Tag: inflammation

Preventive Effects of Probiotic Formula on Metabolic Stress Associated Physical Fatigue in Forced Swimming and LPS-Induced Mouse Models

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder characterized by persistent fatigue and post-exertional symptom exacerbation, frequently associated with immune and metabolic disturbances. To evaluate the therapeutic potential of a probiotic formula, HH-205M, we employed a composite mouse model combining forced swimming stress (FSS) and repeated lipopolysaccharide (LPS) administration. FSS-LPS exposure induced pronounced fatigue-like phenotypes, including reduced physical endurance capacity in treadmill and weight-loaded swimming tests, delayed recovery in post-swim grooming behavior, and increased thermal pain sensitivity.

These behavioral impairments were accompanied by elevated serum creatine kinase (CK), lactate dehydrogenase (LDH), and lactate levels, indicating systemic metabolic stress. At the tissue level, FSS-LPS increased lipid peroxidation and upregulated pro-inflammatory cytokine expression while suppressing antioxidant gene expression in the gastrocnemius muscle. Furthermore, expression of lactate-related genes, Hcar1 (GPR81) and Slc16a1 (MCT1), was reduced, suggesting disruption of lactate transport and sensing pathways under chronic stress and inflammatory conditions.

HH-205M supplementation attenuated the elevations in circulating fatigue-related biomarkers, moderated oxidative and inflammatory responses, and restored Hcar1 and Slc16a1 expression.

These molecular changes were paralleled by improvements in endurance performance and nociceptive sensitivity. HH-205M administration was also associated with distinct shifts in gut microbial composition, including enrichment of Akkermansia and Bacteroides and reduced relative abundance of Alistipes.

Collectively, these findings indicate that the FSS-LPS composite model recapitulates inflammation-associated metabolic disturbances relevant to fatigue-like conditions and that HH-205M administration is associated with concurrent improvements in behavioral and molecular parameters in this model.

Source: Song JG, Bae HJ, Lee DH, Seo J, Lee B, Shin KJ, Chung EC, Lee J, Kim HW, Oh NS. Preventive Effects of Probiotic Formula on Metabolic Stress Associated Physical Fatigue in Forced Swimming and LPS-Induced Mouse Models. J Microbiol Biotechnol. 2026 Apr 10;36:e2603034. doi: 10.4014/jmb.2603.03034. PMID: 41958144. https://pubmed.ncbi.nlm.nih.gov/41958144/

A multiomics recovery factor predicts long COVID in the IMPACC study

Abstract:

BACKGROUND: Following SARS-CoV-2 infection, approximately 10%–35% of patients with COVID-19 experience long COVID (LC), in which debilitating symptoms persist for at least 3 months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities.

METHODS: We utilized machine learning methods on biologic analytes provided over 12 months after hospital discharge from more than 500 patients with COVID-19 in the IMPACC cohort to identify a multiomics “recovery factor,” trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood mass cytometry by time of flight (CyTOF) protein levels. Recovery factor scores were tested for association with LC, disease severity, clinical parameters, and immune subset frequencies. Enrichment analyses identified biologic pathways associated with recovery factor scores.

RESULTS: Participants with LC had lower recovery factor scores compared with recovered participants. Recovery factor scores predicted LC as early as hospital admission, irrespective of acute COVID-19 severity. Biologic characterization revealed increased inflammatory mediators, elevated signatures of heme metabolism, and decreased androgenic steroids as predictive and ongoing biomarkers of LC. Lower recovery factor scores were associated with reduced lymphocyte and increased myeloid cell frequencies. The observed signatures are consistent with persistent inflammation driving anemia and stress erythropoiesis as major biologic underpinnings of LC.

CONCLUSION: The multiomics recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04378777.

FUNDING:

National Institute of Allergy and Infectious Diseases (NIAID), NIH (3U01AI167892-03S2, 3U01AI167892-01S2, 5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI057229-18, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07S1, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-1, 3U19AI1289130, U19AI128913-04S1, R01AI122220); NIH (UM1TR004528); and National Science Foundation (NSF) (DMS2310836).

