Tag: microbiome

Gut Microbiota Dynamics in Relation to Long-COVID-19 Syndrome: Role of Probiotics to Combat Psychiatric Complications

Abstract:

Increasing numbers of patients who recover from COVID-19 report lasting symptoms, such as fatigue, muscle weakness, dementia, and insomnia, known collectively as post-acute COVID syndrome or long COVID. These lasting symptoms have been examined in different studies and found to influence multiple organs, sometimes resulting in life-threating conditions.
In this review, these symptoms are discussed in connection to the COVID-19 and long-COVID-19 immune changes, highlighting oral and psychiatric health, as this work focuses on the gut microbiota’s link to long-COVID-19 manifestations in the liver, heart, kidney, brain, and spleen. A model of this is presented to show the biological and clinical implications of gut microbiota in SARS-CoV-2 infection and how they could possibly affect the therapeutic aspects of the disease. Probiotics can support the body’s systems in fighting viral infections. This review focuses on current knowledge about the use of probiotics as adjuvant therapies for COVID-19 patients that might help to prevent long-COVID-19 complications.
Source: Alenazy MF, Aljohar HI, Alruwaili AR, Daghestani MH, Alonazi MA, Labban RS, El-Ansary AK, Balto HA. Gut Microbiota Dynamics in Relation to Long-COVID-19 Syndrome: Role of Probiotics to Combat Psychiatric Complications. Metabolites. 2022; 12(10):912. https://doi.org/10.3390/metabo12100912 (Full text)

Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with an unclear etiology and pathogenesis. Both an involvement of the immune system and gut microbiota dysbiosis have been implicated in its pathophysiology. However, potential interactions between adaptive immune responses and the microbiota in ME/CFS have been incompletely characterized. Here, we profiled antibody responses of patients with severe ME/CFS and healthy controls against microbiota and viral antigens represented as a phage-displayed 244,000 variant library.

Patients with severe ME/CFS exhibited distinct serum antibody epitope repertoires against flagellins of Lachnospiraceae bacteria. Training machine learning algorithms on this antibody-binding data demonstrated that immune responses against gut microbiota represent a unique layer of information beyond standard blood tests, providing improved molecular diagnostics for ME/CFS.

Together, our results point toward an involvement of the microbiota-immune axis in ME/CFS and lay the foundation for comparative studies with inflammatory bowel diseases and illnesses characterized by long-term fatigue symptoms, including post-COVID-19 syndrome.

Source: Vogl T, Kalka IN, Klompus S, Leviatan S, Weinberger A, Segal E. Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients. Sci Adv. 2022 Sep 23;8(38):eabq2422. doi: 10.1126/sciadv.abq2422. Epub 2022 Sep 23. PMID: 36149952. https://www.science.org/doi/10.1126/sciadv.abq2422 (Full text)

Altered serum bile acid profile in fibromyalgia is associated with specific gut microbiome changes and symptom severity

Abstract:

Alterations in the composition and function of the gut microbiome in women with fibromyalgia have recently been demonstrated, including changes in the relative abundance of certain bile acid metabolizing bacteria. Bile acids can affect multiple physiological processes, including visceral pain, but have yet to be explored for association to the fibromyalgia gut microbiome. In this study, 16S rRNA sequencing and targeted metabolomic approaches were used to characterize the gut microbiome and circulating bile acids in a cohort of 42 women with fibromyalgia and 42 healthy controls.

Alterations in the relative abundance of several bacterial species known to metabolize bile acids were observed in women with fibromyalgia, accompanied by significant alterations in the serum concentration of secondary bile acids, including a marked depletion of α-muricholic acid. Statistical learning algorithms could accurately detect individuals with fibromyalgia using the concentration of these serum bile acids. Serum α-muricholic acid was highly correlated with symptom severity, including pain intensity and fatigue.

