Hello, good afternoon. I hope your conference is off to a good start and you're having a good day. My name is Andy Benson. I'm part of the ANA Professional Development Committee. Before we begin, just a few same reminders. Please, I hope you're using the meeting app. There's lots of information there. Also, most importantly, it's the way that you're going to claim and submit your CE credits. So the evaluations will open up 15 minutes prior to the end of each session. We recommend that you complete these immediately after each session. You have until Monday, September 9th at noon Pacific time to make sure that you complete all that. After that, you will no longer be able to claim any CE credits. For those of us joining virtually, you'll be able to have the same information on the schedule page of the website within each separate live stream session. So you can do that. At the end, you can come up to the mic with questions or you can submit your questions on the application, on the app. So lastly, mark your calendars for the 2025 Annual Congress in Nashville. The abstracts will open up August 14th. There's more information online at ANA.com, gives you all information and a video on how to submit and construct an abstract. So now it is my pleasure to introduce our speaker, Dr. Gary Hugh. Dr. Hugh is an assistant professor and director of research and global outreach in the development of nurse anesthesia with Virginia Commonwealth University. So please join me in welcoming Dr. Hugh as he presents Gut Feelings, Microbial Insights in Anesthesia and Pain Management. Thank you. Thank you, Andrew. Thank you, Andrew, for the introduction. And hello, everyone. Good afternoon. Thanks so much for coming to this session. I feel so grateful to have this opportunity to share this topic with you and everyone in the auditorium and also many others who join us virtually. Actually, I have been following up on this topic for many years, why the NINR, the National Institute of Nursing Research, changed its funding focus to symptom management. I have noticed many researchers in the general nursing area changed their focus to microbiome research and explore the mechanism of the gut microbiome in different symptoms. And last year, I found there was a presentation at the ANA Congress to introduce sight, gut health, and chronic pain. It attracted a lot of attention. Also, probably you have already noticed that in our daily lives, there are more and more podcasts, public lectures, and even products related to the microbiome and health. So I feel even though it is still a very new application in our clinical practice, in our field, it will be great for us to be aware of these concepts and to see their potential applications in our anesthesia practice and maybe create some collaborations together, not just the researchers, but the collaborations with clinicians, with CNAs, because I feel participant engagement research is very important. If we can engage stakeholders early in the research, we can make research more meaningful to you and more useful to our clinical practice. So I have no conflict of interest with the content presented in this session. And in this session, I really hope to go over some of the history briefly about the medical microbiology and also explain some of the key concepts related to the microbiome and also how they communicate with our brain. I hope to look at the application of the human microbiome research in medicine with you and also review the current evidence of the microbiome research in anesthesia. So early discovery of the microorganisms can be attributed to Anthony van Leeuwenhoek in 1670 in Dutch. He discovers diverse microorganisms of various shapes from water, mud, skin, tooth surface, or even dental plaque using his simple microscope. Also, he was the first person to identify the first attribute of microorganisms, biofumes. So you probably have been very familiar with this concept, biofumes. It is assembly of the microbial cells that are enclosed in connecting matrix. The role of the biofumes has been found to be one of the major factors that significantly lead to antibiotic resistance. Bacteria living in biofume can have 10 to 1,000-fold increase in antibiotic resistance compared to the similar bacteria living in a loose structure. So many hands make light work if they are coordinated in the structure like the biofume rather than a loose structure. So the next discovery, actually, this has still influenced our current knowledge and practice significantly is from Robert Koch in 1884. He developed a method for capturing microorganisms using glass plate and agar, a jelly-like substance from the seaweed. His method allowed him to observe microorganisms without having them grow in liquid, which can make it very difficult to see under the microscope. In current labs, we are still using his method, glass plates and agar. Also, he developed the concept about the pathogenicity, which explains the origin of human and animal diseases as a consequence of the microbiome infection. It was an important milestone in the microbiology. Pathogenicity refers to the ability of microorganisms to cause disease. These findings share the focus of the research community and the public on the role of the microorganisms. People notice that microorganisms could be the disease-forming agents. They should be eliminated. Based on the concept of pathogenicity, Robert created the first catalytic criteria for microorganisms and a disease. There are four essential requirements we need to determine a particular microorganism causes a specific disease. First, the microorganisms must be observed in all cases of the diseases, and it should be absent in healthy cases. As shown on the slide, the mouse with the disease has the microorganisms present