Source: Gabernet G, Maciuch J, Gygi JP, Moore JF, Hoch A, Syphurs C, Chu T, Doni Jayavelu N, Corry DB, Kheradmand F, Baden LR, Sekaly RP, McComsey GA, Haddad EK, Cairns CB, Rouphael N, Fernandez-Sesma A, Simon V, Metcalf JP, Agudelo Higuita NI, Hough CL, Messer WB, Davis MM, Nadeau KC, Pulendran B, Kraft M, Bime C, Reed EF, Schaenman J, Erle DJ, Calfee CS, Atkinson MA, Brakenridge SC, Melamed E, Shaw AC, Hafler DA, Augustine AD, Becker PM, Ozonoff A, Bosinger SE, Eckalbar W, Maecker HT, Kim-Schulze S, Steen H, Krammer F, Westendorf K; IMPACC Network; Peters B, Fourati S, Altman MC, Levy O, Smolen KK, Montgomery RR, Diray-Arce J, Kleinstein SH, Guan L, Ehrlich LI. A multiomics recovery factor predicts long COVID in the IMPACC study. J Clin Invest. 2025 Sep 9;135(21):e193698. doi: 10.1172/JCI193698. PMID: 40924481; PMCID: PMC12582403. https://pmc.ncbi.nlm.nih.gov/articles/PMC12582403/ (Full text)

Genetic depletion of the early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to the M1 inflammatory mode, and compromises myelin integrity in skeletal muscle

Abstract:

Objective: M1 macrophage activation is crucial in chronic inflammatory diseases, yet its molecular mechanism is unclear.

Results: Our study showed that hemizygous deletion of the early autophagy gene atg13 (Tg+/-ATG13) disrupts cellular autophagy, hinders mitochondrial oxidative metabolism, and increases reactive oxygen species (ROS) levels in splenic macrophages, leading to M1 polarization. After reducing the expression of the autophagy markers WDFY3 and LC3, flow cytometric analysis of M1/M2 markers (CD40, CD86, CD115, CD163, and CD206), decreasing oxygen metabolism, as evaluated by the ROS-sensor dye DCFDA, and Seahorse oxygen consumption studies revealed that ablation of the atg13 gene impairs mitochondrial function, triggering M1 polarization.

Additionally, redox imbalance may impair Sirtuin-1 activity via nitrosylation, increasing the level of acetylated p65 in macrophages and contributing to the inflammatory response in M1Mφs. Additionally, ablation of the atg13 gene resulted in increased infiltration of M1Mφs into the muscle vasculature, deterioration of myelin integrity in nerve bundles, and a reduction in muscle strength following treadmill exercise.

Conclusions: Our study shows that impaired ATG13-driven autophagy increases inflammation through sirtuin-1 inactivation and NF-κB activation, suggesting a role for ATG13 in post-exertional malaise (PEM).

Source: Toriola MA, Timlin E, Bulbule S, Reyes A, Adedeji OM, Gottschalk CG, Barua A, Arnold LA, Roy A. Genetic depletion of the early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to the M1 inflammatory mode, and compromises myelin integrity in skeletal muscle. Inflamm Res. 2026 Jan 27;75(1):26. doi: 10.1007/s00011-025-02158-6. PMID: 41591477; PMCID: PMC12847126. https://pmc.ncbi.nlm.nih.gov/articles/PMC12847126/ (Full text)

Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution. Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms.

The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes. Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID.

The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue.

Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.

Source: Nunes M, Kell L, Slaghekke A, Wüst RC, Fielding BC, Kell DB, Pretorius E. Virus-induced endothelial senescence as a cause and driving factor for ME/CFS and long COVID: mediated by a dysfunctional immune system. Cell Death Dis. 2026 Jan 9;17(1):16. doi: 10.1038/s41419-025-08162-2. PMID: 41513611; PMCID: PMC12789617. https://pmc.ncbi.nlm.nih.gov/articles/PMC12789617/ (Full text)

Urinary Peptidomic Profiling In Post-Acute Sequelae of SARS-CoV-2 Infection: A Case-Control Study

Abstract:

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2-infection (PASC) is challenging to diagnose and treat, and its molecular pathophysiology remains unclear. Urinary peptidomics can provide valuable information on urine peptides that may enable improved and specified PASC diagnosis.
Using standardized capillary electrophoresis-MS, we examined the urinary peptidomes of 50 patients with PASC 10 months after COVID-19 and 50 controls, including healthy individuals (n = 42) and patients with non-COVID-19-associated myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (n = 8).Based on peptide abundance differences between cases and controls, we developed a diagnostic model using a support vector machine. The abundance of 195 urine peptides among PASC patients significantly differed from that in controls, with a predominant abundance of collagen alpha chains. This molecular signature (PASC195) effectively distinguished PASC cases from controls in the training set (AUC of 0.949 [95% CI 0.900–0.998; p < 0.0001]) and independent validation set (AUC of 0.962 [95% CI 0.897–1.00]; p < 0.0001]). In silico assessment suggested exercise, GLP-1RAs and mineralocorticoid receptor antagonists (MRAs) as potentially efficacious interventions. We present a novel and non-invasive diagnostic model for PASC. Reflecting its molecular pathophysiology, PASC195 has the potential to advance diagnostics and inform therapeutic interventions.

