Tag: microbiome

MTHFR and LC, CFS, POTS, MCAS, SIBO, EDS: Methylating the Alphabet

Abstract:

Long Covid (LC), Chronic Fatigue Syndrome (CFS), Postural Orthostatic Tachycardia Syndrome (POTS), Mast Cell Activation Syndrome (MCAS), Small Intestine Bacterial Overgrowth (SIBO), and Ehlers-Danlos Syndrome (EDS) are all loosely connected, some poorly defined, some with overlapping symptoms.

The female preponderance, the prominence of fatigue and chronic inflammation, and methylenetetrahydrofolate reductase (MTHFR) abnormalities may connect them all. Indeed differential methylation may lie at the root. Two – EDS and MTHFR – are genetic. But epigenetic factors may ultimately determine their phenotypic expression.

Oxidative stress, overloaded mitochondria, an antioxidant and nutrient shortfall, and suboptimal gut microbiome appear to be the primary determinants. A deep dive into the folate and methionine cycles is undertaken in an attempt to connect these syndromes.

The active forms of vitamin D and vitamins B2,3,6,9,12 are shown to be biochemically integral to optimal methylation and control of the epigenome. Their status largely determines the symptoms of abnormal MTHFR in all its phenotypes. The wider implications for aging, cancer, cardiovascular disease, neurodegenerative disease, and autoimmune disease are briefly explored.

Source: Chambers P. MTHFR and LC, CFS, POTS, MCAS, SIBO, EDS: Methylating the Alphabet. Preprint from Qeios, 30 Jun 2023. https://www.qeios.com/read/ZPYS4F (Full text)

Oligosaccharides as Potential Regulators of Gut Microbiota and Intestinal Health in Post-COVID-19 Management

Abstract:

The COVID-19 pandemic has had a profound impact worldwide, resulting in long-term health effects for many individuals. Recently, as more and more people recover from COVID-19, there is an increasing need to identify effective management strategies for post-COVID-19 syndrome, which may include diarrhea, fatigue, and chronic inflammation. Oligosaccharides derived from natural resources have been shown to have prebiotic effects, and emerging evidence suggests that they may also have immunomodulatory and anti-inflammatory effects, which could be particularly relevant in mitigating the long-term effects of COVID-19.

In this review, we explore the potential of oligosaccharides as regulators of gut microbiota and intestinal health in post-COVID-19 management. We discuss the complex interactions between the gut microbiota, their functional metabolites, such as short-chain fatty acids, and the immune system, highlighting the potential of oligosaccharides to improve gut health and manage post-COVID-19 syndrome. Furthermore, we review evidence of gut microbiota with angiotensin-converting enzyme 2 expression for alleviating post-COVID-19 syndrome.

Therefore, oligosaccharides offer a safe, natural, and effective approach to potentially improving gut microbiota, intestinal health, and overall health outcomes in post-COVID-19 management.

Source: Cheong KL, Chen S, Teng B, Veeraperumal S, Zhong S, Tan K. Oligosaccharides as Potential Regulators of Gut Microbiota and Intestinal Health in Post-COVID-19 Management. Pharmaceuticals (Basel). 2023 Jun 9;16(6):860. doi: 10.3390/ph16060860. PMID: 37375807; PMCID: PMC10301634. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10301634/ (Full text)

Microbiome and intestinal pathophysiology in post-acute sequelae of COVID-19

Abstract:

Long COVID, also known for post-acute sequelae of COVID-19, describes the people who have the signs and symptoms that continue or develop after the acute COVID-19 phase. Long COVID patients suffer from an inflammation or host responses towards the virus approximately 4 weeks after initial infection with the SARS CoV-2 virus and continue for an uncharacterized duration.

Anyone infected with COVID-19 before could experience long-COVID conditions, including the patients who were infected with SARS CoV-2 virus confirmed by tests and those who never knew they had an infection early. People with long COVID may experience health problems from different types and combinations of symptoms over time, such as fatigue, dyspnea, cognitive impairments, and gastrointestinal (GI) symptoms (e.g., nausea, vomiting, diarrhea, decreased or loss of appetite, abdominal pain, and dysgeusia). The critical role of the microbiome in these GI symptoms and long COVID were reported in clinical patients and experimental models.

