AI-Powered Research Reveals Gut-Immune-Metabolism Link in Chronic Fatigue Syndrome, Offering Hope for Diagnosis and Treatment

Research uncovers ME/CFS's systemic impact for targeted therapies

Jackson LaboratoryJul 26 2025 Millions suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating condition often overlooked due to the lack of diagnostic tools, may be closer to personalized care, according to new research that shows how the disease disrupts interactions between the microbiome, immune system, and metabolism. The findings-potentially relevant to long COVID due to its similarity with ME/CFS-come from data on 249 individuals analyzed using a new artificial intelligence (AI) platform that identifies disease biomarkers from stool, blood, and other routine lab tests. "Our study achieved 90% accuracy in distinguishing individuals with chronic fatigue syndrome, which is significant because doctors currently lack reliable biomarkers for diagnosis. Some physicians doubt it as a real disease due to the absence of clear laboratory markers, sometimes attributing it to psychological factors." Dr. Derya Unutmaz, Study Author and Professor, Immunology, The Jackson Laboratory The research was led by Dr. Julia Oh, formerly at JAX and now a microbiologist and professor at Duke University, in collaboration with ME/CFS clinicians Lucinda Bateman and Suzanne Vernon of the Bateman Horne Center, and Unutmaz, who directs the JAX ME/CFS Collaborative Research Center. Details appear today in Nature Medicine. Mapping the invisible Chronic fatigue syndrome is characterized by severe symptoms that significantly impair physical and mental activities, including persistent fatigue, sleep abnormalities, dizziness, and chronic pain. Experts often compare ME/CFS to long COVID, as both conditions frequently follow viral infections, such as Epstein-Barr virus. In the United States, ME/CFS affects between 836,000 and 3.3 million individuals- many undiagnosed-and costs the economy $18 to $51 billion annually due to healthcare expenditures and lost productivity, according to the Centers for Disease Control and Prevention. Prior studies have noted immune disruptions in ME/CFS, Unutmaz said. This new research builds upon those findings by investigating how the gut microbiome, its metabolites, and immune responses interact. The team linked these connections to 12 classes of patient-reported symptoms, which were aggregated from hundreds of datapoints generated by patient health and lifestyle surveys. These include sleep disturbances, headaches, fatigue, dizziness, and other symptoms the researchers mapped in their entirety from microbiome changes to metabolites, immune responses, and clinical symptoms. "We integrated clinical symptoms with cutting-edge omics technologies to identify new biomarkers of ME/CFS," Oh said. "Linking symptoms at this level is crucial, because ME/CFS is highly variable. Patients experience a wide range of symptoms that differ in severity and duration, and current methods can't fully capture that complexity." To conduct the study, the researchers analyzed comprehensive data collected from the Bateman Horne Center, a leading ME/CFS, Long-Covid, and fibromyalgia research center in Salt Lake City, Utah. Dr. Ruoyun Xiong, also a lead author on the study, developed a deep neural network model called BioMapAI. The tool integrates gut metagenomics, plasma metabolomics, immune cell profiles, blood test data, and clinical symptoms from 153 patients and 96 healthy individuals over four years. Immune cell analysis proved most accurate in predicting symptom severity, while microbiome data best predicted gastrointestinal, emotional, and sleep disturbances. The model connected thousands of patient data points, reconstructing symptoms such as pain and gastrointestinal issues, among several others. It also revealed that patients who were ill for less than four years had fewer disrupted networks than those who were ill for more than ten years. "Our data indicate these biological disruptions become more entrenched over time," Unutmaz said. "That doesn't mean longer-duration ME/CFS can't be reversed, but it may be more challenging." The study included 96 age- and gender-matched healthy controls, showing balanced microbiome-metabolite-immune interactions, in contrast to significant disruptions in ME/CFS patients linked to fatigue, pain, emotional regulation issues, and sleep disorders. ME/CFS patients also had lower levels of butyrate, a beneficial fatty acid produced in the gut, along with other nutrients essential for metabolism, inflammation control, and energy. Patients with elevated levels of tryptophan, benzoate, and other markers indicated a microbial imbalance. Heightened inflammatory responses, particularly involving MAIT cells sensitive to gut microbial health, were also observed. "MAIT cells bridge gut health to broader immune functions, and their disruption alongside butyrate and tryptophan pathways, normally anti-inflammatory, suggests a profound imbalance," said Unutmaz. An actionable dataset Even though the findings require further validation, they significantly advance scientists' understanding of ME/CFS and provide clearer hypotheses for future research, the authors said. Since animal models can't fully reflect the complex neurological, physiological, immune, and other system disruptions seen in ME/CFS, Oh said it will be crucial to study humans directly to identify modifiable factors and develop