Tag: gut dysbiosis

Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem disorder characterized by neuroimmune, autonomic, and gastrointestinal dysfunction. Previous studies identified coherent symptom domains involving Brain, Autonomic, Gut, and Immune manifestations and demonstrated pronounced sex-specific differences in neurocognitive-sensory and autonomic symptom organization. However, whether immune-related and gastrointestinal symptoms form distinct or integrated latent structures in women and men with ME/CFS remains unclear. In addition, the potential influence of menopausal status on these symptom domains has not been systematically investigated.

Methods: Data from 748 adults with a medical diagnosis of ME/CFS were included in this cross-sectional analysis (608 women, 137 men, and 3 non-binary participants). Sex-stratified analyses were restricted to women and men. Symptoms were coded dichotomously. Sex-stratified analyses included cross-tabulations, Cramér’s V, tetrachoric correlations, logistic and linear regression models, exploratory factor analysis, and structural equation modeling (SEM). Additional subgroup analyses compared pre- and postmenopausal women. Model robustness was evaluated using a stratified training dataset.

Results: In women, Immune (flu-like symptoms, susceptibility to infections) and Gut (gastrointestinal complaints, food intolerances) symptoms formed two distinct but related clusters, characterized by moderate within-cluster correlations (tetrachoric ρ = 0.47-0.60) and weaker cross-cluster associations (ρ = 0.30-0.35). Exploratory factor analysis (EFA) supported a two-factor solution. Consistent with this result, the alternative one-factor SEM showed comparatively poor fit (CFI = 0.913; RMSEA = 0.119), whereas the specified two-factor model was just-identified and therefore not suitable for global fit evaluation. In men, all four symptoms loaded onto a single integrated Gut/Immune factor, with within- and cross-domain tetrachoric correlations ranging from 0.43 to 0.68. SEM confirmed excellent fit for a one-factor model (CFI = 0.981; RMSEA = 0.074). Susceptibility to infections emerged as the dominant predictor in regression analyses. Among women, menopausal status selectively affected immune-related symptoms. Women classified as premenopausal reported flu-like symptoms more frequently than women classified as postmenopausal, whereas gastrointestinal symptoms and food intolerances remained stable across groups. These findings suggest differential hormonal sensitivity of immune versus gastrointestinal symptom trajectories.

Conclusions: Immune and gastrointestinal symptoms in ME/CFS exhibit sex-specific latent structures. Women demonstrate two partially separable but related symptom domains, whereas men show a more integrated immune-gastrointestinal architecture. Furthermore, menopausal status appears to selectively modulate immune-related symptom expression while leaving gastrointestinal symptom patterns comparatively stable. Taken together, these results provide an exploratory framework that supports the concept of sex-dependent neuroimmune-autonomic mechanisms in ME/CFS and aligns with a dynamic, hormonally modulated immune component as well as a more persistent, gut-related process. The results highlight the importance of sex- and hormone-sensitive approaches to phenotyping, mechanistic research, and therapeutic stratification in ME/CFS.

Source: Habermann-Horstmeier L, Horstmeier LM. Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling. J Transl Med. 2026 Jul 27;24(1):970. doi: 10.1186/s12967-026-08699-6. PMID: 42522006. https://link.springer.com/article/10.1186/s12967-026-08699-6 (Full text)

Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Insights into Disease Mechanisms

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling clinical condition, whose hallmark characteristic is post-exertional malaise (PEM). It can affect many organs and systems, leading to severe impairment of patients’ quality of life. Although numerous post-infectious, immunological, neurological, metabolic, and endocrine alterations have been documented, neither a definitive diagnostic marker nor approved treatments are available. The etiology and pathophysiology remain incompletely understood; however, emerging evidence suggests that the gut microbiome plays a role in immune responses and the development of ME/CFS.

It is hypothesized that specific disturbances in gut microbiome composition, known as dysbiosis, may compromise the integrity of the intestinal barrier. This consequently leads to translocation of microbial components, which further triggers an immune response and systemic inflammation complicating the clinical presentation of ME/CFS. Furthermore, in terms of the so-called gut-brain axis, microbiome changes may lead to distinct neurocognitive impairments observed in ME/CFS patients.

This review offers the readers a broad perspective on the topic on ME/CFS, with a particular emphasis on the interplay between the gut microbiome and disease mechanisms. Last but not least, recent data on potential treatment strategies for intestinal dysbiosis in ME/CFS patients have been included.

Source: Nikolova R, Donchev D, Vaseva K, Ivanov IN. Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Insights into Disease Mechanisms. Int J Mol Sci. 2025 Dec 31;27(1):425. doi: 10.3390/ijms27010425. PMID: 41516296; PMCID: PMC12785659. https://pmc.ncbi.nlm.nih.gov/articles/PMC12785659/ (Full text)

Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder characterized by immune dysregulation, metabolic impairments, neuroendocrine disturbances, endothelial dysfunction, and gastrointestinal abnormalities.

