Tag: microbiome

The gastrointestinal microbiota in the development of ME/CFS: a critical view and potential perspectives

Abstract:

Like other infections, a SARS-CoV-2 infection can also trigger Post-Acute Infection Syndromes (PAIS), which often progress into myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS, characterized by post-exercise malaise (PEM), is a severe multisystemic disease for which specific diagnostic markers or therapeutic concepts have not been established.

Despite numerous indications of post-infectious neurological, immunological, endocrinal, and metabolic deviations, the exact causes and pathophysiology remain unclear. To date, there is a paucity of data, that changes in the composition and function of the gastrointestinal microbiota have emerged as a potential influencing variable associated with immunological and inflammatory pathways, shifts in ME/CFS. It is postulated that this dysbiosis may lead to intestinal barrier dysfunction, translocation of microbial components with increased oxidative stress, and the development or progression of ME/CFS.

In this review, we detailed discuss the findings regarding alterations in the gastrointestinal microbiota and its microbial mediators in ME/CFS. When viewed critically, there is currently no evidence indicating causality between changes in the microbiota and the development of ME/CFS. Most studies describe associations within poorly defined patient populations, often combining various clinical presentations, such as irritable bowel syndrome and fatigue associated with ME/CFS.

Nevertheless, drawing on analogies with other gastrointestinal diseases, there is potential to develop strategies aimed at modulating the gut microbiota and/or its metabolites as potential treatments for ME/CFS and other PAIS. These strategies should be further investigated in clinical trials.

Source: Andreas Stallmach, Stefanie Quickert, Christian Puta, Philipp A. Reuken. The gastrointestinal microbiota in the development of ME/CFS: a critical view and potential perspectives. Front. Immunol., 27 March 2024, Sec. Microbial Immunology, Volume 15 – 2024. https://doi.org/10.3389/fimmu.2024.1352744 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1352744/full (Full text)

Clinical evidence of the link between gut microbiome and myalgic encephalomyelitis/chronic fatigue syndrome: a retrospective review

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous disorder with elusive causes, but most likely because of clinical and other biological factors. As a vital environmental factor, the gut microbiome is increasingly emphasized in various refractory diseases including ME/CFS. The present study is aimed to enhance our understanding of the relationship between the gut microbiome and ME/CFS through data analysis of various clinical studies.

We conducted a literature search in four databases (PubMed, Cochrane Library, Web of Science, and Google Scholar) until May 31, 2023. Our analysis encompassed 11 clinical studies with 553 ME/CFS patients and 480 healthy controls. A comparative analysis of meta data revealed a significant decrease in α-diversity and a noticeable change in β-diversity in the gut microbiome of ME/CFS patients compared to healthy controls.

The notable ratio of Firmicutes and Bacteroides was 2.3 times decreased, and also, there was a significant reduction in the production of microbial metabolites such as acetate, butyrate, isobutyrate, and some amino acids (alanine, serine, and hypoxanthine) observed in ME/CFS patients.

The lack of comparison under similar conditions with various standardized analytical methods has impeded the optimal calculation of results in ME/CFS patients and healthy controls. This review provides a comprehensive overview of the recent advancements in understanding the role of the gut microbiome in ME/CFS patients. Additionally, we have also discussed the potentials of using microbiome-related interventions and associated challenges to alleviate ME/CFS.

Source: Wang JH, Choi Y, Lee JS, Hwang SJ, Gu J, Son CG. Clinical evidence of the link between gut microbiome and myalgic encephalomyelitis/chronic fatigue syndrome: a retrospective review. Eur J Med Res. 2024 Mar 1;29(1):148. doi: 10.1186/s40001-024-01747-1. PMID: 38429822. https://eurjmedres.biomedcentral.com/articles/10.1186/s40001-024-01747-1 (Full text)

Gut microbiota composition is altered in postural orthostatic tachycardia syndrome and post-acute COVID-19 syndrome

Abstract:

Postural Orthostatic Tachycardia Syndrome (POTS) reflects an autonomic dysfunction, which can occur as a complication to COVID-19. Our aim was to examine gastrointestinal symptoms and gut microbiota composition in patients with POTS and post-acute COVID-19 syndrome (PACS), compared with controls. POTS patients (n = 27), PACS patients (n = 32) and controls (n = 39) delivered fecal samples and completed a 4-day food diary, irritable bowel syndrome-severity scoring system (IBS-SSS), and visual analog scale for IBS (VAS-IBS).

