropists. One example is the Bazuki Group, who are motivated to fund this work because their lives and/or those of loved ones have been touched by mental health disorders. They've suffered. They've suffered terribly. Only then to feel the full power that dietary and metabolic health interventions can have in treating severe treatment-resistant mental health disorders like treatment-resistant depression. With that, I'm going to pivot a little bit and provide some closing thoughts that are going to be sentimental, starting with a quote from the late, great Robin Williams. He once said, "People don't fake depression, they fake being okay." Now, Robin Williams' suicide, when it happened in 2014, was the moment that I realized that anybody can struggle with mental health issues, and it's often not visible. He was a figure that in my childhood was always a symbol of joy, humor, and vitality, the kind of person who could touch your heart, without ever having met you. So this video, as awkward a tribute as it might be, is a tribute to Robin Williams. Now for that special surprise I promised you. Here's a little bit from Zach Williams, Robin Williams' son. I posed to him the question, what does metabolic mental health for you, and why do you think it's important to study this? What do you think the future of metabolic mental health is? Respond however you please. So Zach, take it away.

Hi, I'm Zach Williams, The mental health advocate and mental health has always been a significant part of my life. And today I want to talk about something that isn't often discussed but is incredibly important. Metabolic mental health. For me, mental health isn't just about what's going on in your mind. It's also deeply connected to what's happening in your body. I've experienced firsthand how closely linked our physical and mental well-being really are. After years of struggling with anxiety and depression, I discovered that addressing my metabolic health things like my diet, exercise, and sleep had a profound impact on my mental state. So what exactly is metabolic mental health? It's about understanding that our brain and our body aren't separate systems. They're deeply intertwined. Our metabolism, the process by which our body converts food into energy, plays a crucial role in how we feel mentally. When our metabolism is out of balance, it can lead to feelings of fatigue, memory, stress, and even mental health issues like anxiety and depression. There's growing evidence that our diet, our gut health, and our overall metabolic fun— function can influence our brain chemistry. For me, taking care of my metabolic health means being mindful of what I eat, staying active, and making sure I get enough rest. It's not just about avoiding junk food or hitting the gym. It's about understanding how my lifestyle choices impact my overall well-being. I've learned that when I support my body's metabolic processes, I feel more energized, more focused, and more resilient mentally. I encourage everyone to explore this connection between metabolic and mental health. It's about finding a balance that works for you, whether that's adjusting your diet, incorporating more movement into your day, or simply paying attention to how your body responds to different habits. By nurturing both your physical and mental health, you can create a foundation for long-term well-being. Remember, mental health is holistic. It's not just in your head, it's in every part of your body. By taking care of your metabolic health, you're also taking care of your mental health, and that's something worth investing in.