Immune alterations include reduced natural killer cell cytotoxicity, T-cell exhaustion, abnormal B-cell subsets, and the presence of diverse autoantibodies, suggesting an autoimmune component.

Gut dysbiosis and increased intestinal permeability may promote systemic inflammation and contribute to neurocognitive symptoms via the gut-brain axis. Neuroendocrine findings such as hypothalamic-pituitary-adrenal (HPA) axis hypofunction and altered thyroid hormone metabolism further compound metabolic and immune abnormalities.

Metabolomic and mitochondrial studies identify impaired ATP generation, redox imbalance, and compensatory shifts toward alternative energy pathways underlying hallmark symptoms like post-exertional malaise.

Endothelial dysfunction driven by oxidative and nitrosative stress, along with autoantibody-mediated receptor interference, may explain orthostatic intolerance and impaired perfusion. Collectively, ME/CFS appears to arise from a self-sustaining cycle of chronic inflammation, metabolic insufficiency, and neuroimmune imbalance.

Source: Dudova D, Bozhkova M, Petrov S, Nikolova R, Kalfova T, Ivanovska M, Vaseva K, Nikolova M, Ivanov IN. Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2025 Dec 26;27(1):268. doi: 10.3390/ijms27010268. PMID: 41516145; PMCID: PMC12785471. https://pmc.ncbi.nlm.nih.gov/articles/PMC12785471/ (Full text)

Multi-Strain Probiotic Improves Tryptophan Metabolism and Symptoms in Chronic Fatigue Syndrome Patients with Co-Occurring Irritable Bowel Syndrome: An Open-Label Pilot Study

Simple Summary:

Chronic Fatigue Syndrome (CFS) is a debilitating condition often accompanied by gut health issues, but effective treatments are scarce. Recent research suggests that an imbalance in gut bacteria (dysbiosis) may contribute to CFS symptoms by producing harmful substances that affect the nervous system. We investigated whether a specific multi-strain probiotic (CDS22-formula) could improve symptoms in women with CFS and co-occurring IBS. Over 12 weeks, patients took a high-dose probiotic supplement. We monitored their fatigue levels and analyzed urine samples to track changes in tryptophan metabolism—a key pathway linking the gut to the brain. The results showed that the probiotic intervention was associated with an improved gut bacteria profile. Importantly, this coincided with a reduction in neurotoxic metabolites and a significant decrease in fatigue severity. Our findings suggest that targeting the gut microbiome can be a valuable strategy for managing chronic fatigue, potentially by modulating the production of metabolites that affect brain function.
Abstract:

Background/Objectives: Gut dysbiosis in Chronic Fatigue Syndrome (CFS) drives low-grade inflammation and shifts tryptophan metabolism toward neurotoxic pathways. The causal link between bacterial translocation, kynurenine pathway dysregulation, and symptom severity remains under-defined. We evaluated the impact of a high-concentration multi-strain probiotic on the “gut-kynurenine axis” and clinical status in CFS patients with co-morbid IBS-U and confirmed dysbiosis.
Methods: Forty female patients with confirmed dysbiosis (GA-map™ Dysbiosis Index > 2) received the CDS22 formula (450 billion CFU/day) for 12 weeks. We compared urinary tryptophan metabolite profiles (LC-MS/MS), gut dysbiosis markers (3-indoxyl sulfate), and fatigue severity (FSS) against 40 age-matched healthy controls.
Results: Baseline analysis revealed profound metabolic perturbations: elevated bacterial proteolytic markers (3-IS), substrate depletion (low tryptophan), and a neurotoxic signature (high quinolinic acid [QA], low kynurenic acid [KYNA]). Following the intervention, fatigue scores declined by 40.3%, with 97.5% of patients reaching the remission threshold (FSS < 36). Biochemically, 3-IS levels decreased to the range observed in healthy controls and attenuated xanthurenic acid levels. Although absolute QA concentrations remained elevated compared to controls, the neuroprotective KYNA/QA ratio increased significantly (+45%). Increased systemic tryptophan availability correlated directly with clinical symptom reduction (Spearman’s rho = −0.36, p = 0.024).
Conclusions: The CDS22 formulation was associated with a restoration of intestinal eubiosis and functional tryptophan partitioning. Clinical remission coincides with a metabolic shift favoring neuroprotection (increased KYNA/QA ratio), validating the gut–kynurenine axis as a modifiable therapeutic target. Peripheral metabolic improvement relative to the healthy baseline appeared sufficient for symptom relief in this specific phenotype, despite incomplete clearance of neurotoxic metabolites.
Source:

The gut microbial composition is different in chronic fatigue syndrome than in healthy controls

Abstract:

The pathogenesis of Chronic Fatigue Syndrome (CFS) is yet unknown. This study aimed to assess the gut microbial composition in CFS patients versus in healthy controls (HCs).

The composition of fecal bacteria was examined in twenty-five CFS patients and sixteen HCs using Illumina sequencing of 16 S rRNA gene amplicons targeting the V3-V4 bacterial gene regions. 143 (46%) of the microbial genera were found only in the CFS. In addition, the gut microbial composition in the CFS patients contained a much higher proportion of the 10 most commonly found bacteria compared to the HCs group. A significantly lower observed number of operational taxonomic units (OTUs) was noted in CFS compared to HCs (p = 0.045).