Here, we provide an overall view of the critical role of the GI tract and microbiome in the development of long COVID, including the clinical GI symptoms in patients, dysbiosis, viral-microbiome interactions, barrier function, and inflammatory bowel disease patients with long COVID. We highlight the potential mechanisms and possible treatment based on GI health and microbiome. Finally, we discuss challenges and future direction in the long COVID clinic and research.

Source: Zhang J, Zhang Y, Xia Y, Sun J. Microbiome and intestinal pathophysiology in post-acute sequelae of COVID-19. Genes Dis. 2023 Jun 19. doi: 10.1016/j.gendis.2023.03.034. Epub ahead of print. PMID: 37362775; PMCID: PMC10278891. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278891/ (Full text)

Comprehensive profiling of the human intestinal DNA virome and prediction of disease-associated bacterial hosts in severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disorder of unknown etiology with severely affected patients being house- and/or bedbound. A historical association with chronic virus infection and subsequent recent reports correlating intestinal microbial dysbiosis with disease pathology prompted us to analyze the intestinal virome in a small cohort of severely-affected ME/CFS patients and same household healthy controls (SHHC).

Datasets from whole metagenomic sequencing (WMS) and sequencing of virus-like particles (VLP)-enriched metagenomes from the same fecal sample yielded diverse, high-quality vOTUs with high read coverage and high genome completeness. The core intestinal virome was largely composed of tailed phages in the class Caudoviricetes with no significant differences in alpha diversity between ME/CFS and SHHC groups. However, the WMS dataset had a higher Shannon measure than the VLP dataset (p < 0.0001), with VLP- and WMS-derived sequences indicating differential abundances within several viral families and different viral compositions in beta diversity.

This confirms that combining different isolation methodologies identifies a greater diversity of viruses including extracellular phages and integrated prophages. DNA viromes and bacteriomes from ME/CFS and SHHC groups were comparable with no differences in any alpha or beta diversity measures. One vOTU derived from the VLP-derived dataset was assigned to ssDNA human virus smacovirus 1. Using an in-silico approach to predict cohort-based bacterial hosts, we identified members of the Anaerotruncus genus interacting with unique viruses present in ME/CFS microbiomes; this may contribute to the GI microbial dysbiosis described in ME/CFS patients.

Source: Shen-Yuan Hsieh, George M Savva, Andrea Telatin, Sumeet K Tiwari, Mohammad A Tariq, Fiona Newberry, Katharine A Seton, Catherine Booth, Amolak S Bansal, Tom Wileman, Evelien Andriaenssens, Simon R Carding. Comprehensive profiling of the human intestinal DNA virome and prediction of disease-associated bacterial hosts in severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). medRxiv 2023.06.29.23291738; doi: https://doi.org/10.1101/2023.06.29.23291738 https://www.medrxiv.org/content/10.1101/2023.06.29.23291738v1

Causal Effects between Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two-Sample Mendelian Randomization Study

Abstract:

Background: Evidence from previous studies have implicated an important association between gut microbiota (GM) and Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), but whether there is a definite causal relationship between GM and ME/CFS has not been elucidated.

Method: This study obtained instrumental variables of 211 GM taxa from the Genome Wide Association Study (GWAS), and mendelian randomization (MR) study was carried out to assess the effect of gut microbiota on ME/CFS risk from UK Biobank GWAS (2076 ME/CFS cases and 460857 controls). Inverse variance weighted (IVW) was the primary method to analyze causality in this study, and a series of sensitivity analyses was performed to validate the robustness of the results.

The inverse variance weighted (IVW) method indicated that genus Paraprevotella (OR:1.001, 95%CI:1.000-1.003, p-value<0.05) and Ruminococca-ceae_UCG_014(OR 1.003, 95% CI 1.000 to 1.005, p-value < 0.05) were positively associated with ME/CFS risk. Results from the weighted median method supported genus Paraprevotella (OR 1.003, 95% CI 1.000 to 1.005, p-value < 0.05) as a risk factor for ME/CFS.