in its tissue, while the healthy mouse does not. And a second criteria is the microorganism must be able to isolate it in a pure culture from the disease host. And then when the culture microorganisms is introduced again into a healthy mouse, a healthy host, it must cause the same disease observed in the original host with the disease. And the last requirement is the microorganisms must be re-isolated from the experimentally infected host and shown to be the same as the original microorganisms. These are the four criteria. Only meeting these four requirements, we can determine a direct cause or effect relationship between microorganisms and a disease. In the current research world today, we still use this method. We have developed many scientific approaches to determine the causality between specific microorganisms and the disease. However, all of them still use these criteria, these four requirements as a foundation. So in the past century, there are many studies already found only a small proportion of the microorganisms are associated with disease or pathogenicities. It has totally shifted paradigm, shifted paradigm or original concept about the microorganisms is the disease-forming agents, changing the mind, because people find that the overwhelming majority of the microorganisms in the human are essential for system functioning. For example, the gastrointestinal withholds the largest microbiome community in our human body, around 80 to 85 percent, which is essential for maintenance of the physiological process for us, way beyond our own scope, our own cells. For example, microorganisms help with immune system, cell growth, blood vessel formation, nerve function, hormone regulation, bone health, and energy production. Microorganisms are involved in biosynthesis in our body, help with creating vitamins, hormones, and the chemicals that transmit signals in our nervous system, and microorganisms help with metabolism, help break down the big compounds of the proteins, digest different parts of the food, process the medications, and remove the chemicals that are foreign to our body. The reason we can study microbiome should be attributed to this great international collaboration, the Human Genome Project in 1990. This is an incredible journey of discovery led by researchers from around the world. In those years, the researchers achieved something truly remarkable. They created the first complete sequence of the human genome. This means they mapped out every part of our DNA. This accomplishment has had a huge impact. It gave us a kind of foundation understanding of the human blueprint, and it greatly advanced our knowledge of human biology. And from this study, they found more than 3 billion nucleoside-based pairs that make up a human DNA, around like 22,000 human genes, and a 99% genetic similarity between all humans. And they identified the structure, organization, and function of the human genes. Also, they found the genetic contributions to different diseases. Before we go to the microbiome, let's look at this and refresh this kind of basic concept together, genomics. In 1953, James Watson and Francis Crick made a groundbreaking discovery about the structure of DNA. They proposed that DNA is shaped like a double helix, which is like a twisted ladder. The steps in this ladder are made of pairs of DNA bases, and genes are a short section of the DNA. Chromosome, a structure within the cell that contains a person's genes, and it strengthens the DNA structure to keep them safe and stable in our body. And genome is the term to kind of include all of the information, all of the genetic material in our body. If we use some simple example, we can consider the base pairs of the DNA is the alphabet letters. DNA is the words. Genes is the sentences. Chromosome is the paragraphs. And the genome is the complete book, including all of the genetic information. So for the traditional definition for the microbiota or the microbiome, microbiota refers to the community of the microorganisms, all of the microorganism cells themselves. And a microbiome refers to the genomes of these microorganisms, which is the genetic materials and the genetic information of all of these microorganisms. So due to the successful HDP model and updated the DNA sequencing technologies, Human Microbiome Project 1 started in 2007. It's another huge international research collaboration. HMP1 was a groundbreaking study into understanding the different microbiota we have and live in our body. And also, this project is a baseline study focused on the attributes of all of these microorganism communities from different body sites in healthy population. It maps out the composition of these microorganism communities, how they function, and what kind of biochemical process and the metabolic routes they use to sustain themselves, grow, and interact with their environment and with their host, which is us, the human body. Besides these important findings, one of the key insights from HMP1 is that it extended our definition, actually, what it means to be the human. We are not just made of our own cells, but also the trillions of microorganisms that live with us and play a crucial role in our health. So human microbiome is now considered to be our super organ. The number of the microbiota cells in the human body is estimated at 10 times the number of our own cells. And the number of the different microbiota species we have already identified living in our body is huge. More than 10,000. And the number of the microbiota genes in human body is 100 times larger than the human genes we have. And the huge bacteria or the microorganism community is highly variable between individuals. While the human genome is 99% identical between any two individuals, the composition of the