A total of 98 DNA aliquots were sequenced to an average depth of 28.3 million (M) read pairs (Illumina 2 × 150 PE) per sample. Diversity and taxonomic levels of the microbiome, as well as functional abundances were calculated for POTS and PACS groups, then compared with controls. There were several differences in taxonomic composition between POTS and controls, whereas only the abundance of Ascomycota and Firmicutes differed between PACS and controls. The clinical variables total IBS-SSS, fatigue, and bloating and flatulence significantly correlated with multiple individual taxa abundances, alpha diversity, and functional abundances.

We conclude that POTS, and to a less extent PACS, are associated with differences in gut microbiota composition in diversity and at several taxonomic levels. Clinical symptoms are correlated with both alpha diversity and taxonomic and functional abundances.

Source: Hamrefors V, Kahn F, Holmqvist M, Carlson K, Varjus R, Gudjonsson A, Fedorowski A, Ohlsson B. Gut microbiota composition is altered in postural orthostatic tachycardia syndrome and post-acute COVID-19 syndrome. Sci Rep. 2024 Feb 9;14(1):3389. doi: 10.1038/s41598-024-53784-9. PMID: 38336892; PMCID: PMC10858216. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10858216/ (Full text)

The Microbiota in Long COVID

Abstract:

Interest in the coronavirus disease 2019 (COVID-19) has progressively decreased lately, mainly due to the great effectivity of vaccines. Furthermore, no new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants able to circumvent the protection of these vaccines, while presenting high transmissibility and/or lethality, have appeared. However, long COVID has emerged as a huge threat to human health and economy globally.
The human microbiota plays an important role in health and disease, participating in the modulation of innate and adaptive immune responses. Thus, multiple studies have found that the nasopharyngeal microbiota is altered in COVID-19 patients, with these changes associated with the onset and/or severity of the disease.
Nevertheless, although dysbiosis has also been reported in long COVID patients, mainly in the gut, little is known about the possible involvement of the microbiota in the development of this disease. Therefore, in this work, we aim to fill this gap in the knowledge by discussing and comparing the most relevant studies that have been published in this field up to this point.
Hence, we discuss that the relevance of long COVID has probably been underestimated, and that the available data suggest that the microbiota could be playing a pivotal role on the pathogenesis of the disease. Further research to elucidate the involvement of the microbiota in long COVID will be essential to explore new therapeutic strategies based on manipulation of the microbiota.
Source: Álvarez-Santacruz C, Tyrkalska SD, Candel S. The Microbiota in Long COVID. International Journal of Molecular Sciences. 2024; 25(2):1330. https://doi.org/10.3390/ijms25021330 https://www.mdpi.com/1422-0067/25/2/1330 (Full text)

Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn’s Disease and chronic fatigue syndrome

Abstract:

Background: Patients with Crohn’s disease (CD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) exhibit elevated antibody responses against gut microbiota flagellins. However, flagellin-specific antibody repertoires and functional roles in the diseases remain incompletely understood. Bacterial flagellins can be categorized into three types depending on their interaction with toll-like receptor 5 (TLR5): (1) “stimulator” and (2) “silent” flagellins, binding TLR5 through a conserved N-terminal motif, with only stimulators activating TLR5 due to a specific C-terminal domain; (3) “evader” flagellins of pathogens, which circumvent TLR5 activation via mutated N-terminal TLR5 binding motifs. Here we studied the characteristics, epitope binding, and sequence (dis)similarity of anti-flagellin antibody responses in CD and ME/CFS.
Methods: Since conventional antibody profiling methods like enzyme-linked immunosorbent assays [ELISAs] do not allow for large-scale measurements of antibody repertoires, we leveraged phage-display immunoprecipitation sequencing (PhIP-Seq) to characterize 344,000 rationally selected peptide antigens in 256 patients with CD, 40 patients with ME/CFS and in two equally sized groups of age- and sex-matched healthy controls from population-based cohorts in the Netherlands and U.K., respectively. Different sequence alignment strategies were employed to compare flagellin peptide structures with observed antibody-bound flagellin peptide reactivity.
Results: Both patients with CD and ME/CFS exhibited elevated antibody responses against distinct regions of flagellin peptides compared to healthy individuals (P<0.001). N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling ‘stimulator’ and ‘silent’ flagellins more than evaders. However, C-terminal antibody-bound flagellins showed higher resemblance to stimulator than to silent flagellins in CD, but not in ME/CFS. This group of antibody-bound flagellins was exclusively identified in a subset (10-20%) of patients with CD and characterized by its strong overrepresentation (exceeding 20-fold), underscoring its potential significance in distinguishing pathophysiologic subtypes of CD.
Conclusion: Antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between diseases. Our results highlight the diagnostic potential of these antibody responses and their impact on innate/adaptive immunity balance.

