Henry A. Nasrallah, MD
Professor of Psychiatry, Neurology, and Neuroscience
The University of Cincinnati College of Medicine
Cincinnati, OH
In this episode, Dr. Henry Nasrallah examines the emerging science linking the gut microbiota to psychiatric conditions such as depression, anxiety, bipolar disorder, and schizophrenia. He explains how disturbances in gut health—often referred to as “leaky gut”—can contribute to neuroinflammation and psychiatric symptoms, and discusses the therapeutic potential of probiotics, prebiotics, and dietary interventions. Dr. Nasrallah highlights novel findings on how gut-brain communication impacts cognition, mood, and psychosis, with a look at the future of microbiome-based psychiatry.
Watch Part 1: It Takes Guts to Be Mentally Ill, Part 1: A Brief Overview of the Human Gut Microbiota
Henry A. Nasrallah, MD is Professor of Psychiatry, Neurology, and Neuroscience at the University of Cincinnati College of Medicine. A leading expert in schizophrenia and neuropsychiatric disorders, Dr. Nasrallah’s research focuses on the neurobiology of serious mental illness, including the roles of neuroinflammation, brain structural changes, and the gut-brain axis in the pathophysiology of psychosis and mood disorders. He is widely recognized for his work in psychopharmacology, early intervention, and innovative therapeutic strategies targeting central nervous system dysfunction.
This presentation is part of the Emerging Approaches in Schizophrenia Editorial Focus collection from Psychiatrist.com News. The collection focuses on the latest advances in schizophrenia treatment, with an emphasis on emerging therapies that go beyond traditional dopaminergic approaches.
Transcript
00:00 – Introduction: Gut-Brain Psychiatry
Hello, this is Dr. Henry Nasrallah, Professor of Psychiatry, Neurology, and Neuroscience at the University of Cincinnati College of Medicine. And I’ll be presenting to you why it takes guts to be mentally ill. And in this part two, I’ll discuss the relationship between the gut microbiota and psychosis.
00:34 – Leaky Gut, Inflammation, and Psychiatric Symptoms
Leaky gut is a pathological condition because it leads to inflammation. You can see here the sequence of events, stress, infections, antibiotics, poor diet lead to disruption of the intestinal barrier, the gut wall, which is called the leaky gut. And that leads to bacterial translocation and that can trigger immune activation and increase in cytokines and basically neuroinflammation.
And neuroinflammation has been found to basically be associated with cognitive dysfunction, with mood disorders, with psychosis, with anxiety. So, the leaky gut has to be repaired in people who have it. That includes administering prebiotics and probiotics and modifying the diet into a good diet that avoids high fat, high inflammation.
So, there are many medical disorders actually that can be associated with dysbiosis of the gut microbiota. These include neurodegenerative disorders like MS and Parkinson’s disease and Alzheimer, cardiovascular disease, coronary artery disease and hypertension, intestinal disorders like Crohn’s disease, ulcerative colitis, irritable bowel syndrome, celiac disease, and metabolic disorders, including metabolic syndrome, obesity, type 1 and 2 diabetes, hypertension, and so on, and pregnancy-related conditions, including both gestational hypertension and gestational diabetes. So, here are some psychiatric disorders that have been associated with dysbiosis of the gut microbiota.
Anxiety, depression, autism spectrum, ADHD, bipolar disorder, and schizophrenia. It’s basically all the major psychiatric disorders are associated with dysbiosis. Now, a healthy microbiome implies that there is normal gut microbiota, normal behavioral cognition, healthy levels of inflammatory cells and mediators, and normal intestinal permeability, absence of leaky gut.
So, the microbiota in major depression, it’s been shown that there is decrease in microbiota richness and diversity in depression, elevation of inflammatory biomarkers, and increase in cortisol levels. That’s, again, related to the disruption of the HPA axis. And in rats and animal studies, which have been depleted from microbiota, the following are observed, anhedonia in terms of behavior, anxiety in behavior, intestinal transit time, and plasma CRP, C-reactive protein, which is inflammatory.