microorganisms between two individuals difference considerably, and even between the twins, or even between the family members who live in the same living area. And in addition to being variable, the composition of the microorganisms is also very dynamic. The changes in our body over the time, not only the scale of the years, months, but also days in response to aging, diet, occupation, physical activity, differently the medication they receive, like anesthesia and analgesics. Due to the success of the Human Microbiome Project, the DNA sequencing technology, multiple techniques for analyzing microbiota and microbiome have advanced to allow for more advanced DNA sequencing and really reduce the cost. And the good microbiome studies continue to benefit from all kinds of powerful technology, like the AI, like machine learning, and they allow for more comprehensive analysis. So in 2014, they started another centralized funded project. This project, project two, was designed to explore host and microbiome interactions, and using all of these advanced technologies to gain a more holistic view of interacting mechanism over time, not only in healthy population, but in the population, the pre-terminology birth, pre-term birth, inflammatory bowel diseases, and pre-diabetes populations. It's really focused on longitudinal cohort studies to understand microbiome by own and changes over the time. So in the first three years of this project two, research on the human microbiome has advanced from a fledgling field to a flourishing area of medical research. In those three years, many institutions and companies actually start doing human microbiome research by themselves. So more than $1.7 billion outside of this centralized funding was invested annually on the microbiome research. So there is no reason to have a centralized microbiome project anymore, so they decided to close the centralized funding on human microbiome project and expect it. Even they closed the funding, human microbiome research is still growing. And up to now, the role of the gut microbiome in iterative Bost syndrome has been the best study area among all of the diseases, including the mechanism, association, causation, and the clinical application in that research. Based on many of the new research findings, the concept of the microbiome has also been advanced and updated. So the most definition regards the microbiome not only as the genome information of the microbiota, it becomes a more comprehensive concept, including microbiota, all of these microorganisms themselves, but also the theater of the activity includes the structure elements in microorganisms, genetic information, external environment, microbiota metabolites, and the metabolites are sometimes called the microbiota products from the microorganisms themselves. And definitely all other interactions microorganisms have in that environment with the host, with the environment. So in that definition, the microbiota dysbiosis now is defined as an imbalance in the microbial communities resting in our particular environment, such as the gut, skin, or oral cavity. This imbalance can result from a reduction in the microbial diversity, and this diversity could be overgrowth of the harmful microorganisms or sometimes could be the depletion or reduce of the beneficial microorganisms. Because of the disrupts, because of dysbiosis, it will influence the normal theater of activities of microorganisms, including the structure elements, genetic elements, environment conditions, their functions, their interactions. In this way, microbiota dysbiosis potentially leads to various health issues. So now in the microbiome research, identifying a common set of stable components, a core microbiome has been a major goal in human microbiome research for decades. We know it's different from, you know, for different individuals, but then try to find some common or stable components among us. The core human microbiome is kind of the set of the microbiota and their theater of activities present in the all or the vast majority of humans. And the changes of the core microbiome in our body will cause the dysbiosis, which leads to disease status. And these changes could result from a combination of the factors, such as the host gene information, host physiological status, health or disease or stressful, host lifestyle, eating, exercise, sleep, and also our living environment. So in studies, there is still a debate on how we can define the concept of the core microbiome. Currently, there are three different approaches. The first one is based on the community. A community based definition of the core microbiome is those microorganisms consistently found in the study host population. A core microbiome in that definition consists of the microorganisms that are common to multiple communities across different hosts. A different definition, a different approach is the function based. It's actually more realistic. It's focused on the set of the function rather than the community. This approach really to identify the multiple sets of microorganisms to identify the multiple stages. Sometimes they can fill into the same category because they provide the same functions. For example, in our human gut, multiple microorganisms are responsible for the degradation of the complex carbohydrates and the production of the specific healthy chemicals in the body. In that case, a specific functional capacity rather than the presence of the microorganisms could define the core microbiome. And there is a third approach, kind of advanced based on these two. It's called the ecological perspective. So people in that approach think not those, you know, the microorganisms who interact with our human host, those who do not interact with us directly, but contribute to