Conclusions: This study reveals a causal relationship between genus.paraprevotella, genus.Ruminococcaceae_UCG_014 and ME/CFS, and our findings provide novel insights for further elucidating the developmental mechanisms mediated by the gut microbiota of ME/CFS.

Source: Gang He, Yu Cao, Wangzi Xu and Houzhao Wang. Causal Effects between Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two-Sample Mendelian Randomization Study. Front. Microbiol. Volume 14 – 2023 | doi: 10.3389/fmicb.2023.1190894 https://www.frontiersin.org/articles/10.3389/fmicb.2023.1190894/abstract

Investigating antibody reactivity to the intestinal microbiome in severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystemic disease of unknown aetiology that is characterised by disabling chronic fatigue and involves both the immune and gastrointestinal (GI) systems. Patients display alterations in GI microbiome with a significant proportion experiencing GI discomfort and pain and elevated blood biomarkers for altered intestinal permeability compared with healthy individuals.

To investigate a possible GI origin of ME/CFS we designed a feasibility study to test the hypothesis that ME/CFS pathogenesis is a consequence of increased intestinal permeability that results in microbial translocation and a breakdown in immune tolerance leading to generation of antibodies reactive to indigenous intestinal microbes. Secretory IgA and serum IgG levels and reactivity to intestinal microbes were assessed in five pairs of severe ME/CFS patients and matched same-household healthy controls. For profiling serum IgG we developed IgG-Seq which combines flow-cytometry based bacterial cell sorting and metagenomics to detect mucosal IgG reactivity to the microbiome.

We uncovered evidence for immune dysfunction in severe ME/CFS patients that was characterised by reduced capacity and reactivity of serum IgG to stool microbes, irrespective of their source. This study provides the rationale for additional studies in larger cohorts of ME/CFS patients to further explore immune-microbiome interactions.

Source: Katharine A. Seton, Marianne Defernez, Andrea Telatin, Sumeet K. Tiwari, George M. Savva, Antonietta Hayhoe, Alistair Noble, Ana Carvalho, Steve James, Amolak Bansal, Thomas Wileman, Simon R. Carding. Investigating antibody reactivity to the intestinal microbiome in severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). medRxiv 2023.05.21.23290299; doi: https://doi.org/10.1101/2023.05.21.23290299 https://www.medrxiv.org/content/10.1101/2023.05.21.23290299v1.full-text (Full text)

Randomized, double-blinded, placebo-controlled pilot study: Efficacy of faecal microbiota transplantation on chronic fatigue syndrome

Abstract:

Background: Chronic fatigue syndrome (CFS) is a disabling illness of unknown aetiology. Disruption of gut microbiota may play a role in several neurological disorders. In this study, the effect of faecal microbiota transplantation (FMT) on fatigue severity and health-related quality of life (HRQOL) in patients with CFS was evaluated

Methods: Randomized, placebo-controlled pilot trial. Patients and researchers were blinded to treatment assignment. 11 patients with CFS (10 female and 1 male, mean age 42.2 years and mean duration of CFS 6.3 years) were randomly assigned to receive either FMT from a universal donor (n = 5) or autologous FMT (n = 6) via colonoscopy. Patients’ HRQOL was assessed by using visual analog scale (VAS) and self-reporting questionnaires Modified Fatigue Impact Scale (MFIS), 15D and EQ-5D-3L. Patients’ HRQOL was evaluated at baseline, and 1 and 6 months after the FMT.

Results: The baseline VAS scores in the FMT and placebo groups were 62.4 and 76.0 (p = 0.29). 1-month scores were 60.0 and 73.7 and 6-months scores 72.8 and 69.5, respectively. Total MFIS scores in the FMT and placebo groups were 59.6 and 61.0 at the baseline (p = 0.80), 53.5 and 62.0 at 1 month and 58.6 and 56.2 at 6 months. Compared to the baseline scores, differences at 1 and 6 months were statistically insignificant both in VAS and in MFIS. The 15D and EQ-5D-3L profiles did not change after the FMT or placebo. FMT-related adverse events were not reported.

