Connie: Good evening, dear friends. Thank you for joining us today on this beautiful Saturday evening. Today, we invited Dr. Hofstadter to our program. Thanks for being here, Dr. Hofstadter.
Dr. Hofstadter: Thanks for having me. I’m excited to be here. Hi everyone.
Connie: Gut microbes are a bunch of normal micro-organisms in the human intestine, such as Bifidobacteria and Lactobacilli. They can synthesize a variety of vitamins necessary for human growth and development, such as B vitamins including B1, B2, B6, B12, vitamin K, and cigarettes Acid, pantothenic acid, et cetera. In addition, they can also use protein residues to synthesize essential amino acids, such as aspartic acid, phenylalanine, valine, and threonine, et cetera. These gut microbes also participate in the metabolism of carbohydrates and proteins and can promote iron and magnesium, zinc, and other mineral elements as well, all are nutrients playing essential roles in human health, and not getting enough of these nutrients will lead to a variety of diseases. There are 10 trillion bacteria in the human intestines, which can affect body weight and digestive ability, resist the risk of infection and autoimmune diseases, and control the body’s response to cancer treatment drugs. Today, we are going to discuss these gut microbes and their’ relations with genetic or neurodevelopmental disorders.
Dr. Hofstadter: That was a great introduction. At the very beginning, there is an important concept that I want to start off, which is the gut-microbiota-brain axis. As its name implies, it’s a system composed of the brain and the intestine in the human body. It’s now widely accepted that host genetics influences gut microbiota composition. However, the surge in information generated from metagenomics, metabolomics, and bioinformatics analysis has emphasized the role and significance of gut microbiota in shaping host genetics, immune and nervous system through the gut-microbiota-brain axis. The gut microbe affects various brain functions, including our thoughts, emotions, and memory. Three-quarters of our body’s neurotransmitters are produced in the intestines, which is why the signals between the brain and the GI tract are essential for the establishment and maintenance of homeostasis, immune health, and hormone levels.
Connie: Yeah, a very important concept that is closely related to our topic today. Recent research found that any dysbiosis in the healthy gut microbial community can lead to overexpression of T helper cells, resulting in inflammation and disturbed central nervous system. So researchers think that the intestinal flora may be involved in regulating the immune system. But how can gut microbes affect the nervous system? Is there any specific evidence?
Dr. Hofstadter: Yes, there is. A large amount of evidence shows that there is a complex interaction between the host and the microorganism. Let me use a simple example to show you how gut microbe can affect the nervous system. The enteric nervous system drives the peristalsis of the intestine every few minutes through the contraction and relaxation of muscles, so that the environment in the intestine is regulated. The balance of the intestinal microflora is essential for maintaining intestinal health and preventing chronic inflammation. Under normal circumstances, healthy gut microbes are adapted to this dynamic environment, and the composition of these microbes may be affected by the enteric nervous system.
Connie: But there are still some problems that need to be solved. Specifically, how do these gut microbe and nervous systems get connected?
Dr. Hofstadter: Well. Intestinal microbes can interact with the brain in three particularly important ways. Starting with the first one, gut microbes can directly pass through the pneumogastric nerve and the neural network that surrounds the intestine and then transmits signals to the brain. And then gut microbes can also affect the nervous system through immune cells that exist in the intestine and move to the brain, which is what you mentioned earlier. The last method by which the microbes use to interact with the brain is that the metabolites produced by intestinal microorganisms can firstly enter the bloodstream, then enter the brain, and ultimately affect behavior. When certain metabolites of gut bacteria are injected into functionally healthy mice, they can cause anxiety and abnormal behaviors related to autism. This further supports the possibility of microbial metabolic molecules connecting the brain, intestines, and neuro-emotional circuits in the neuroendocrine metabolic stress response system.
Connie: Very interesting. You mentioned that certain metabolites of gut bacteria can cause anxiety and abnormal behaviors related to autism in mice. Does the same situation apply to humans? Because you know, several disorders such as intellectual disability, communication disorders, autism spectrum disorder, attention-deficit/hyperactivity disorder, conduct disorders, cerebral palsy, impairments in vision and hearing, schizophrenia, Parkinson’s, resulting from abnormal brain development or impaired central nervous system falls under the category of neurodevelopmental or neurodegenerative disorders.
Dr. Hofstadter: Yeah that same applies to humans. Traditionally, the cumulative effect of genetic, biological, psychosocial, and environmental factors disposes to the development of such neurodevelopmental disorders. But there is research verified that any disturbance in gut microbiota composition induced due to bacterial infection or antibiotic therapy has been connected as one of the probable contributors to autism. Interestingly, autistic patients frequently suffer from gastrointestinal disorders, which, you know, can be pointing out towards the role of gut microbiota in gastrointestinal pathophysiology of neurodevelopmental disorders. One such recent study demonstrated altered bacterial and fungal community structure in a cohort of autistic individuals.
Connie: Do you think it is possible that we can utilize the results of these studies and apply probiotics to treat neurological diseases?
Dr. Hofstadter: Definitely we can. Some researchers reviewed the potential management of autism spectrum disorder by targeting the microbiota-gut-brain axis through probiotic intervention. In a double-blind, placebo-controlled clinical study, supplementation of probiotic Lactobacillus Plantarum improved the population of lactobacilli or enterococci and reduced Clostridium in the intestine of autistic subjects.
Connie: In other words, the possible mode of probiotic intervention in the management of autism could be mediated by the microbiota-gut-brain axis. Can you tell us the mechanism behind it?
Dr. Hofstadter: Yeah. The precise mechanisms include the fine-tuning of circulating neurotransmitters and neuroimmune related autism biomarkers within the axis, such as myeloperoxidase, improved integrity of the intestinal barrier, and via altering serum metabolites. By the way, myeloperoxidase is a marker for inflammation and oxidation in autistic individuals.