the stability of the core microbiome to be considered as part of the core microbiome. So we saw in the studies a rapidly growing body of the evidence suggests the association between the human microbiome and various health conditions. This includes the gastrointestinal disease, but also many other medical conditions not in our gut. And also the neurological and the psychiatry conditions are related to the microbiome. In the field anesthesia, evidence on the interactions of gut microbiome with the central and the periphery nervous systems offers many new mechanisms insights for us, which are really relevant to our work. And we will introduce the current evidence on microbiome in anesthesia shortly. So, you know, although we know there are so many associations from the studies between the human microbiome and the various diseases, it should be noted that the association from a specific microbiome to the certain disease does not establish a causal relationship. Microbiome dysbiosis could be a cause of certain diseases, definitely. But in some cases, they might be the consequences of the disease. And also in some cases, and that's kind of the possible, is both the dysbiosis and the disease are actually caused by a third factor, diet, medications, physical activity, and many others. So this is one of the reasons we need to, you know, have more research and also follow the criteria for establishing the causality between specific mechanisms and the disease to explain the findings, because association then mean cause and effect relationship. And many animal models have been invented to make the research process possible and help us to identify the mechanism. For the project, for the human microbiome project, it not only contributes the research findings that are important to our health, but also provides another valuable perspective on the One Health Initiative. In 2017, a World Health Organization started a One Health Initiative It's a kind of integrated, unifying approach that aims to balance and optimize the health of people, animals, plants, and ecosystems. It recognizes the health of the humans, animals, plants, and ecosystems are closely linked and interdependent. By adding the microbiome research findings to this area, we might have another way to really think about these links and connections. Many changes in the wider environment, in the ecosystems, might not influence our health directly, not influence our body directly, but might significantly influence another huge species which live with us, or actually live in our bodies, the microorganisms. There are changes, the microorganism changes in our body will have an impact on us. So the next question is, how the changes of the microorganisms in our body, especially in our gut, will influence our mental health, and of course our skin, kidney, maybe, you know, the heart diseases. The mechanism has been studied. The connections between the gut microbiome and other organs have been identified and named as gut organ axis. Healthy microorganisms in our gut leads to healthy functions of our organs. Dysbiosis of the gut microbiota might cause some diseases and conditions in our organs. So among all of these gut organ axis, I believe this one is probably the most interesting to us. For CRNAs, gut microbiome and gut-brain axis will add another dimension to our current understanding of the central nervous system. What we eat, the way we are born, like whether via the nature birth or C-section, our environment, surroundings, physical activities, medications, including anesthesia and analgesics, our genetic makeup, all of these can affect our gut microbiome. And then via the mediating effect of the gut-brain axis, they will influence our mental health, cognitive behaviors, social interactions, neurological functions, and even eating behaviors and appetite. The gut-brain axis also has a moderating effect on the direct impact of these causes or interventions on the outcomes. Sometimes it's kind of scary. I have a sweet tooth, but sometimes I wonder whether I have a sweet tooth or the microorganisms in my body prefer, you know, the sweet food, and they need some sweet treats. It is not a research question anymore. It is like a classic story in a science fiction or horror movie. The microbiome doesn't just help to keep our brain functioning by helping to provide the nutrition from the food. Now, they might also be the real boss for us to control our thoughts and behavior. Definitely, using the word control is too much, but the gut does impact on our brain via the gut-brain axis. And the gut-brain axis is complex, and you can tell from this diagram, it is a complex biochemical communication between the gut and also the central nervous system. Currently, studies identify three major pathways for the communication. The first pathway is gut microorganisms and their metabolites can interact directly with the intestinal immune system. All of these dysbiosis shapes the local immune system's response toward poor inflammatory states. These local immune cells can lead to functional changes that extend for our gastrointestinal system and influence the immune cells in our brain. A second pathway is these gut microorganisms and their metabolites can interact directly with different endocrine cells in our gastrointestinal tract to release hormone or neurotransmitter into our circulation system, or the hormone and also the neurotransmitter as part of the gut metabolites can pass the gastrointestinal into our circulation system. Both will influence the neural indoor system in our brain. And the third pathway is the gut microorganisms and their metabolites can interact directly with our enteric neuron system. The activation of the peripheral nervous system will continue to stimulate our central