targeted treatments. "The microbiome and metabolome are dynamic,"Oh said. "That means we may be able to intervene-through diet, lifestyle, or targeted therapies-in ways that genomic data alone can't offer." BioMapAI also achieved roughly 80% accuracy in external data sets, confirming key biomarkers identified in the original group. This consistency across diverse data was striking, the authors said. "Despite diverse data collection methods, common disease signatures emerged in fatty acids, immune markers, and metabolites," Oh said. "That tells us this is not random. This is real biological dysregulation." The researchers intend to share their dataset broadly with BioMapAI, which supports analyses across diverse symptoms and diseases, effectively integrating multi-omics data that are difficult to replicate in animal models. "Our goal is to build a detailed map of how the immune system interacts with gut bacteria and the chemicals they produce," Oh said. "By connecting these dots we can start to understand what's driving the disease and pave the way for genuinely precise medicine that has long been out of reach." Jackson Laboratory Journal references: Xiong, R., et al. (2025). AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome. Nature Medicine. doi.org/10.1038/s41591-025-03788-3

Your Gut May Be the Key to Chronic Fatigue, Long COVID - Neuroscience News

Q: What did the study uncover about ME/CFS? A: The study revealed that ME/CFS disrupts key interactions between the gut microbiome, immune system, and metabolism, identifying biological markers that distinguish patients from healthy individuals with up to 90% accuracy. Q: How does the AI platform, BioMapAI, help? A: BioMapAI integrates thousands of data points -- including microbiome profiles, blood tests, immune markers, and symptoms -- to identify patterns and disruptions unique to ME/CFS, making precision medicine approaches more feasible. Q: Why are these findings important for patients? A: The research not only strengthens the biological legitimacy of ME/CFS but also offers personalized insight into symptom origins, potentially guiding future dietary, lifestyle, and therapeutic interventions -- especially for long COVID and related conditions. Summary: A groundbreaking study using AI has revealed how ME/CFS disrupts critical connections between the immune system, gut microbiome, and metabolism. The new platform, BioMapAI, achieved 90% accuracy in identifying ME/CFS patients based on stool, blood, and symptom data -- offering long-overdue validation for millions living with this debilitating illness. Researchers found that patients had distinct biological signatures, including lower levels of beneficial fatty acids, disrupted immune cell activity, and metabolic imbalances. These findings could guide personalized treatments and provide a scientific foundation for future therapies, especially for long COVID sufferers with overlapping symptoms. Millions suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating condition often overlooked due to the lack of diagnostic tools, may be closer to personalized care, according to new research that shows how the disease disrupts interactions between the microbiome, immune system, and metabolism. The findings -- potentially relevant to long COVID due to its similarity with ME/CFS -- come from data on 249 individuals analyzed using a new artificial intelligence (AI) platform that identifies disease biomarkers from stool, blood, and other routine lab tests. "Our study achieved 90% accuracy in distinguishing individuals with chronic fatigue syndrome, which is significant because doctors currently lack reliable biomarkers for diagnosis," said study author Dr. Derya Unutmaz, Professor in immunology at The Jackson Laboratory (JAX). "Some physicians doubt it as a real disease due to the absence of clear laboratory markers, sometimes attributing it to psychological factors." The research was led by Dr. Julia Oh, formerly at JAX and now a microbiologist and professor at Duke University, in collaboration with ME/CFS clinicians Lucinda Bateman and Suzanne Vernon of the Bateman Horne Center, and Unutmaz, who directs the JAX ME/CFS Collaborative Research Center. Details appear today in Nature Medicine. Mapping the Invisible Chronic fatigue syndrome is characterized by severe symptoms that significantly impair physical and mental activities, including persistent fatigue, sleep abnormalities, dizziness, and chronic pain. Experts often compare ME/CFS to long COVID, as both conditions frequently follow viral infections, such as Epstein-Barr virus. In the United States, ME/CFS affects between 836,000 and 3.3 million individuals -- many undiagnosed -- and costs the economy $18 to $51 billion annually due to healthcare expenditures and lost productivity, according to the Centers for Disease Control and Prevention. Prior studies have noted immune disruptions in ME/CFS, Unutmaz said. This new research builds upon those findings by investigating how the gut microbiome, its metabolites, and immune responses interact. The team linked these connections to 12 classes of patient-reported symptoms, which were aggregated from hundreds of datapoints generated by patient health and lifestyle surveys. These include sleep disturbances, headaches, fatigue, dizziness, and other symptoms the researchers mapped in their entirety from microbiome changes to metabolites, immune responses, and clinical symptoms. "We integrated clinical