Statement of Significance of the Study

Despite the recent emergence of omics-derived candidates for post-acute sequelae of SARS-CoV-2 infection (PASC), the pending validation of proposed markers and lack of consensus result in the continuous reliance on symptom-based criteria, being subject to diagnostic uncertainties and potential recall bias. Building upon prior findings of renal involvement in acute COVID-19 pathophysiology and PASC-associated alterations, we hypothesized that the use of urinary peptides for PASC-specific biomarker discovery, unlike conventional specimens that have been utilized thus far, may offer complementary information on putative disease mechanisms.

In the present study, 195 significantly expressed peptides were used to form a classifier termed PASC195, which effectively discriminated PASC from non-PASC (p < 0.0001), including healthy individuals and non-COVID-19-associated myalgic encephalomyelitis/chronic fatigue syndrome, in both the derivation (n = 60) and an independent validation set (n = 40). The peptidome profile associated with PASC was consistent with a shift in collagen turnover, with most PASC195 peptides derived from alpha chains. Ongoing inflammatory responses, hemostatic imbalances, and endothelial damage were indicated by cross-sectional variations in endogenous peptide excretion.

Source: Gülmez D, Siwy J, Kurz K, Wendt R, Banasik M, Peters B, Dudoignon E, Depret F, Salgueira M, Nowacki E, Kurnikowski A, Mussnig S, Krenn S, Gonos S, Löffler-Ragg J, Weiss G, Mischak H, Hecking M, Schernhammer E, Beige J; UriCoV Working Group. Urinary Peptidomic Profiling In Post-Acute Sequelae of SARS-CoV-2 Infection: A Case-Control Study. Proteomics. 2025 Nov 21:e70074. doi: 10.1002/pmic.70074. Epub ahead of print. PMID: 41273049. https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/pmic.70074 (Full text)

Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion

Abstract:

The overarching symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM), an exacerbation of symptoms following physical or mental exertion. To investigate the molecular underpinnings of PEM, we performed longitudinal plasma proteomics using the Somascan® 7K aptamer-based assay to monitor 6,361 unique plasma proteins in 132 individuals (96 females and 36 males) subjected to two maximal cardiopulmonary exercise tests separated by a 24-hour recovery period.

The cohort included 79 ME/CFS cases compared to 53 age- and BMI-matched sedentary controls, allowing us to distinguish disease-specific molecular alterations from those due to physical deconditioning. Longitudinal profiling revealed widespread proteomic changes following exertion, with the most pronounced alterations observed in ME/CFS participants during the recovery phase, coinciding with the onset of PEM.

Compared to controls, ME/CFS subjects showed persistent dysregulation of immune, metabolic, and neuromuscular pathways. Key findings included suppression of T and B cell signaling, downregulation of IL-17 and cell-cell communication pathways, and upregulation of glycolysis/gluconeogenesis, suggestive of mitochondrial stress and impaired immune recovery from exercise. Proteomic associations with physiological performance (VO2max, anaerobic threshold) revealed disruptions between protein abundance and exercise capacity in ME/CFS versus controls.

Correlations with symptom severity linked changes in immune-related proteins and ME/CFS symptoms including muscle pain, recurrent sore throat, and lymph node tenderness. Sex-stratified analyses revealed distinct molecular responses between females and males, emphasizing the importance of considering sex as a biological variable in ME/CFS research.

Finally, our analysis of sedentary controls contributes new data of molecular responses to acute exertion in a predominantly female sedentary cohort, a population historically underrepresented in exercise physiology studies. Together, these findings underscore the value of dynamic, proteomic profiling over time for characterizing maladaptive responses to exertion in ME/CFS and provide a foundation for deeper mechanistic investigation into PEM.

Source: Germain A, Glass KA, Eckert MA, Giloteaux L, Hanson MR. Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion. Mol Cell Proteomics. 2025 Nov 12:101467. doi: 10.1016/j.mcpro.2025.101467. Epub ahead of print. PMID: 41237904. https://www.mcponline.org/article/S1535-9476(25)00566-3/fulltext (Full text)

Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS

Abstract:

Long COVID (LC) manifests with sex-specific differences, particularly in those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our study reveals that female LC patients (LCF) with ME/CFS show a shift toward myelopoiesis, reduced lymphocytes, increased neutrophils/monocytes, and depleted regulatory T cells-suggesting persistent immune activation. Elevated CD71+ erythroid cells and disrupted erythropoiesis contribute to fatigue and tissue damage in LCF.