Taken together, these findings suggest serum bile acid alterations are implicated in nociplastic pain. The changes observed in the composition of the gut microbiota and the concentration of circulating secondary bile acids seem congruent with the phenotype of increased nociception, and are quantitatively correlated with symptom severity.

This is a first demonstration of circulating bile acid alteration in individuals with fibromyalgia, potentially secondary to upstream gut microbiome alterations. If corroborated in independent studies, these observations may allow for the development of molecular diagnostic aids for fibromyalgia as well as mechanistic insights into the syndrome.

Source: Minerbi A, Gonzalez E, Brereton N, Fitzcharles MA, Chevalier S, Shir Y. Altered serum bile acid profile in fibromyalgia is associated with specific gut microbiome changes and symptom severity. Pain. 2022 May 19. doi: 10.1097/j.pain.0000000000002694. Epub ahead of print. PMID: 35587528. https://pubmed.ncbi.nlm.nih.gov/35587528/

The Role of Kynurenine Pathway and NAD + Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, complex, and highly debilitating long-term illness. People with ME/CFS are typically unable to carry out their routine activities. Key hallmarks of the disease are neurological and gastrointestinal impairments accompanied by pervasive malaise that is exacerbated after physical and/or mental activity. Currently, there is no validated cure of biomarker signature for this illness. Impaired tryptophan (TRYP) metabolism is thought to play significant role in the pathobiology of ME/CFS.

TRYP is an important precursor for serotonin and the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+). TRYP has been associated with the development of some parts of the brain responsible for behavioural functions. The main catabolic route for TRYP is the kynurenine pathway (KP). The KP produces NAD+ and several neuroactive metabolites with neuroprotective (i.e., kynurenic acid (KYNA)) and neurotoxic (i.e., quinolinic acid (QUIN)) activities. Hyperactivation of the KP, whether compensatory or a driving mechanism of degeneration can limit the availability of NAD+ and exacerbate the symptoms of ME/CFS.

This review discusses the potential association of altered KP metabolism in ME/CFS. The review also evaluates the role of the patient’s gut microbiota on TRYP availability and KP activation. We propose that strategies aimed at raising the levels of NAD+ (e.g., using nicotinamide mononucleotide and nicotinamide riboside) may be a promising intervention to overcome symptoms of fatigue and to improve the quality of life in patients with ME/CFS. Future clinical trials should further assess the potential benefits of NAD+ supplements for reducing some of the clinical features of ME/CFS.

Source: Dehhaghi M, Panahi HKS, Kavyani B, Heng B, Tan V, Braidy N, Guillemin GJ. The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Aging Dis. 2022 Jun 1;13(3):698-711. doi: 10.14336/AD.2021.0824. PMID: 35656104; PMCID: PMC9116917. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9116917/ (Full text)

Therapeutic Implications of the Microbial Hypothesis of Mental Illness

Abstract:

There is increasingly compelling evidence that microorganisms may play an etiological role in the emergence of mental illness in a subset of the population. Historically, most work has focused on the neurotrophic herpesviruses, herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) as well as the protozoan, Toxoplasma gondii. In this chapter, we provide an umbrella review of this literature and additionally highlight prospective studies that allow more mechanistic conclusions to be drawn.

Next, we focus on clinical trials of anti-microbial medications for the treatment of psychiatric disorders. We critically evaluate six trials that tested the impact of anti-herpes medications on inflammatory outcomes in the context of a medical disorder, nine clinical trials utilizing anti-herpetic medications for the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or schizophrenia, and four clinical trials utilizing anti-parasitic medications for the treatment of schizophrenia.

We then turn our attention to evidence for a gut dysbiosis and altered microbiome in psychiatric disorders, and the potential therapeutic effects of probiotics, including an analysis of more than 10 randomized controlled trials of probiotics in the context of schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD).