03:13 – Functions of the Gut Microbiota
What are the functions of the gut microbiota? First, digestion of foodstuff with energy harvest and metabolism and synthesis of vitamins, reduction of short-chain fatty acids, SCFAs, as we call them, through fermentation of dietary fibers, immune cell development and protection against pathogens and autoimmunity, and balancing the good and bad microbial composition and metabolic functions, and hormone production, regulation, especially cortisol, and promotion of fat storage and hypothalamic pituitary adrenal axis function. And so the bottom line is that the microbiota will modulate the CNS and lead to a variety of psychiatric disorders. So here’s basically a figure showing the bidirectional traffic between the gut microbiome and the enteric brain, as well as the major brain, the big CNS brain.
As you can see, there’s a lot of bidirectional influences with neurotransmitters, which are produced in large amounts, by the way, from the enteric brain, cytokines, short-chain fatty acids, immune cells, and don’t forget the vagus nerve. Vagus nerve, it connects the large brain in our head to the smaller brain inside the gut. This smaller brain is comprised of about 100 million neurons.
Let’s remember the big brain has about 100 billion neurons. And so there’s a lot of back and forth interaction. So the microbiome and neurotransmitters, just remember, as I said earlier, that the gut microbiome produces 90% of the body’s serotonin, which is both a hormone and an excitatory neurotransmitter that contributes to anxiety and depression, which is well known now.
And that’s why we have a lot of medications for depression and anxiety that influence the serotonin. And then it also has catecholamines, which predominate in physiology, norepinephrine, epinephrine, dopamine, and they all impact gut motility, nutrient absorption, GI innate immune system as well. And then in germ-free mice that have been deprived of microbiota, there’s increase of hippocampal serotonin, increase of plasma serum tryptophan, and a decreased tryptophan metabolism in k-neuronin, and decreased serum serotonin.
05:53 – Microbiome Disruption and Alcohol
All of these have been shown to be associated with human mood and anxiety disorders and psychosis as well. Alcohol is pretty bad for you. We all know that if people drink, however, alcohol use and consumption, as well as withdrawal, can cause neuroinflammation and immune dysregulation in the brain.
And alcohol can cause dysbiosis, which is the alteration in the composition of the microbiota, which has a negative effect on healthy microbe host homeostasis. Remember, those microbiota are commensal, which means they are friendly to the human body, unless, of course, you injure them. The microbiome in psychiatric disorders, per se, show the following relationships.
First, in major depression, there is a significant compositional differences compared to healthy controls. So certain bacterial genera were depleted, and you can see coprococcus and the vialista, and better quality of life was associated with fecal bacterium and coprococcus, and certain probiotics appear to be beneficial, especially the bifidobacterium and lactobacillus. Now, the lactobacillus is found in yogurt, as you know, but not all yogurts have, you know, the right type of lactobacillus.
There are dozens of them. In bipolar disorder, several studies reported, and some replicated studies include decreased level of fecal bacterium. Another study reported the genus Flavonifractum, which basically induces oxidative stress to be associated with bipolar disorder, and like MDD, the probiotics, lactobacillus, and the bifidobacterium can be helpful.
06:42 – Microbial Patterns in Psychiatric Disorders
Anxiety disorder, a wealth of preclinical studies, show a role of the gut microbiome in stress response and anxiety behavior in animals, and probiotics can help animals, but no strong data exists for humans yet, even though probiotics are huge sellers in the market. PTSD, the relative abundance of actinobacteria and leptosphera, all these phyla were decreased in PTSD patients. Schizophrenia and psychotic disorders, the microbiome in patients with first episode psychosis at the beginning, and in schizophrenia, are distinctly different from healthy subjects at the beginning of the illness, and treatment-resistant patients had the strongest difference in microbiota diversity.