Connie: It’s commonly known that depression is one of the leading factors for mood and psychiatric disorders targeting almost every sector of society in both the developed and developing world. Emotional depression can range from gloomy to grief, low self-esteem, depression, and even pessimism, suicide attempts or behavior, even stupor, some cases have obvious anxiety and motor agitation. In severe cases, psychotic symptoms such as hallucinations and delusions may occur. What I’m really trying to get to is: Does depression also have a relation with the microbiota-gut-brain axis pattern?
Dr. Hofstadter: Well, with depression gets more serious as our society advances, the relationship between the entire genome of gut microorganisms, depression, and anxiety has been increasingly evaluated in the past few years. Stress-induced neurological changes in the brain have been strongly associated with depression and its associated complications. Gut microbiota through the gut-brain axis manipulate the hypothalamic pituitary adrenal axis and affect mood through the pneumogastric nerve and endocrine system. Many studies demonstrated the beneficial effects of probiotic administration on depression and its related complications in animal and human subjects. A study administered L. helveticus NS8 to Sprague Dawley rats. Researchers found that stress induced behavioral deficits were improved and the levels of corticosterone were attenuated. In another study, L. helveticus R0052 and Bifidobacterium longum R0175 prevented stress-induced changes in neurogenesis, barrier integrity, and stress reactivity in rat models.
Connie: That sounds promising. And I have heard an amazing result that mice treated with probiotic lactobacilli significantly decreased the levels of kynurenine in blood. Take into account that kynurenine is a circulating metabolite and is known to promote depression. However， the anti-depression efficacy of probiotic strains and their metabolites has not been validated in human clinical studies, because there is only a handful of published studies. Kind of disappointing.
Dr. Hofstadter: Yeah, definitely. Few recent reports proposed that altering gut microbiota composition by probiotic administration can be a viable adjuvant treatment option for subjects with major depressive disorder. Anyways, after researchers reviewed the available literature on the efficacy of probiotics for depression management in human subjects, they found the overall positive effects of probiotics on depression symptoms. Probiotics may be more effective against depression symptoms when administered alongside antidepressants.
Connie: Then what about their effects on Parkinson’s and Alzheimer’s diseases? Traditionally, Parkinson’s and Alzheimer’s diseases are among the neurodegenerative disorders that are generally recognized closely relating to aging. Are these two diseases related to gut microbes?
Dr. Hofstadter: Of course. Let me put it simply. The first symptom of Parkinson’s disease patients is usually constipation, followed by loss of taste and smell. These gastrointestinal disorders exist long before symptoms of motor neuron dysfunction, such as tremor or gait disturbance, appear.
Connie: But Alzheimer’s disease and general cognitive decline are traditionally characterized by significant changes in the brain, immune dysfunction, and increased oxidative stress. It seems like, you know, that there is no obvious evidence that the gut microbe can regulate the nervous system.
Dr. Hofstadter: Not exactly. Like you said, Alzheimer’s disease and general cognitive decline are characterized by significant changes in the brain, immune dysfunction, and increased oxidative stress. In various animal model experiments, these factors can be affected by diet and gut microbes. One of the important links involves the neurotrophic factor, which is a protein responsible for protecting and supporting healthy neurons. The production of this neurotrophic factor depends on gut bacteria and is significantly reduced in Alzheimer’s disease patients. As we age, the composition of the gut microbe changes, which may be related to neurodegenerative diseases. Furthermore, reactive oxygen species-mediated oxidative stress contributes to neuroinflammation. Brain areas affected in neurodegenerative disorders are sensitive to oxidative stress.
Connie: So, do probiotics affect neurodegenerative diseases by affecting the aging of the host?
Dr. Hofstadter: Gut microflora, particularly probiotic strains, are known for their strong antioxidant ability rendering protection to cells prone to oxidative stress. In general, aging is associated with a shift in gut microbial diversity. There have been reports that a significant variation is in gut microbial diversity of elderly patients suffering from neurodegenerative disorders. The GI tract also supports neuronal development and maintenance through the gut-brain axis.
Connie: So you mean it’s possible that following the management of gut microflora might help in the management of these neurodegenerative disorders?
Dr. Hofstadter: Yes, it is promising. Several microbial neural metabolites, biogenic amines, phenolic compounds, fatty acids, hormones, neuropeptides are known to contribute to managing such disorders. In a recent randomized, double-blind, placebo-controlled trial, individuals with Parkinson’s were administered probiotics for 12 weeks, following which significant changes in metabolic profile, such as reduced C-reactive protein and malondialdehyde and increased glutathione peroxidase.
Connie: Then what is the mechanism of this process?
Dr. Hofstadter: Well, actually there might not be an exact mechanism of this process. One of the possible routes through which gut microflora impact Parkinson’s can be through reducing the expression of alpha-synuclein in the gut and checking its spread to the central nervous system. Understanding the link between gut microbiota composition and genetic disorders, particularly those linked to the central nervous system, and identifying strains or consortiums of probiotic strains having promising therapeutic effects, can be a novel approach for preventing or managing these disorders. Yet there is still a long way to go.
Connie: That makes sense. After all these years, the gut-brain axis has indeed gained wide interest due to the emerging key role of gut microbiota in several disorders regulated through the brain and central nervous system, expanding probiotic efficacy in chronic disorders apart from their established role in gut disorders. Okay, that’s it from us today. I hope you enjoyed our episode as much as I did. Thanks, Dr. Hofstadter, for your time and input. And thanks everyone for listening. We will see you next Saturday.
Dr. Hofstadter: Thanks, everyone. I hope we will see you next time.