Conclusion: FMT was safe but did not relieve symptoms or improve the HRQOL of patients with CFS. Small number of study subjects limits the generalizability of these results

Trial registration: ClinicalTrials.gov Identifier NCT04158427, https://register.clinicaltrials.gov, date of registration 08/08/2019

Source: Salonen TE, Jokinen E, Satokari R, Lahtinen P. Randomized, double-blinded, placebo-controlled pilot study: Efficacy of faecal microbiota transplantation on chronic fatigue syndrome. ResearchSquare [Preprint] April 25, 2023. https://doi.org/10.21203/rs.3.rs-2805527/v1 https://www.researchsquare.com/article/rs-2805527/v1 (Full text)

Positive Effects of Probiotic Therapy in Patients with Post-Infectious Fatigue

Abstract:

Post-infectious fatigue is a common complication that can lead to decreased physical efficiency, depression, and impaired quality of life. Dysbiosis of the gut microbiota has been proposed as a contributing factor, as the gut–brain axis plays an important role in regulating physical and mental health. This pilot study aimed to investigate the severity of fatigue and depression, as well as the quality of life of 70 patients with post-infectious fatigue who received a multi-strain probiotic preparation or placebo in a double-blind, placebo-controlled trial.
Patients completed questionnaires to assess their fatigue (fatigue severity scale (FSS)), mood (Beck Depression Inventory II (BDI-II)), and quality of life (short form-36 (SF-36)) at baseline and after 3 and 6 months of treatment. Routine laboratory parameters were also assessed, including immune-mediated changes in tryptophan and phenylalanine metabolism.
The intervention was effective in improving fatigue, mood, and quality of life in both the probiotic and placebo groups, with greater improvements seen in the probiotic group. FSS and BDI-II scores declined significantly under treatment with both probiotics and placebo, but patients who received probiotics had significantly lower FSS (p < 0.001) and BDI-II (p < 0.001) scores after 6 months.
Quality of life scores improved significantly in patients who received probiotics (p < 0.001), while patients taking a placebo only saw improvements in the “Physical limitation” and “Energy/Fatigue” subcategories. After 6 months neopterin was higher in patients receiving placebo, while no longitudinal changes in interferon-gamma mediated biochemical pathways were observed.
These findings suggest that probiotics may be a promising intervention for improving the health of patients with post-infectious fatigue, potentially through modulating the gut–brain axis.
Source: Obermoser K, Brigo N, Schroll A, Monfort-Lanzas P, Gostner JM, Engl S, Geisler S, Knoll M, Schennach H, Weiss G, Fuchs D, Bellmann-Weiler R, Kurz K. Positive Effects of Probiotic Therapy in Patients with Post-Infectious Fatigue. Metabolites. 2023; 13(5):639. https://doi.org/10.3390/metabo13050639 https://www.mdpi.com/2218-1989/13/5/639 (Full text)

Astragalus polysaccharide ameliorated complex factor-induced chronic fatigue syndrome by modulating the gut microbiota and metabolites in mice

Abstract:

Chronic fatigue syndrome (CFS) is a debilitating disease with no symptomatic treatment. Astragalus polysaccharide (APS), a component derived from the traditional Chinese medicine A. membranaceus, has significant anti-fatigue activity. However, the mechanisms underlying the potential beneficial effects of APS on CFS remain poorly understood.

A CFS model of 6-week-old C57BL/6 male mice was established using the multiple-factor method. These mice underwent examinations for behavior, oxidative stress and inflammatory indicators in brain and intestinal tissues, and ileum histomorphology. 16 S rDNA sequencing analysis indicated that APS regulated the abundance of gut microbiota and increased production of short chain fatty acids (SCFAs) and anti-inflammatory bacteria.

In addition, APS reversed the abnormal expression of Nrf2, NF-κB, and their downstream factors in the brain-gut axis and alleviated the reduction in SCFAs in the cecal content caused by CFS. Further, APS modulated the changes in serum metabolic pathways induced by CFS.