Increased ruminococcus, and it was related to low negative symptoms, and rectiroidus was associated with depression. So, perturbation in the microbiome in psychiatric disorders have been found, and here’s a meta-analysis of 59 studies. There’s a lot of studies going on.
This number has actually increased since that meta-analysis. Significant decrease in microbial richness in bipolar disorder compared to controls, a decrease in phylogenetic diversity, and difference in beta diversity in major depression and psychosis compared to healthy controls, and a trans-diagnostic pattern. Now, this is, by the way, the latest advance in diagnosis in psychotic disorder is that there’s a trans-diagnostic pattern.
All of those psychotic disorders share many, many genes, and so they’re classified in DSM-5 as separate silos, but we find that they actually overlap a lot with regards to their genes. So, there’s a trans-diagnostic pattern of microbiota signatures in major depression, bipolar disorder, schizophrenia, and anxiety, and all of those share genes, along with autism, by the way. And this suggests that those disorders have a reduction of anti-inflammatory butyrate-producing bacteria.
11:49 – Microbiota-Targeted Therapies and Future Directions
And this butyrate is so important because it’s anti-inflammatory, and we find that many patients with psychiatric disorders, especially psychosis, have less of the microbiota that make, that produce butyrate, which can help reduce the inflammation. So, in schizophrenia itself, studies were done in various stages. In the prodrome stage, before the onset of psychosis, fecal bacteria show an increase in short-chain fatty acids, which can activate the microglia and produce psychosis.
In the first episode stage, there’s a low number of certain fecal bacteria, including bifidobacterium, E. coli, and lactobacillus, and there’s a high level of other bacteria like clostridium coccusoidus, which is really a bad type of germ. And after six months of antipsychotic therapy, you know, antipsychotic treatment, the above pattern was reversed. So, it looks like the antipsychotics that help patients get rid of delusions, hallucinations, also correct the diversity of the microbiota, which suggests that perhaps the lack of diversity may be contributing to the psychosis itself.
And other studies show differences between schizophrenia and healthy individuals as well, and the greater the difference, the more severe the psychosis and the less response to treatment. So, there’s degrees of, you know, loss of diversity. So, let’s basically end up by talking about what are the probiotics and prebiotics.
These are the attempts to basically correct the loss of diversity in the microbiota. Probiotics are actually live bacteria that are given to people, to patients, to supplement the bacteria in the gut. They are found in yogurt and fermented foods such as sauerkraut and kimchi, and can be single strains or blend of microbes.
They’re not similar. And prebiotics are dietary fiber that basically can feed the gut’s beneficial bacteria. Prebiotics are found in fruits and vegetables.
That’s why we always suggest that patients eat a lot of healthy foods and vegetables, and usually contain complex carbohydrates like in potatoes. They are fiber-rich and not digestible by the body and are less well studied than the probiotics. So, both probiotics and prebiotics are used widely.
Probiotics and prebiotics are generally unregulated with all of the literature about them and the buzz. Unfortunately, they are not regulated at all by the FDA or any other agency. And the probiotics represent a 37 billion market worldwide.
And there are over 120 species of lactobacillus alone, which many are used as probiotics. And the organisms represented in the commercial products rather can differ from batch to batch and from one product to the next. You can see it’s really a hit and miss sometimes with those products.
And the effectiveness of any given strain can also differ from one individual to another. That’s where individual differences exist as well. So, to summarize, the microbiota universe inside our gut can have good and bad effects on mental health.
This field of research is still in its very early stages, even though we have a lot of data, but it’s still minimum compared to what will eventually come. And it’s growing rapidly. And manipulating the diversity of the gut microbiota with interventions like healthy diet, probiotics, and fecal transplantation, which is gaining a lot of momentum, actually, promise to be novel therapeutic strategies for several psychiatric disorders.
And thank you very much for listening to this presentation.