nervous system. So the gut-brain access provides a lot, you know, the mechanisms for us and is supported by many studies on this mechanism. Some microbiome research has been translated into applications and there is a report showing the human microbiome market in the United States estimated to increase from the 164 million in 2022 to reach 1.5 billion by 2027, which in three years from today. It's kind of the growth rate is the 50, more than 50 percent. Now these are seven kind of applications of the microbiome research in our daily life. For example, the clinical assessment and interventions, and you might see some personalized lifestyle coaching and a disease prevention program based on the microbiome. Functional foods and the beverage, not only the caffeine, vitamins, now they add some of the microbiome in this beverage of food. And the personal care products, because we have the also microbiome in our skin, so there are more personal care products to promote the healthy of the skin microbiome. Medication development, research, and also definitely for one health initiative, not only for the human health, but for the environment, for the plants, for the animals. So for us, for healthcare professionals, the application of the microbiome research in the clinical assessment and interventions definitely is the most relevant to our work, and it will definitely influence the personalized medicine. Let's use anesthesia as an example. So in the future, we might add the microbiome as important indicator in addition to other individual information to help us assess the level of different risks. To determine the most effective anesthetics and also anesthetics with the fewest side effects. And I use specific intervention maybe to change the patient's gut microbiome to help them to have a better preparation for the anesthesia. So as the DNA sequencing and the microbiome metabolite testing has become more advanced and the cost has become less expensive in broad the medicine area or the general medicine, there has been some applications of the microbiome research in clinical assessment. So people get one time fecal sampling or multiple fecal sampling over time. Detection of the changes in the microorganisms or the changes in the microorganism metabolites allows for the prediction, screening, diagnosis, or prognosis of the disease, like cancer, like the irritable bowel syndrome, fibromyalgia, stroke progress, acute coronary syndrome. And in recent years, the microbiome has been studied to understand how microbiome can interact with the medications. The gut microbiome assessment might help us to determine who might benefit most from certain medications, who might have strong tolerance to or reluctance to some medications, and who might have the significant effect if they receive this type of the medications. So over the past few decades, pharmacogenomics has become a well-established field that studies how human genome information affects the biotransformation, metabolism, and action in our body. One of the best examples is the CYP gene macros. I think you're probably already very familiar with these. So people with different CYP gene macros, they might have totally different responses to pain medications. So in the future, we might, you know, have another area is the pharmacomycobiomics. It's a long term. Forgive me. Yeah, so for this new area, and we know we have all of the these antibiotics medications can influence the microorganisms in our gut or other areas. Now, we know this for a long time, but for this new kind of the area, so more evidence has shown that, you know, non-antibiotic medications can actually also influence the gut microbiome. And a number of, a huge number of the gut microorganisms can contribute to the gut microbiome to the drug biotransformation, metabolism, and action in our body. For example, on the diagram, the medication antacapone, which is used with other medications in treatments of Parkinson's disease, more than 60 groups of the gut microorganisms are involved in this drug metabolism. And the medication actually can, you know, affect around 10 groups of the microorganisms in our gut. There are four different ways how gut microbiota can interact with medications to influence the treatment effectiveness and also side effects. Two direct ways, as we introduced in the previous slide, for the medication to treat, you know, the Parkinson's disease, drug can alter the compensation and metabolites activity of the gut microbiota, as kind of presented on by the arrow on the diagram, pointing from the drugs to the gut microbiota. And there is another pathway, direct pathway, is the gut microbiota and its metabolites can influence the metabolism effectiveness and the side effects of the drug, which is shown by the arrow pointing from the gut microbiota to the drugs. In addition to these two direct pathways, there are another two indirect ways. Drugs have effects on our body and change our host environment, which then influence gut microbiota. And the microbiota might influence our liver function and also maybe some enzymes function, which then influence the drug biotransformation in our body. So this diagram is showing another area, which is the gut microbiome interventions. This diagram just published as part of a literature review in a journal in May 2024. It did an excellent job to summarizing the gut microbiome interventions and putting them in these three categories, microorganisms supplementing, supplement and a microorganism suppression and a metabolites modulation. So in the first category, all of the interventions aim to increase the beneficial microorganisms. First, we can use the probiotics or the prebiotics or the nutrition plan to increase the beneficial microorganisms in our gut. Do you know the