Source: Savitz J, Yolken RH. Therapeutic Implications of the Microbial Hypothesis of Mental Illness. Curr Top Behav Neurosci. 2022 May 24. doi: 10.1007/7854_2022_368. Epub ahead of print. PMID: 35606640. https://pubmed.ncbi.nlm.nih.gov/35606640/

The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

Abstract:

Myalgic encephalomyelitis (ME) or Chronic Fatigue Syndrome (CFS) is a neglected, debilitating multi-systemic disease without diagnostic marker or therapy. Despite evidence for neurological, immunological, infectious, muscular and endocrine pathophysiological abnormalities, the etiology and a clear pathophysiology remains unclear. The gut microbiome gained much attention in the last decade with manifold implications in health and disease. Here we review the current state of knowledge on the interplay between ME/CFS and the microbiome, to identify potential diagnostic or interventional approaches, and propose areas where further research is needed.

We iteratively selected and elaborated on key theories about a correlation between microbiome state and ME/CFS pathology, developing further hypotheses. Based on the literature we hypothesize that antibiotic use throughout life favours an intestinal microbiota composition which might be a risk factor for ME/CFS. Main proposed pathomechanisms include gut dysbiosis, altered gut-brain axis activity, increased gut permeability with concomitant bacterial translocation and reduced levels of short-chain-fatty acids, D-lactic acidosis, an abnormal tryptophan metabolism and low activity of the kynurenine pathway. We review options for microbiome manipulation in ME/CFS patients including probiotic and dietary interventions as well as fecal microbiota transplantations. Beyond increasing gut permeability and bacterial translocation, specific dysbiosis may modify fermentation products, affecting peripheral mitochondria. Considering the gut-brain axis we strongly suspect that the microbiome may contribute to neurocognitive impairments of ME/CFS patients.

Further larger studies are needed, above all to clarify whether D-lactic acidosis and early-life antibiotic use may be part of ME/CFS etiology and what role changes in the tryptophan metabolism might play. An association between the gut microbiome and the disease ME/CFS is plausible. As causality remains unclear, we recommend longitudinal studies. Activity levels, bedridden hours and disease progression should be compared to antibiotic exposure, drug intakes and alterations in the composition of the microbiota. The therapeutic potential of fecal microbiota transfer and of targeted dietary interventions should be systematically evaluated.

Source: König RS, Albrich WC, Kahlert CR, Bahr LS, Löber U, Vernazza P, Scheibenbogen C, Forslund SK. The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Front Immunol. 2022 Jan 3;12:628741. doi: 10.3389/fimmu.2021.628741. PMID: 35046929; PMCID: PMC8761622. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761622/ (Full text)

 

TLR Antagonism by Sparstolonin B Alters Microbial Signature and Modulates Gastrointestinal and Neuronal Inflammation in Gulf War Illness Preclinical Model

Abstract:

The 1991 Persian Gulf War veterans presented a myriad of symptoms that ranged from chronic pain, fatigue, gastrointestinal disturbances, and cognitive deficits. Currently, no therapeutic regimen exists to treat the plethora of chronic symptoms though newer pharmacological targets such as microbiome have been identified recently. Toll-like receptor 4 (TLR4) antagonism in systemic inflammatory diseases have been tried before with limited success, but strategies with broad-spectrum TLR4 antagonists and their ability to modulate the host-microbiome have been elusive.

Using a mouse model of Gulf War Illness, we show that a nutraceutical, derived from a Chinese herb Sparstolonin B (SsnB) presented a unique microbiome signature with an increased abundance of butyrogenic bacteria. SsnB administration restored a normal tight junction protein profile with an increase in Occludin and a parallel decrease in Claudin 2 and inflammatory mediators high mobility group box 1 (HMGB1), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the distal intestine. SsnB also decreased neuronal inflammation by decreasing IL-1β and HMGB1, while increasing brain-derived neurotrophic factor (BDNF), with a parallel decrease in astrocyte activation in vitro.