Source: A R Bourgonje, N V Hörstke, M Fehringer, G Innocenti, T Vogl, DOP27 Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn’s Disease and chronic fatigue syndrome, Journal of Crohn’s and Colitis, Volume 18, Issue Supplement_1, January 2024, Page i122, https://doi.org/10.1093/ecco-jcc/jjad212.0067 https://academic.oup.com/ecco-jcc/article/18/Supplement_1/i122/7586226 (Full text available as PDF file)

Nutrition and Chronobiology as Key Components of Multidisciplinary Therapeutic Interventions for Fibromyalgia and Associated Chronic Fatigue Syndrome: A Narrative and Critical Review

Abstract:

Fibromyalgia (FM) is often accompanied by chronic fatigue syndrome (CFS). It is a poorly understood disorder that mainly affects women and leads to chronic pain, fatigue, and insomnia, among other symptoms, which decrease quality of life. Due to the inefficiency of current pharmacological treatments, increasing interest is being directed towards non-pharmacological multicomponent therapies. However, nutrition and chronobiology are often overlooked when developing multicomponent therapies.

This narrative and critical review explore the relevance of nutritional and chronobiological strategies in the therapeutic management of FM and the often-associated CFS. Reviewed literature offers scientific evidence for the association of dietary habits, nutrient levels, body composition, gut microbiota imbalance, chronobiological alterations, and their interrelation with the development and severity of symptoms. This review highlights the key role of nutrition and chronobiology as relevant and indispensable components in a multidisciplinary approach to FM and CFS.

Source: Carrasco-Querol N, Cabricano-Canga L, Bueno Hernández N, Gonçalves AQ, Caballol Angelats R, Pozo Ariza M, Martín-Borràs C, Montesó-Curto P, Castro Blanco E, Dalmau Llorca MR, et al. Nutrition and Chronobiology as Key Components of Multidisciplinary Therapeutic Interventions for Fibromyalgia and Associated Chronic Fatigue Syndrome: A Narrative and Critical Review. Nutrients. 2024; 16(2):182. https://doi.org/10.3390/nu16020182 https://www.mdpi.com/2072-6643/16/2/182 (Full text)

Gut Microbiome Composition and Dynamics in Hospitalized COVID-19 Patients and Patients with Post-Acute COVID-19 Syndrome

Abstract:

The gut microbiome plays a pivotal role in the modulation of host responses during viral infections, and recent studies have underscored its significance in the context of coronavirus disease 2019 (COVID-19). We aimed to investigate the dynamics and compositional changes in the gut microbiome of COVID-19 patients, addressing both the acute phase and the recovery process, with a particular focus on the emergence of post-COVID-19 conditions.
Involving 146 COVID-19 patients and 110 healthy controls, this study employed a shotgun metagenomics approach for cross-sectional and longitudinal analyses with one- and three-month follow-ups. We observed a decline in taxonomic diversity among hospitalized COVID-19 patients compared to healthy controls, while a subsequent increase in alpha diversity was shown during the recovery process.
A notable contribution of Enterococcus faecium was identified in the acute phase of the infection, accompanied by an increasing abundance of butyrate-producing bacteria (e.g., Roseburia, Lachnospiraceae_unclassified) during the recovery period. We highlighted a protective role of the Prevotella genus in the long-term recovery process and suggested a potential significance of population-specificity in the early gut microbiome markers of post-acute COVID-19 syndrome.
Our study represents distinctive gut microbiome signatures in COVID-19, with potential diagnostic and prognostic implications, pinpointing potential modulators of the disease progression.
Source: Brīvība M, Silamiķele L, Birzniece L, Ansone L, Megnis K, Silamiķelis I, Pelcmane L, Borisova D, Rozenberga M, Jagare L, et al. Gut Microbiome Composition and Dynamics in Hospitalized COVID-19 Patients and Patients with Post-Acute COVID-19 Syndrome. International Journal of Molecular Sciences. 2024; 25(1):567. https://doi.org/10.3390/ijms25010567 https://www.mdpi.com/1422-0067/25/1/567 (Full text)

Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach

Abstract:

The dermatological manifestations of Long Covid (LC) have languished in the shadows of chronic fatigue and brain fog. Yet they are all linked by gut dysbiosis and the cytokine triad of TNF-α, IL-1β, and IL-6. The gut microbiome common not only to LC, psoriasis, AA, and vitiligo but also to neurodegenerative disease has been recently described. This gut microbiome induces an altered tryptophan metabolism linked to autoimmune disease. SARS CoV2 invades enterochromaffin cells rich in ACE2 receptors and curtails absorption of the essential amino acid tryptophan and subsequent synthesis of serotonin and melatonin.