Finally, it was verified that butyrate exerted antioxidant and anti-inflammatory effects in neuronal cells. In conclusion, APS could increase the SCFAs content by regulating the gut microbiota, and SCFAs (especially butyrate) can further regulate the oxidative stress and inflammation in the brain, thus alleviating CFS.

This study explored the efficacy and mechanism of APS for CFS from the perspective of gut-brain axis and provides a reference to further explore the efficacy of APS and the role of SCFAs in the central nervous system.

Source: Wei X, Xin J, Chen W, Wang J, Lv Y, Wei Y, Li Z, Ding Q, Shen Y, Xu X, Zhang X, Zhang W, Zu X. Astragalus polysaccharide ameliorated complex factor-induced chronic fatigue syndrome by modulating the gut microbiota and metabolites in mice. Biomed Pharmacother. 2023 May 9;163:114862. doi: 10.1016/j.biopha.2023.114862. Epub ahead of print. PMID: 37167729. https://www.sciencedirect.com/science/article/pii/S0753332223006522?via%3Dihub (Full study)

Gut Microbiota Dysbiosis Correlates With Long COVID-19 at One-Year After Discharge

Abstract:

Background: Long coronavirus disease 2019 (COVID-19) in recovered patients (RPs) is gradually recognized by more people. However, how long it will last and the underlining mechanism remains unclear.
Methods: We conducted a prospective follow-up study to evaluate the long-term symptoms and clinical indices of RPs at one-year after discharge from Union Hospital, Wuhan, China between December 2020 to May 2021. We also performed the 16S rRNA sequencing of stool samples from RPs and healthy controls (HCs) and analyzed the correlation between the gut microbiota and long COVID-19.
Results: In total, 187 RPs were enrolled, among them, 84 (44.9%) RPs reported long COVID-19 symptoms at one-year after discharge. The most common long-term symptoms were cardiopulmonary symptoms, including chest tightness after activity (39/187, 20.9%), palpitations on exercise (27/187, 14.4%), sputum (21/187, 11.2%), cough (15/187, 8.0%) and chest pain (13/187, 7.0%), followed by systemic symptoms including fatigue (34/187, 18.2%) and myalgia (20/187, 10.7%), and digestive symptoms including constipation (14/187, 7.5%), anorexia (13/187, 7.0%), and diarrhea (8/187, 4.3%). Sixty-six (35.9%) RPs presented either anxiety or depression (42/187 [22.8%] and 53/187 [28.8%] respectively), and the proportion of anxiety or depression in the long symptomatic group was significantly higher than that in the asymptomatic group (41/187 [50.6%] vs. 25/187 [24.3%]). Compared with the asymptomatic group, scores of all nine 36-Item Short Form General Health Survey domains were lower in the symptomatic group (all P < 0.05).
One hundred thirty RPs and 32 HCs (non-severe acute respiratory syndrome coronavirus 2 infected subjects) performed fecal sample sequencing. Compared with HCs, symptomatic RPs had obvious gut microbiota dysbiosis including significantly reduced bacterial diversities and lower relative abundance of short-chain fatty acids (SCFAs)-producing salutary symbionts such as Eubacterium_hallii_group,  Subdoligranulum,  Ruminococcus, Dorea, Coprococcus, and Eubacterium_ventriosum_group. Meanwhile, the relative abundance of Eubacterium_hallii_group,  Subdoligranulum, and Ruminococcus showed decreasing tendencies between HCs, the asymptomatic group, and the symptomatic group.
Conclusion: This study demonstrated the presence of long COVID-19 which correlates with gut microbiota dysbiosis in RPs at one-year after discharge, indicating gut microbiota may play an important role in long COVID-19.
Source: Zhang D, Zhou Y, Ma Y, Chen P, Tang J, Yang B, Li H, Liang M, Xue Y, Liu Y, Zhang J, Wang X. Gut Microbiota Dysbiosis Correlates With Long COVID-19 at One-Year After Discharge. J Korean Med Sci. 2023;38(15):e120. https://doi.org/10.3346/jkms.2023.38.e120 (Full text)