Mechanistically, SsnB inhibited the binding of HMGB1 and myeloid differentiation primary response protein (MyD88) to TLR4 in the intestine, thus attenuating TLR4 downstream signaling. Studies also showed that SsnB was effective in suppressing TLR4-induced nod-like receptor protein 3 (NLRP3) inflammasome activation, a prominent inflammatory disease pathway. SsnB significantly decreased astrocyte activation by decreasing colocalization of glial fibrillary acid protein (GFAP) and S100 calcium-binding protein B (S100B), a crucial event in neuronal inflammation. Inactivation of SsnB by treating the parent molecule by acetate reversed the deactivation of NLRP3 inflammasome and astrocytes in vitro, suggesting that SsnB molecular motifs may be responsible for its anti-inflammatory activity.

Source: Bose D, Mondal A, Saha P, Kimono D, Sarkar S, Seth RK, Janulewicz P, Sullivan K, Horner R, Klimas N, Nagarkatti M, Nagarkatti P, Chatterjee S. TLR Antagonism by Sparstolonin B Alters Microbial Signature and Modulates Gastrointestinal and Neuronal Inflammation in Gulf War Illness Preclinical Model. Brain Sci. 2020 Aug 8;10(8):532. doi: 10.3390/brainsci10080532. PMID: 32784362; PMCID: PMC7463890. https://www.mdpi.com/2076-3425/10/8/532 (Full text)

The Emerging Role of Gut Microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Current Evidence and Potential Therapeutic Applications

Abstract:

The well-known symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are chronic pain, cognitive dysfunction, post-exertional malaise and severe fatigue. Another class of symptoms commonly reported in the context of ME/CFS are gastrointestinal (GI) problems. These may occur due to comorbidities such as Crohn’s disease or irritable bowel syndrome (IBS), or as a symptom of ME/CFS itself due to an interruption of the complex interplay between the gut microbiota (GM) and the host GI tract. An altered composition and overall decrease in diversity of GM has been observed in ME/CFS cases compared to controls. In this review, we reflect on genetics, infections, and other influences that may factor into the alterations seen in the GM of ME/CFS individuals, we discuss consequences arising from these changes, and we contemplate the therapeutic potential of treating the gut to alleviate ME/CFS symptoms holistically.

Source: Varesi A, Deumer US, Ananth S, Ricevuti G. The Emerging Role of Gut Microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Current Evidence and Potential Therapeutic Applications. J Clin Med. 2021 Oct 29;10(21):5077. doi: 10.3390/jcm10215077. PMID: 34768601. https://pubmed.ncbi.nlm.nih.gov/34768601/

Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms

Abstract:

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease of unknown cause for which there is no specific therapy. Patients suffering from ME/CFS commonly experience persistent fatigue, post-exertional malaise, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever and irritable bowel syndrome (IBS). Recent evidence implicates gut microbiome dysbiosis in ME/CFS. However, most prior studies are limited by small sample size, differences in clinical criteria used to define cases, limited geographic sampling, reliance on bacterial culture or 16S rRNA gene sequencing, or insufficient consideration of confounding factors that may influence microbiome composition. In the present study, we evaluated the fecal microbiome in the largest prospective, case-control study to date (n=106 cases, n=91 healthy controls), involving subjects from geographically diverse communities across the United States.

Results Using shotgun metagenomics and qPCR and rigorous statistical analyses that controlled for important covariates, we identified decreased relative abundance and quantity of Faecalibacterium, Roseburia, and Eubacterium species and increased bacterial load in feces of subjects with ME/CFS. These bacterial taxa play an important role in the production of butyrate, a multifunctional bacterial metabolite that promotes human health by regulating energy metabolism, inflammation, and intestinal barrier function. Functional metagenomic and qPCR analyses were consistent with a deficient microbial capacity to produce butyrate along the acetyl-CoA pathway in ME/CFS. Metabolomic analyses of short-chain fatty acids (SCFAs) confirmed that fecal butyrate concentration was significantly reduced in ME/CFS. Further, we found that the degree of deficiency in butyrate-producing bacteria correlated with fatigue symptom severity among ME/CFS subjects. Finally, we provide evidence that IBS comorbidity is an important covariate to consider in studies investigating the microbiome of ME/CFS subjects, as differences in microbiota alpha diversity, some bacterial taxa, and propionate were uniquely associated with self-reported IBS diagnosis.