difference between the probiotics and the prebiotics? So for the probiotics, it's kind of to give you the beneficial microorganisms directly and the prebiotics is the kind of the food for the good microorganisms in your body. So that's the difference between these two. And besides these, people feel, you know, no matter probiotics or the prebiotics or nutrition, they are not, you know, have the immediate impact. They will take some time. So they actually, scientists invented some genetically engineered microorganisms which are more specific and targeted, which is the genetic edits the microorganism put into your body to provide beneficial metabolites and to help the, you know, healthy for your body. And there's another approach in that category. It's called a fecal microbiota transplantation. It's kind of, you know, using the fecal sample from the healthy donor and different to do some of detailed process, not directly, but do some detailed process and the transplant to the patients with the disease. It's super effective. And I share this with one of my CNA friends and she said that she already gave some anesthesia to the patient who did this, the fecal transplantation. So it's very effective in the patient, for example, for the C difficile infection. And many studies already showed the effectiveness because they have the harmful microorganisms and all of the environment. So they need a whole transplantation to build the whole system or environment. Although it's not being studied in other areas, but it's kind of the theoretical effective in other microbiome related disorders, but definitely need more research support. And for second category is kind of to reduce the harmful microorganisms. We can use various bacteria and RNA or DNA secret techniques to make change, to kill those harmful microorganisms or to use the DNA editing techniques to change their DNA to make them die. The harmful microorganisms in our gut or our body. And the third approach, they feel, you know, microorganisms, we need the microorganisms, sometimes we need their gut metabolites, metabolites from the microorganisms. So maybe we can skip the microorganisms directly. We just provide the metabolites to modulate all of these metabolites. So that's the different interventions in the third category to add or change the metabolites from the microorganisms in our gut. So in field of anesthesia, we need more microbiome research. It seems like microbiome might help us address some long-lasting anesthesia question. Why are patients' response to anesthetics and analgesic medications so variable? Why do certain patients develop the postoperative cognitive dysfunction that some patients might develop chronical post-surgical pain? So let's look at these together. What is the current evidence of the gut microbiome research in the field of anesthesia? In this presentation, I hope to focus on two topics. One is the gut microbiome interactions with anesthesia and opioids. And the other is the role of the gut microbiome in patient outcome following anesthesia administration, including the cognitive dysfunction and also chronic pain. For interactions with the anesthetics and the opioids, I only identify a few studies. Most of them are actually in the preclinical or animal studies. Some of them in human studies, but much fewer than those in animal studies. We definitely need more research on this topic and to conduct more observational studies to understand the interactions between the microbiome with these medications and RCT study to test its cause and effect relationships. So based on the current evidence, the interactions between opioids and the microbiome are all bidirectional, by two-way communications. So seven animal studies and three human studies demonstrate that the composition of the gut microbiome could be affected by exposure to anesthesia. It's kind of one of the publications. It's kind of a discussion paper, but also including some of the studies. So in that title, it said anesthesia bullies gut microbiome because microbiome can be influenced by the anesthetics, no matter how long exposure to the anesthetics. So the significant effect from the anesthetics is from the inhalation anesthesia, and the lasting time could be 21 days. Sedatives or Propofol has less influences and less lasting time for the changes in our microorganisms composition. So there's one animal study to explore the gut microbiome and the effectiveness of the anesthetics. So this study found the microbiota dysbiosis can lead to a slow onsite and delayed recovery under the pantobacterial anesthesia. And even we try to improve the microbiota dysbiosis, it did not reverse the medication effect. There are six animal studies work on the opioids on the gut microbiome in para-operative settings. So they found as early one day after morphine or oxycodone treatment, changes in the gut microbiota composition and also the metabolites had happened. And there are some conflicting findings about if we stop these medications, whether the microbiota composition will change. It's kind of the conflicting findings. For morphine, all of the composition and function of gut microbiome were partially reversed. But for the oxycodone, changes in that did not, and it's consistent. Two animal studies work on how the gut microbiome can influence the opioids. And they found the dysbiosis decreased the effectiveness of the morphine analgesic. And we use, this is different from the anesthetics, so we try to improve the dysbiosis and provide the probiotics, especially with these two beneficial microorganisms, B and L. When we try to improve this and use this intervention, it can increase the effectiveness of the morphine. So those studies are specific for opioids use in para-operative settings. If we change the