symptoms with cutting-edge omics technologies to identify new biomarkers of ME/CFS," Oh said. "Linking symptoms at this level is crucial, because ME/CFS is highly variable. Patients experience a wide range of symptoms that differ in severity and duration, and current methods can't fully capture that complexity." To conduct the study, the researchers analyzed comprehensive data collected from the Bateman Horne Center, a leading ME/CFS, Long-Covid, and fibromyalgia research center in Salt Lake City, Utah. Dr. Ruoyun Xiong, also a lead author on the study, developed a deep neural network model called BioMapAI. The tool integrates gut metagenomics, plasma metabolomics, immune cell profiles, blood test data, and clinical symptoms from 153 patients and 96 healthy individuals over four years. Immune cell analysis proved most accurate in predicting symptom severity, while microbiome data best predicted gastrointestinal, emotional, and sleep disturbances. The model connected thousands of patient data points, reconstructing symptoms such as pain and gastrointestinal issues, among several others. It also revealed that patients who were ill for less than four years had fewer disrupted networks than those who were ill for more than ten years. "Our data indicate these biological disruptions become more entrenched over time," Unutmaz said. "That doesn't mean longer-duration ME/CFS can't be reversed, but it may be more challenging." The study included 96 age- and gender-matched healthy controls, showing balanced microbiome-metabolite-immune interactions, in contrast to significant disruptions in ME/CFS patients linked to fatigue, pain, emotional regulation issues, and sleep disorders. ME/CFS patients also had lower levels of butyrate, a beneficial fatty acid produced in the gut, along with other nutrients essential for metabolism, inflammation control, and energy. Patients with elevated levels of tryptophan, benzoate, and other markers indicated a microbial imbalance. Heightened inflammatory responses, particularly involving MAIT cells sensitive to gut microbial health, were also observed. "MAIT cells bridge gut health to broader immune functions, and their disruption alongside butyrate and tryptophan pathways, normally anti-inflammatory, suggests a profound imbalance," said Unutmaz. An Actionable Dataset Even though the findings require further validation, they significantly advance scientists' understanding of ME/CFS and provide clearer hypotheses for future research, the authors said. Since animal models can't fully reflect the complex neurological, physiological, immune, and other system disruptions seen in ME/CFS, Oh said it will be crucial to study humans directly to identify modifiable factors and develop targeted treatments. "The microbiome and metabolome are dynamic," Oh said. "That means we may be able to intervene -- through diet, lifestyle, or targeted therapies -- in ways that genomic data alone can't offer." BioMapAI also achieved roughly 80% accuracy in external data sets, confirming key biomarkers identified in the original group. This consistency across diverse data was striking, the authors said. "Despite diverse data collection methods, common disease signatures emerged in fatty acids, immune markers, and metabolites," Oh said. "That tells us this is not random. This is real biological dysregulation." The researchers intend to share their dataset broadly with BioMapAI, which supports analyses across diverse symptoms and diseases, effectively integrating multi-omics data that are difficult to replicate in animal models. "Our goal is to build a detailed map of how the immune system interacts with gut bacteria and the chemicals they produce," Oh said. "By connecting these dots we can start to understand what's driving the disease and pave the way for genuinely precise medicine that has long been out of reach." Additional authors include Elizabeth Aiken, Ryan Caldwell, Lina Kozhaya, and Courtney Gunter (The Jackson Laboratory), and Suzanne D. Vernon and Lucinda Bateman (Bateman Horne Center). AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness with a multifactorial etiology and heterogeneous symptomatology, posing major challenges for diagnosis and treatment. Here we present BioMapAI, a supervised deep neural network trained on a 4-year, longitudinal, multi-omics dataset from 249 participants, which integrates gut metagenomics, plasma metabolomics, immune cell profiling, blood laboratory data and detailed clinical symptoms. By simultaneously modeling these diverse data types to predict clinical severity, BioMapAI identifies disease- and symptom-specific biomarkers and classifies ME/CFS in both held-out and independent external cohorts. Using an explainable AI approach, we construct a unique connectivity map spanning the microbiome, immune system and plasma metabolome in health and ME/CFS adjusted for age, gender and additional clinical factors. This map uncovers altered associations between microbial metabolism (for example, short-chain fatty acids, branched-chain amino acids, tryptophan, benzoate), plasma lipids and bile acids, and heightened inflammatory responses in mucosal and inflammatory T cell subsets (MAIT, γδT) secreting IFN-γ and GzA. Overall, BioMapAI provides unprecedented systems-level insights into ME/CFS, refining existing hypotheses and hypothesizing unique mechanisms -- specifically, how multi-omics dynamics are associated to the disease's heterogeneous symptoms.

