Evidence browser

Gut MicrobiomeImmune System

Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn's disease and chronic fatigue syndrome.

Bourgonje, Arno R, Hörstke, Nicolai V, Fehringer, Michaela et al.·Microbiome·2024

This study looked at immune responses in ME/CFS and Crohn's disease patients by measuring antibodies against proteins from gut bacteria called flagellins. Researchers found that both patient groups had elevated antibodies against these bacterial proteins, but the pattern of where these antibodies attached differed between the two diseases. These antibody patterns could potentially help doctors diagnose ME/CFS and understand how the immune system may be responding abnormally to gut bacteria.

The persistent viral infections in the development and severity of myalgic encephalomyelitis/chronic fatigue syndrome.

Rasa-Dzelzkaleja, Santa, Krumina, Angelika, Capenko, Svetlana et al.·Journal of translational medicine·2023

This study examined whether three common viruses—HHV-6, HHV-7, and parvovirus B19—play a role in ME/CFS by comparing 200 ME/CFS patients with 150 healthy people. The researchers found that ME/CFS patients were much more likely to have these viruses in an active state (replicating) rather than dormant, and those with active infections had higher levels of inflammatory markers. The severity of ME/CFS symptoms appeared linked to the presence and activity level of these viral infections.

Association analysis between symptomology and herpesvirus IgG antibody concentrations in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis.

Domingues, Tiago Dias, Malato, João, Grabowska, Anna D et al.·Heliyon·2023

This study looked at whether past infections with common herpesviruses (like the virus that causes cold sores or chickenpox) are connected to specific symptoms in ME/CFS patients. Researchers tested blood samples from 222 ME/CFS patients and 46 MS patients to measure antibodies against six different herpesviruses, then compared these results to reported symptoms. They found some connections—particularly between a virus called HSV1 and brain fog in ME/CFS patients—but overall, herpesvirus antibodies explained symptoms better in MS patients than in ME/CFS patients.

A multicenter virome analysis of blood, feces, and saliva in myalgic encephalomyelitis/chronic fatigue syndrome.

Briese, Thomas, Tokarz, Rafal, Bateman, Lucinda et al.·Journal of medical virology·2023

Researchers looked for viruses in blood, saliva, and stool samples from ME/CFS patients and compared them to healthy people. They used advanced testing methods to search for viral genetic material but found no consistent differences between the two groups, except that ME/CFS patients had fewer anelloviruses (a common, typically harmless virus). This suggests that if viruses play a role in ME/CFS, the problem may not be the presence of the virus itself, but rather how the body's immune system responds to it.

Cytokine network analysis in a community-based pediatric sample of patients with myalgic encephalomyelitis/chronic fatigue syndrome.

Jason, Leonard A, Gaglio, Caroline L, Furst, Jacob et al.·Chronic illness·2023

Researchers studied immune system chemicals called cytokines in children and teens with ME/CFS by comparing blood samples from sick patients and healthy controls. They found that children with ME/CFS had different patterns of these immune chemicals compared to healthy kids, with certain inflammatory markers being more active. This suggests ME/CFS involves real biological changes in how the immune system works, particularly in severe cases.

Mood Symptoms and Chronic Fatigue Syndrome Due to Relapsing-Remitting Multiple Sclerosis Are Associated with Immune Activation and Aberrations in the Erythron.

Almulla, Abbas F, Abdul Jaleel, Al-Karrar Kais, Abo Algon, Ali Abbas et al.·Brain sciences·2023

This study looked at 63 people with multiple sclerosis (MS) and 30 healthy controls to understand why MS patients experience chronic fatigue, depression, and anxiety. Researchers found that about half of the MS patients had signs of immune system overactivation and problems with red blood cell levels. These immune and blood abnormalities were linked to their fatigue and mood symptoms.

Post-COVID sequelae effect in chronic fatigue syndrome: SARS-CoV-2 triggers latent adenovirus in the oral mucosa.

Hannestad, Ulf, Apostolou, Eirini, Sjögren, Per et al.·Frontiers in medicine·2023

This study found that people with ME/CFS who caught COVID-19 showed signs of a dormant virus (adenovirus) waking up in their mouth and throat. The researchers compared saliva samples from ME/CFS patients and healthy people, and only the ME/CFS patients showed this reactivation after COVID-19 infection. This suggests that ME/CFS patients may have a weakened immune system that cannot keep these latent viruses under control when faced with a new infection like COVID-19.

Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID.

Al-Hakeim, Hussein Kadhem, Khairi Abed, Anwar, Rouf Moustafa, Shatha et al.·Frontiers in molecular neuroscience·2023

This study looked at 90 Long COVID patients and measured specific molecules in their blood related to how their body processes an amino acid called tryptophan. The researchers found that patients with the most severe Long COVID symptoms had low tryptophan levels and high levels of a related compound called kynurenine, along with markers of inflammation. These three measurements together explained about 40% of why patients had fatigue, pain, depression, and anxiety symptoms.

Distinguishing features of long COVID identified through immune profiling.

Klein, Jon, Wood, Jamie, Jaycox, Jillian R et al.·Nature·2023

Researchers studied 275 people with and without long COVID to understand what happens in the immune system. They found that people with long COVID have different patterns of immune cells and antibodies, including stronger responses to past viral infections like Epstein-Barr virus, and lower levels of the stress hormone cortisol. Using computer analysis, they identified specific immune markers that could help identify who has long COVID.

BiomarkersImmune System

Energy MetabolismImmune System

A multi-omics based anti-inflammatory immune signature characterizes long COVID-19 syndrome.

Kovarik, Johannes J, Bileck, Andrea, Hagn, Gerhard et al.·iScience·2023

Researchers compared blood samples from three groups: healthy people, people who recovered from COVID-19 without ongoing symptoms, and people with long COVID who have chronic fatigue and other persistent symptoms. They found that people with long COVID have lower levels of inflammation markers and higher levels of compounds that reduce inflammation, which is unexpected since many assumed long COVID involved high inflammation.

E2 ModerateCohortPEM requiredCross-Sectional

Exploring the joint potential of inflammation, immunity, and receptor-based biomarkers for evaluating ME/CFS progression.

Berkis, Uldis, Svirskis, Simons, Krumina, Angelika et al.·Frontiers in immunology·2023

This study looked for blood markers that could help doctors understand how severe ME/CFS is and track disease progression. Researchers measured inflammation-related proteins, immune system components, and antibodies against nerve receptors in blood samples from healthy people and patients with mild, moderate, and severe ME/CFS. They found that certain markers—especially antibodies against beta2-adrenergic and M4 receptors, along with specific immune proteins—showed promise for distinguishing disease severity, with over 90% accuracy in identifying who has ME/CFS versus who is healthy.

BiomarkersImmune System

E2 ModerateCohortPEM requiredLongitudinal

Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort.

Legler, Franziska, Meyer-Arndt, Lil, Mödl, Lukas et al.·EClinicalMedicine·2023

This study followed 106 people with long-term fatigue after COVID-19 for up to 20 months to see how they recovered over time. Researchers found that some patients met the diagnostic criteria for ME/CFS and had persistent, severe symptoms including fatigue and post-exertional malaise (worsening after activity), while others improved more substantially. Lower muscle strength at the start of illness was linked to ongoing symptoms, especially in those with ME/CFS.

BiomarkersImmune SystemPost-Exertional Malaise

Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site clinical assessment of ME/CFS (MCAM) sub-study.

Querec, Troy D, Lin, Jin-Mann S, Chen, Yang et al.·Journal of translational medicine·2023

Researchers tested whether a specific immune cell function called natural killer (NK) cytotoxicity could be a reliable blood test to help diagnose ME/CFS. They compared 174 people with ME/CFS to 86 healthy people and found no meaningful difference between the two groups. This means the test is not accurate enough to use in clinics right now, and scientists need to keep searching for better biological markers of ME/CFS.

Autoantibodies to selenoprotein P in chronic fatigue syndrome suggest selenium transport impairment and acquired resistance to thyroid hormone.

Sun, Qian, Oltra, Elisa, Dijck-Brouwer, D A Janneke et al.·Redox biology·2023

Some people with ME/CFS have antibodies that attack a protein called selenoprotein P, which normally helps transport selenium (a mineral needed for thyroid function) throughout the body. This study found that ME/CFS patients with these antibodies have lower selenium levels and struggle to convert thyroid hormone into its active form, which could explain why they feel tired and have other thyroid-like symptoms even when standard thyroid tests appear normal.

Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: implications for disease-related biomarker discovery.

Martín, Franz, Blanco-Suárez, Manuel, Zambrano, Paola et al.·Frontiers in immunology·2023

This study found that people with ME/CFS and fibromyalgia may have a 'leaky gut'—where the intestinal barrier doesn't work as well as it should. Researchers measured several substances in the blood that indicate gut barrier problems and inflammation, and found higher levels in both patient groups compared to healthy people. These findings suggest that gut dysfunction might play a role in these conditions and could eventually help doctors identify and understand these diseases better.

NeuroinflammationImmune System

Chronic Fatigue, Depression and Anxiety Symptoms in Long COVID Are Strongly Predicted by Neuroimmune and Neuro-Oxidative Pathways Which Are Caused by the Inflammation during Acute Infection.

Al-Hakeim, Hussein Kadhem, Al-Rubaye, Haneen Tahseen, Almulla, Abbas F et al.·Journal of clinical medicine·2023

This study examined whether severe COVID-19 infection—particularly high fever and low oxygen levels—can trigger lasting fatigue, depression, and anxiety through inflammation and oxidative stress in the body. Researchers compared 86 long COVID patients with 39 healthy controls and found that about one-third of long COVID patients had very high signs of immune activation and cellular damage. The study suggests that the severity of initial COVID infection may predict who develops long-term symptoms through measurable changes in inflammatory markers.

Influence of Chronic Fatigue Syndrome Codiagnosis on the Relationship between Perceived and Objective Psychoneuro-Immunoendocrine Disorders in Women with Fibromyalgia.

Otero, Eduardo, Gálvez, Isabel, Ortega, Eduardo et al.·Biomedicines·2023

This study compared women with fibromyalgia (FM), some of whom also had been diagnosed with chronic fatigue syndrome (CFS), to healthy women. Researchers measured both what patients reported feeling (like stress and pain levels) and actual biological markers in their blood (like stress hormones and immune chemicals). They found that FM patients generally felt worse than healthy women, and their blood work matched this—showing higher stress hormones and lower mood-boosting chemicals. Interestingly, FM patients who also had a CFS diagnosis showed different blood markers than those with FM alone, suggesting these two conditions may overlap in ways that current diagnosis methods don't catch.

Immune SystemPost-Exertional Malaise

Low-dose naltrexone use for the management of post-acute sequelae of COVID-19.

Bonilla, Hector, Tian, Lu, Marconi, Vincent C et al.·International immunopharmacology·2023

This study looked at whether a medication called low-dose naltrexone (LDN) might help people with long COVID symptoms. Researchers reviewed 59 patients who took LDN and found that those who used it reported fewer overall symptoms, felt less fatigue and brain fog, experienced better sleep, and had improved ability to do daily activities. While these early results are encouraging, the study was not designed like a typical clinical trial, so more rigorous testing is needed to know if LDN truly works.

Energy MetabolismImmune SystemPost-Exertional Malaise

Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infection.

Guo, Lihui, Appelman, Brent, Mooij-Kalverda, Kirsten et al.·EBioMedicine·2023

This study found that people with long-COVID have persistent activity of an enzyme called IDO2 in their blood cells and brain tissue, months or years after initial infection. This enzyme breaks down tryptophan (an amino acid) into other compounds that may trigger cellular stress and energy problems. The researchers also discovered that blocking a specific receptor (called AHR) could stop this process in laboratory tests, suggesting a potential treatment target.

Observational Study of Repeat Immunoadsorption (RIA) in Post-COVID ME/CFS Patients with Elevated ß2-Adrenergic Receptor Autoantibodies-An Interim Report.

Stein, Elisa, Heindrich, Cornelia, Wittke, Kirsten et al.·Journal of clinical medicine·2023

This study tested a blood-cleaning procedure called immunoadsorption in 10 patients with ME/CFS that developed after COVID-19. The treatment removes harmful antibodies from the blood that may be attacking the body's nerve receptors. Seven patients showed meaningful improvement in physical function within four weeks, suggesting this approach may help some people with post-COVID ME/CFS.