Cytokine profiling indicates a stronger pro-inflammatory response in LCF compared to males (LCM), along with markers of gut barrier dysfunction. Hormonal analysis shows reduced testosterone in LCF and estradiol in LCM. Transcriptomic data reveal neuroinflammatory signatures in LCF, potentially explaining cognitive symptoms. We also identify biomarkers that distinguish LCF from LCM and correlate with sex-specific clinical symptoms.

Overall, LC with ME/CFS is characterized by sex-specific immune, hormonal, and transcriptional alterations, with females exhibiting more severe inflammation. These insights underscore the need for sex-tailored interventions, including consideration of hormone replacement therapy.

Source: Shahbaz S, Osman M, Syed H, Mason A, Rosychuk RJ, Cohen Tervaert JW, Elahi S. Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS. Cell Rep Med. 2025 Nov 7:102449. doi: 10.1016/j.xcrm.2025.102449. Epub ahead of print. PMID: 41205594. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00522-1 (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)

A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID

Abstract:
The underlying pathologies driving post-acute infectious syndromes (e.g. myalgic encephalomyelitis / chronic fatigue syndrome, long COVID, etc) remain poorly understood. Given the extreme burden these illnesses impose on suffers, and the dramatic increase in cases following the COVID-19 pandemic, it is important to establish a deeper understanding of these pathologies.
We propose a model of how ME/CFS (and related illnesses), might emerge following a viral insult. Central to this hypothesis is the recognition that the core diagnostic features of ME/CFS involve bodily systems known to be governed by the brainstem. This is consistent with the growing literature suggesting that spinal and craniocervical pathologies are over-represented in people with ME/CFS and other post-infectious disorders.
We hypothesize that a non-trivial number of cases of ME/CFS and Long Covid (LC) may have a “mechanical basis.” We propose that an infectious insult may trigger an initial loss of connective tissue integrity in susceptible individuals (e.g. those with pre-existing hypermobility spectrum disorders), which in turn leads to instability at the craniocervical junction, and ultimately mechanical deformation of the brainstem. This ultimately causes widespread autonomic nervous system and immune system dysfunction due to aberrant signaling from the deformed nuclei.
This causal chain may also lead to a vicious cycle: if the dysregulation produced by the initial brainstem deformation leads to a deranged immune response or state of chronic hyper-inflammation, further expression of connective tissue degrading and remodeling factors such as MMPs and mast cells may be triggered. This could further degrade the connective tissues of the craniocervical junction and, in turn, increase mechanical deformation of the brainstem, leading to symptom exacerbation over time and leading to the chronic, lifelong presentation typical of ME/CFS.
Source: Wood, J., Varley, T., Hartman, J., Melia, N., Kaufman, D., & Falor, T. (2025). A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID. Preprints. https://doi.org/10.20944/preprints202506.0874.v1 https://www.preprints.org/manuscript/202506.0874/v1 (Full text)

Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection

Abstract:

SARS-CoV-2 can cause a variety of post-acute sequelae including Long COVID19 (LC), a complex, multisystem disease characterized by a broad range of symptoms including fatigue, cognitive impairment, and post-exertional malaise. The pathogenesis of LC is incompletely understood.

In this study, we performed comprehensive cellular and transcriptional immunometabolic profiling within a cohort that included SARS-CoV-2-naïve controls (NC, N=30) and individuals with prior COVID-19 (~4-months) who fully recovered (RC, N=38) or went on to experience Long COVID symptoms (N=58).

Compared to the naïve controls, those with prior COVID-19 demonstrated profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level. Specifically, there was an enrichment in immature monocytes with sustained inflammasome activation and oxidative stress, elevated arachidonic acid levels, decreased tryptophan, and variation in the frequency and phenotype of peripheral T-cells. Those with LC had increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes by single cell RNA sequencing. Our findings support a profound and persistent immunometabolic dysfunction that follows SARS-CoV-2 which may form the pathophysiologic substrate for LC.

Our findings suggest that trials of therapeutics that help restore immune and metabolic homeostasis may be warranted to prevent, reduce, or resolve LC symptoms.

Source: Lage SL, Bricker-Holt K, Rocco JM, Rupert A, Donovan FX, Abramzon YA, Chandrasekharappa SC, McNinch C, Cook L, Amaral EP, Rosenfeld G, Dalhuisen T, Eun A, Hoh R, Fehrman E, Martin JN, Deeks SG, Henrich TJ, Peluso MJ, Sereti I. Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection. medRxiv [Preprint]. 2025 Apr 17:2025.04.16.25325949. doi: 10.1101/2025.04.16.25325949. PMID: 40321289; PMCID: PMC12047922. https://pmc.ncbi.nlm.nih.gov/articles/PMC12047922/ (Full text)