Conclusions Our findings indicate that there is a core deficit in the butyrate-producing capacity of the gut microbiome in ME/CFS subjects compared to healthy controls. The relationships we observed among symptom severity and these gut microbiome disturbances may be suggestive of a pathomechanistic linkage, however, additional research is warranted to establish any causal relationship. These findings provide support for clinical trials that explore the utility of dietary, probiotic and prebiotic interventions to boost colonic butyrate production in ME/CFS.

Source: Cheng Guo, Xiaoyu Che, Thomas Briese, Orchid Allicock, Rachel A. Yates, Aaron Cheng, Amit Ranjan, Dana March, Mady Hornig, Anthony L. Komaroff, Susan Levine, Lucinda Bateman, Suzanne D. Vernon, Nancy G. Klimas, Jose G. Montoya, Daniel L. Peterson, W. Ian Lipkin, Brent L. Williams. Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms. medRxiv 2021.10.27.21265575; doi: https://doi.org/10.1101/2021.10.27.21265575 https://www.medrxiv.org/content/10.1101/2021.10.27.21265575v1?fbclid=IwAR16pb6by73xZx5lZM3j-5dOc_YT2JapILaRS-DcUZj5EHZxnoSa2fAAIuE (Full text available to download)

Multi-omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system, debilitating disability manifesting as severe fatigue and post-exertional malaise. The chronic dysfunctions in ME/CFS are increasingly recognized as significant health factors with potential parallels with “long COVID”. However, the etiology of ME/CFS remains elusive with limited high-resolution human studies. In addition, reliable biomarker-based diagnostics have not been well-established, but may assist in disease classification, particularly during different temporal phases of the disease. Here, we performed deep multi-omics (shotgun metagenomics of gut microbiota and plasma metabolomics) and clinical phenotyping of healthy controls (n=79) vs. two cohorts of ME/CFS patients: those with short-term disease (<4 years, n=75), and patients with long-term disease (>10y, n=79).

Overall, ME/CFS was characterized by reduced gut microbiome diversity and richness with high heterogeneity, and depletion of sphingomyelins and short-chain fatty acids in the plasma. We found significant differences when stratifying by cohort; short-term ME/CFS was associated with more microbial dysbiosis, but long-term ME/CFS was associated with markedly more severe phenotypic and metabolic abnormalities. We identified a reduction in the gene-coding capacity (and relative abundance of butyrate producers) of microbial butyrate biosynthesis together with a reduction in the plasma concentration of butyrate, especially in the short-term group. Global co-association and detailed gene pathway correlation analyses linking the microbiome and metabolome identified additional potential biological mechanisms underlying host-microbiome interactions in ME/CFS, including bile acids and benzoate pathways.

Finally, we built multiple state-of-the-art classifiers to identify microbes, microbial gene pathways, metabolites, and clinical features that individually or together, were most able to differentiate short or long-term MECFS, or MECFS vs. healthy controls. Taken together, our study presents the highest resolution, multi-cohort and multi-omics analysis to date, providing an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.

Source: Ruoyun Xiong, Courtney Gunter, Elizabeth Fleming, Suzanne Vernon, Lucinda Bateman, Derya Unutmaz, Julia Oh. Multi-omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). bioRxiv 2021.10.27.466150; doi: https://doi.org/10.1101/2021.10.27.466150 https://www.biorxiv.org/content/10.1101/2021.10.27.466150v1 (Full study available for download)