This review suggests that an etiologic prebiotic (d-mannose)/probiotic (lactobacilli, bifidobacteria)/postbiotic (butyrate) approach to autoimmune skin disease that improves intestinal barrier integrity and that suppresses the triad of TNF-α, IL-6, and IL-1β may enhance or even eliminate the traditional immunotherapy of targeted monoclonal antibodies, Janus kinase inhibitors, and steroids. Health benefits of this approach extend well beyond suppression of autoimmune skin disease.

Source: Chambers, P.W.; Chambers, S.E. Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach. Preprints 2023, 2023121881. https://doi.org/10.20944/preprints202312.1881.v2 https://www.preprints.org/manuscript/202312.1881/v2 (Full text available as PDF file)

KombOver: Efficient k-core and K-truss based characterization of perturbations within the human gut microbiome

Abstract:

The microbes present in the human gastrointestinal tract are regularly linked to human health and disease outcomes. Thanks to technological and methodological advances in recent years, metagenomic sequencing data, and computational methods designed to analyze metagenomic data, have contributed to improved understanding of the link between the human gut microbiome and disease. However, while numerous methods have been recently developed to extract quantitative and qualitative results from host-associated microbiome data, improved computational tools are still needed to track microbiome dynamics with short-read sequencing data.

Previously we have proposed KOMB as a de novo tool for identifying copy number variations in metagenomes for characterizing microbial genome dynamics in response to perturbations. In this work, we present KombOver (KO), which includes four key contributions with respect to our previous work: (i) it scales to large microbiome study cohorts, (ii) it includes both k-core and K-truss based analysis, (iii) we provide the foundation of a theoretical understanding of the relation between various graph-based metagenome representations, and (iv) we provide an improved user experience with easier-to-run code and more descriptive outputs/results.

To highlight the aforementioned benefits, we applied KO to nearly 1000 human microbiome samples, requiring less than 10 minutes and 10 GB RAM per sample to process these data. Furthermore, we highlight how graph-based approaches such as k-core and K-truss can be informative for pinpointing microbial community dynamics within a myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) cohort. KO is open source and available for download/use at: https://github.com/treangenlab/komb.

Source: Sapoval N, Tanevski M, Treangen TJ. KombOver: Efficient k-core and K-truss based characterization of perturbations within the human gut microbiome. Pac Symp Biocomput. 2024;29:506-520. PMID: 38160303; PMCID: PMC10764071. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10764071/ (Full text)

Dysregulation of the Kynurenine Pathway, Cytokine Expression Pattern, and Proteomics Profile Link to Symptomology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Dysregulation of the kynurenine pathway (KP) is believed to play a significant role in neurodegenerative and cognitive disorders. While some evidence links the KP to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), further studies are needed to clarify the overall picture of how inflammation-driven KP disturbances may contribute to symptomology in ME/CFS.

Here, we report that plasma levels of most bioactive KP metabolites differed significantly between ME/CFS patients and healthy controls in a manner consistent with their known contribution to symptomology in other neurological disorders. Importantly, we found that enhanced production of the first KP metabolite, kynurenine (KYN), correlated with symptom severity, highlighting the relationship between inflammation, KP dysregulation, and ME/CFS symptomology.

Other significant changes in the KP included lower levels of the downstream KP metabolites 3-HK, 3-HAA, QUIN, and PIC that could negatively impact cellular energetics. We also rationalized KP dysregulation to changes in the expression of inflammatory cytokines and, for the first time, assessed levels of the iron (Fe)-regulating hormone hepcidin that is also inflammation-responsive. Levels of hepcidin in ME/CFS decreased nearly by half, which might reflect systemic low Fe levels or possibly ongoing hypoxia.

We next performed a proteomics screen to survey for other significant differences in protein expression in ME/CFS. Interestingly, out of the seven most significantly modulated proteins in ME/CFS patient plasma, 5 proteins have roles in maintaining gut health, which considering the new appreciation of how gut microbiome and health modulates systemic KP could highlight a new explanation of symptomology in ME/CFS patients and potential new prognostic biomarker/s and/or treatment avenues.

Source: Kavyani B, Ahn SB, Missailidis D, Annesley SJ, Fisher PR, Schloeffel R, Guillemin GJ, Lovejoy DB, Heng B. Dysregulation of the Kynurenine Pathway, Cytokine Expression Pattern, and Proteomics Profile Link to Symptomology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Mol Neurobiol. 2023 Nov 28. doi: 10.1007/s12035-023-03784-z. Epub ahead of print. PMID: 38015302. https://pubmed.ncbi.nlm.nih.gov/38015302/