setting to the chronic opioid use, there are much more studies in animals and much more studies in clinical settings in human. In the populations who have opioid use disorder or chronic opioid use, they have microbiota dysbiosis, which can be featured as increase the harmful gut microorganisms and decrease the beneficial gut microorganisms, which are the two we just mentioned in the previous slides. And these changes do not, you know, decrease the integrity of the gut epithelium, but also increase the neurons of excitability and really desensitize opioid receptors in our brain through the gut-brain axis. And desensitization can result in a reduced response to the opioid, which can cause a decreased effect and increase opioid tolerance. If we look at the studies in the patient outcomes relating to the post-operative cognitive dysfunction, we know the rate of patients having the POCD can be varied depending on the type of the operation. On average, 10% to 50% patients have post-operative delirium within the one week of the surgery, and 20% to 30% might have the delayed neurocognitive recovery within 30 days, and 10% to 14% might still have the dysfunction after six months. And for this population, there have been many studies to identify the indicators, the risk factors, and also provide different mechanism explanations. One of the most common mechanism explanation in recent study is the neuroinflammation. Neuroinflammation is the mechanism to lead to the, you know, cognitive dysfunction after the surgery. The microbiome research kind of confirmed the mechanism, and it illustrates how gut microbiota dysbiosis can make neuroinflammation even worse through the gut-brain axis. The gut microbiome can add another harmful pathway via the systematic inflammation. Microbiota, the metabolites, cytokines, or other inflammation factors induced by the gut microorganisms and also microbiota metabolites leaked from the gut to our circulation systems, they will pass the blood-brain barrier to influence our central nervous system and make the neuroinflammation worse. In terms of the chronic post-surgical pain, the incidence of the chronic pain is also varied with the type of the surgery, but the mechanism currently, a periphery pain sensitization and essential pain sensitization are the current two common mechanisms to explain this clinical problem. Many risk factors, including the factors from patient, anesthesia, surgery, and perioperative pain conditions have been identified from multiple studies and are synthesized in reviews. One international team combined all of these factors into one clinical tool. They first developed and tested this tool in 2,900 patients. They identified six clinical predictors and retested in 1,200 patients to confirm the validity of these six clinical predictors. And in the recent publication, they actually did a search on human genetics and a look at the microbiome research. The reason they didn't add these two indicators in these six predictors, they still find these studies are very primary, especially for the microbiome research. So early evidence from four translational studies in humans have already done in this area and to kind of explore the mechanism of the gut-brain axis in the chronic pain, especially for the chronic post-surgical pain, and found the connection between it. The microbiome might impact the incidence of the chronic post-operative pain. These two studies on the slide are actually perfect examples showing the four requirements for determining the causality between specific microorganisms and diseases. First study explored the association between the composition of the gut microbiome and a chronic pain after surgery for breast cancer. So in this case control study of 132 women undergoing surgery for breast cancer, gut microbiota composition was significantly changed among the 66 women who developed the chronic post-operative pain at three months as compared to the 66 patients who were pain-free. They found the association or differences between these two groups in the composition of the microorganisms. And they did the second study, didn't stop there to only identify the association. They conducted another study. So the second study tried to explore the potential cause and effect relationship of the gut microbiota using the fecal transplantation from the chronic post-operative pain and the pain-free patient to gene-free mice undergoing the spinal nerve injury. So the mechanical pain threat decreased more and the pain sensitivity increased more in the mice receiving the fecal microbiome transplantation from the chronic post-operative pain group than from the healthy controls. That means these specific microorganisms do, you know, potentially cause the chronic pain. The microorganisms in the disease patients, in the patients with the chronic pain, when they transfer or translate it into the mice, they developed the chronic pain. Okay, so although we only have a very small number of the, you know, the studies on chronic post-operative surgical pain, and there is a very good number of the studies on other types of chronic pain, I recently published this in my review and a meta-analysis indicating a huge number of the patients showed that the gut microbiota compensation and their activities in the patient with this chronic pain have statistically significant changes compared to the controls who do not have chronic pain. So after we learn all of this, you know, current evidence, what will be the future for us? What do you think will be the, you know, the potential application of the microbiome research in our clinical practice? And this is an interesting study just published a few weeks ago, and the researchers at the University of Chicago, they developed a new generative AI that models the