Previously undetectable biomarkers in gut microbiome may predict 'invisible' chronic fatigue syndrome, long COVID

Millions suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating condition often overlooked due to the lack of diagnostic tools, may be closer to personalized care, according to new research that shows how the disease disrupts interactions between the microbiome, immune system, and metabolism. The findings -- potentially relevant to long COVID due to its similarity with ME/CFS -- come from data on 249 individuals analyzed using a new artificial intelligence (AI) platform that identifies disease biomarkers from stool, blood, and other routine lab tests. "Our study achieved 90% accuracy in distinguishing individuals with chronic fatigue syndrome, which is significant because doctors currently lack reliable biomarkers for diagnosis," said study author Dr. Derya Unutmaz, Professor of immunology at The Jackson Laboratory (JAX). "Some physicians doubt it as a real disease due to the absence of clear laboratory markers, sometimes attributing it to psychological factors." The research was led by Dr. Julia Oh, formerly at JAX and now a microbiologist and professor at Duke University, in collaboration with ME/CFS clinicians Lucinda Bateman and Suzanne Vernon of the Bateman Horne Center, and Unutmaz, who directs the JAX ME/CFS Collaborative Research Center. Details appear in Nature Medicine. Mapping the invisible Chronic fatigue syndrome is characterized by severe symptoms that significantly impair physical and mental activities, including persistent fatigue, sleep abnormalities, dizziness, and chronic pain. Experts often compare ME/CFS to long COVID, as both conditions frequently follow viral infections, such as Epstein-Barr virus. In the United States, ME/CFS affects between 836,000 and 3.3 million individuals -- many undiagnosed -- and costs the economy $18 to $51 billion annually due to health care expenditures and lost productivity, according to the Centers for Disease Control and Prevention. Prior studies have noted immune disruptions in ME/CFS, Unutmaz said. This new research builds upon those findings by investigating how the gut microbiome, its metabolites, and immune responses interact. The team linked these connections to 12 classes of patient-reported symptoms, which were aggregated from hundreds of datapoints generated by patient health and lifestyle surveys. These include sleep disturbances, headaches, fatigue, dizziness, and other symptoms the researchers mapped in their entirety from microbiome changes to metabolites, immune responses, and clinical symptoms. "We integrated clinical symptoms with cutting-edge omics technologies to identify new biomarkers of ME/CFS," Oh said. "Linking symptoms at this level is crucial, because ME/CFS is highly variable. Patients experience a wide range of symptoms that differ in severity and duration, and current methods can't fully capture that complexity." To conduct the study, the researchers analyzed comprehensive data collected from the Bateman Horne Center, a leading ME/CFS, long COVID, and fibromyalgia research center in Salt Lake City, Utah. Dr. Ruoyun Xiong, also a lead author on the study, developed a deep neural network model called BioMapAI. The tool integrates gut metagenomics, plasma metabolomics, immune cell profiles, blood test data, and clinical symptoms from 153 patients and 96 healthy individuals over four years. Immune cell analysis proved most accurate in predicting symptom severity, while microbiome data best predicted gastrointestinal, emotional, and sleep disturbances. The model connected thousands of patient data points, reconstructing symptoms such as pain and gastrointestinal issues, among several others. It also revealed that patients who were ill for less than four years had fewer disrupted networks than those who were ill for more than ten years. "Our data indicate these biological disruptions become more entrenched over time," Unutmaz said. "That doesn't mean longer-duration ME/CFS can't be reversed, but it may be more challenging." The study included 96 age- and gender-matched healthy controls, showing balanced microbiome-metabolite-immune interactions, in contrast to significant disruptions in ME/CFS patients linked to fatigue, pain, emotional regulation issues, and sleep disorders. ME/CFS patients also had lower levels of butyrate, a beneficial fatty acid produced in the gut, along with other nutrients essential for metabolism, inflammation control, and energy. Patients with elevated levels of tryptophan, benzoate, and other markers indicated a microbial imbalance. Heightened inflammatory responses, particularly involving MAIT cells sensitive to gut microbial health, were also observed. "MAIT cells bridge gut health to broader immune functions, and their disruption alongside butyrate and tryptophan pathways, normally anti-inflammatory, suggests a profound imbalance," said Unutmaz. An actionable dataset Even though the findings require further validation, they significantly advance scientists' understanding of ME/CFS and provide clearer hypotheses for future research, the authors said. Since animal models can't fully reflect the complex neurological, physiological, immune, and other system disruptions seen in ME/CFS, Oh said it will be crucial to study humans directly to identify modifiable factors and develop targeted treatments. "The microbiome and metabolome are dynamic," Oh said. "That means we may be able to intervene -- through diet, lifestyle, or targeted therapies -- in ways that genomic data alone can't offer." BioMapAI also achieved roughly 80% accuracy in external data sets, confirming key biomarkers identified in the original group. This consistency across diverse data was striking, the authors said. "Despite diverse data collection methods, common disease signatures emerged in fatty acids, immune markers, and metabolites," Oh said. "That tells us this is not random. This is real biological dysregulation." The researchers intend to share their dataset broadly with BioMapAI, which supports analyses across diverse symptoms and diseases, effectively integrating multi-omics data that are difficult to replicate in animal models. "Our goal is to build a detailed map of how the immune system interacts with gut bacteria and the chemicals they produce," Oh said. "By connecting these dots we can start to understand what's driving the disease and pave the way for genuinely precise medicine that has long been out of reach." Additional authors include Elizabeth Aiken, Ryan Caldwell, Lina Kozhaya, and Courtney Gunter (The Jackson Laboratory), and Suzanne D. Vernon and Lucinda Bateman (Bateman Horne Center).