Significant between-group differences in the gut microbial composition in CFS compared to HCs were noted. The three most discriminating Amplicon Sequencing Variants (ASVs): ASV 191, ASV 44, and ASV 75, were identified as significantly more abundant in the healthy control group compared to the patient group. In addition, the Neural Network (multilayer perceptron) was able to discriminate gut microbial composition from CFS versus HCs with excellent performance (AUC = 0.935).

The gut microbial composition is different in CFS patients compared to HCs. Further studies should assess the pathophysiological consequences of these differences as well as the effectiveness of therapies aimed at modifying the gut microbial composition in CFS patients.

Source: Prylińska-Jaśkowiak M, Tabisz H, Kujawski S, Godlewska BR, Słomko J, Januszko-Giergielewicz B, Murovska M, Morten KJ, Sokołowski Ł, Zalewski P. The gut microbial composition is different in chronic fatigue syndrome than in healthy controls. Sci Rep. 2025 Sep 26;15(1):33075. doi: 10.1038/s41598-025-16438-y. PMID: 41006438. https://www.nature.com/articles/s41598-025-16438-y (Full text)

Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. ME/CFS patients often report a prodrome consistent with infection. We present a multi-omics analysis based on plasma metabolomic and proteomic profiling, and immune responses to microbial stimulation, before and after exercise.

We report evidence of an exaggerated innate immune response after exposures to microbial antigens; impaired energy production involving the citric acid cycle, beta-oxidation of fatty acids, and urea cycle energy production from amino acids; systemic inflammation linked with lipid abnormalities; disrupted extracellular matrix homeostasis with release of endogenous ligands that promote inflammation; reduced cell-cell adhesion and associated gut dysbiosis; complement activation; redox imbalance reflected by disturbances in copper-dependent antioxidant pathways and dysregulation of the tryptophan-serotonin-kynurenine pathways.

Many of these underlying abnormalities worsened following exercise in ME/CFS patients, but not in healthy subjects; many abnormalities reinforced each other and several were correlated with the intensity of symptoms. Our findings may inform targeted therapeutic interventions for ME/CFS and PEM.

Source: Che X, Ranjan A, Guo C, Zhang K, Goldsmith R, Levine S, Moneghetti KJ, Zhai Y, Ge L, Mishra N, Hornig M, Bateman L, Klimas NG, Montoya JG, Peterson DL, Klein SL, Fiehn O, Komaroff AL, Lipkin WI. Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS. medRxiv [Preprint]. 2025 Jul 24:2025.07.23.25332049. doi: 10.1101/2025.07.23.25332049. PMID: 40778181; PMCID: PMC12330418. https://pmc.ncbi.nlm.nih.gov/articles/PMC12330418/ (Full text available as PDF file)

Concentrations of uremic bacterial metabolites in patients with post-COVID-19 syndrome

Abstract:

Post-COVID-19 syndrome (PCS) is characterized by persistent symptoms and reduced mental and physical performance following the acute phase of COVID-19. The underlying mechanisms remain unclear but may involve gut microbiota dysbiosis and immune-related changes in amino acid metabolism. This pilot study aimed to investigate whether specific bacterial uremic metabolites (BUM) are altered in patients with post-infectious syndromes and whether these alterations are associated with PCS symptoms.

We examined BUM in 25 PCS patients, 8 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients, and 8 healthy controls (Ctrls). Concentrations of BUM were determined in second morning urine samples using mass spectrometry (Biovis Diagnostik, Limburg, Germany). Standardized questionnaires assesed physical, cognitive, psychological, and somatic symptoms and mental health status.

PCS and ME/CFS patients exhibited significantly higher scores for post-exertional malaise (PEM) and somatic symptom severity compared to healthy controls (p<0.001). Elevated BUM concentrations were found in 64% of PCS patients, compared to 37.5% of both healthy controls and ME/CFS patients. While overall BUM levels did not significantly differ between groups, heatmap clustering revealed distinct metabolic patterns.

Elevated tryptamine and 4-hydroxyphenylpropionic acid (HPHPA) and higher hippuric acid and trimethylamine concentrations, were exclusively analysed in patients with post-infectious syndromes. Our pilot study suggests that urine metabolomic analysis may be a useful approach for investigating the role of gut dysbiosis and BUM in patients with PCS.

Source: Brigo N, Mayr W, Taenzer M, Löffler-Ragg J, Schroll A, Engl S, Schütz B, Rappl P, Heine T, Weiss G, Kurz K. Concentrations of uremic bacterial metabolites in patients with post-COVID-19 syndrome. Front Cell Infect Microbiol. 2025 May 29;15:1582972. doi: 10.3389/fcimb.2025.1582972. PMID: 40510799; PMCID: PMC12159039. https://pmc.ncbi.nlm.nih.gov/articles/PMC12159039/ (Full text)