infant microbiome, and this digital twin of the infant creates a virtual model that predicts the changing dynamics of the microbiota species in the gut. Now how they change as the infant develops and interacts with all of the medications, using the data from the fecal samples collected from the preterm infants in the NICUs, researchers use these algorithms to predict which babies were at risk for decreased cognitive function. And surprisingly, and maybe amazingly, the accuracy is 76 percent using the digital twin and using the fecal samples. So based on the evidence review, we can tell we definitely need more microbiome research in human studies, especially in the field of anesthesia, association, causation, mechanism, and clinical application. We need all kinds of the studies in the field of anesthesia. Although we still have a long way to go, I think it could be something on our radar. The microbiome research could be on our radar, and we could be aware of this research. Because there are different applications or implications for our future anesthesia practice. For example, maybe in the future, every patient, before they receive the anesthesia, they will have an invasive and low-cost fecal sample to create a microbiome profile in our health information system, in our anesthesia system, to help us to, you know, understand what would be the best way to, you know, support this patient, provide the care, to develop maybe the best possible cocktail of the anesthetics and analgesics based on the patient's microbiome information. And also maybe microbiome interventions will be our new tool, new kind of the skills in our future, in our health, in, you know, nurse anesthesia education program. So we can use some of the microbiome interventions to improve the patient's responses to the medications we use, and to decrease the risk of post-operative cognitive dysfunctions and post-operative chronic pain, when we do not only give the anesthetics and also the analgesics, but also give some microbiota or some of the probiotics or some of the engineered microorganisms during the surgery to the patient. So when, you know, like the biofume in the microorganisms, many hands make light work. So we need to create the collaboration together and to really, you know, move this field forward. So thank you. Thanks so much for coming to this session. Thank you. Any questions from the audience here, and also any questions from, you know, the online, or any suggestions, comments? Thank you for the very informative lecture. My name is Julia Harris from California. I am a Ph.D. student at University of California, San Francisco, and I've taken some machine learning classes and that kind of thing. So I was wondering which techniques were used in the research that you presented, or maybe you can highlight one or two examples. You mean the technologies to use to do the microbiome research? Correct. I read in your, or I think I did, in your description of the lecture that machine learning was used. So could you kind of rephrase that or bring, highlight how that played a part? Definitely. So now there, because there are a lot of advanced gene sequencing techniques, so we can collect massive information from the DNA information, and there are a couple of the AI techniques we can use that kind of, you know, there are some from the actually the microbiome companies, they have the techniques we can use, and also some of the, even the generative AI, they can help with all of this data, and one kind of the app we can use in the chat GPT even, they have the big data, it's called a data analysis, it's a place, because for the SPS, it's kind of very limited with the sample of the data. You can only deal with probably 1,000 samples, it's going very smooth, but if you have more than 1,000 samples, SPS is making the process very slow, so you can use some other software like in the GPT, they have data analysis software, and also there's another one we use a lot, it's called the R software, and they need some coding to provide the, you know, the statistical methods, but now with the AI technologies, you can use your own language and create coding for you, and put the coding in the R software to help you deal with, you know, all of this, the massive information from the DNA sequencing. Understood, so you're using like, are you using like ridge regression, LASU, that kind of thing to figure out which factors are associated with which outcomes, or are you using like, was it, oh, I'm blanking on some of them, but random forest and that kind of thing for predictors in the six? Yeah, and actually, so now I'm using the AI, I'm trying to use the AI for the pain assessment, so I'm not doing the study, so the reason I want to share this, because I found it's a very important topic, but I'm, and I'm trying to, I'm planning to, you know, dig into this to do some research, because I'm very interested in pain management and assessment, so I haven't done any data analysis on this, but because my interest is the pain assessment in the patient during the anesthesia, so we collect a lot of the physiological indicators, like the skin conductance, it's, you know, every minute there's a value, so there's a method of data, so we now use the R software, and also the data analysis app in the GPT to help us to identify the attributes and also the trends, not only using the t-test and ANOVA, but also these kind of AI technologies to identify the attributes between the, in the data, in the huge data. Okay, thank you. Thank you. Andrea, any, okay. Thanks so much. Thanks so much for coming.

ANA Professional Development Committee

CE credits

2025 Annual Congress

Nashville

gut microbiome research

anesthesia

pain management

Human Genome Project

personalized anesthesia

machine learning