Is It Chronic Fatigue? Listen to Your Gut, Research Suggests

By Ernie Mundell HealthDay ReporterTUESDAY, July 29, 2026 (HealthDay News) -- Artificial intelligence (AI) may be guiding doctors towards a gut-focused means of accurately diagnosing chronic fatigue syndrome (CFS), new research shows. The illness appears to disrupt relationships between a person's gut microbiome, immune system and metabolism, explained a team led by Julia Oh. She's a microbiologist and professor at Duke University, but worked on the study while at The Jackson Laboratory (JAX) in Farmington, Conn. In Oh's view, the new findings' importance goes beyond diagnostics. "Our goal is to build a detailed map of how the immune system interacts with gut bacteria and the chemicals they produce," she explained in a JAX news release. "By connecting these dots we can start to understand what's driving the disease and pave the way for genuinely precise medicine that has long been out of reach." The study involved 153 people with CFS, matched to 96 healthy individuals. Participants were tracked over four years. The findings were published July 25 in Nature Medicine. Chronic fatigue syndrome (also known as myalgic encephalomyelitis, or ME) is characterized by persistent fatigue, sleep abnormalities, dizziness and chronic pain, all of which can severely curtail daily living. The U.S. Centers for Disease Control and Prevention (CDC) says anywhere from 836,000 to 3.3 million Americans may be affected by CFS, costing the nation up to $51 billion in lost productivity and medical bills. CFS is often linked with long COVID, since both can follow an infection. It's, therefore, possible that the new findings have relevance to long COVID, as well, the research team said. The current study builds on prior work linking CFS to disruptions in immune system function. Oh's group used high-tech AI to analyze relationships between the immune system and bacterial colonies in the gut (microbiome) and related metabolites. They cross-referenced those gut/immune relationships with specific symptoms that are common to CFS: Sleep disturbances, headaches, fatigue and dizziness, as well as other symptoms. "We integrated clinical symptoms with cutting-edge '-omics' technologies to identify new biomarkers of ME/CFS," Oh explained. "Linking symptoms at this level is crucial, because ME/CFS is highly variable. Patients experience a wide range of symptoms that differ in severity and duration, and current methods can't fully capture that complexity." The team found that an analysis of immune cell function could help pinpoint the severity of a patient's CFS, while the microbiome helped predict gastrointestinal, emotional and sleep disturbances. Overall, "our study achieved 90% accuracy in distinguishing individuals with chronic fatigue syndrome, which is significant because doctors currently lack reliable biomarkers for diagnosis," study co-author Dr. Derya Unutmaz, a professor in immunology at JAX, said. Any advance in CFS diagnosis is valuable, he said, because "some physicians doubt it as a real disease due to the absence of clear laboratory markers, sometimes attributing it to psychological factors." Furthermore, the research suggests that in CFS disruptions in related biological networks "become more entrenched over time," Unutmaz said in the news release. "That doesn't mean longer-duration ME/CFS can't be reversed, but it may be more challenging," he explained. Oh stressed that the effects of CFS on the body remain a moving target. "The microbiome and metabolome are dynamic," she explained. "That means we may be able to intervene -- through diet, lifestyle or targeted therapies." And certain patterns did appear as the team's research progressed. "Common disease signatures emerged in fatty acids, immune markers and metabolites," Oh explained. "That tells us this is not random. This is real biological dysregulation." More information There's more on CFS at Johns Hopkins Medicine. SOURCE: The Jackson Laboratories, news release, July 25, 2025