Tag: lipopolysaccharides

Immunological Patient Stratification in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease characterized by profound fatigue, post-exertional malaise (PEM), and neurocognitive dysfunction. Immune dysregulation and gastrointestinal symptoms are commonly observed in ME/CFS patients. Despite affecting approximately 0.89% of the general population, the underlying pathophysiological mechanisms remain poorly understood. This study aimed to elucidate the relationship between immunological characteristics and intestinal barrier function in ME/CFS patients.

ME/CFS patients were stratified into two groups based on their immune competence. After documentation of detailed medical records, serum and plasma samples were collected for assessment of inflammatory immune mediators and biomarkers for intestinal barrier integrity by ELISA. We found reduced complement protein C4a levels in immunodeficient ME/CFS patients suggesting a sub-group specific innate immune dysregulation. ME/CFS patients without immunodeficiencies exhibit a mucosal barrier leakage, as indicated by elevated levels of Lipopolysaccharide-binding protein (LBP).

Stratifying ME/CFS patients based on immune competence enabled the distinction of two subgroups with different pathophysiological patterns. The study highlights the importance of emphasizing precise patient stratification in ME/CFS, particularly in the context of defining suitable treatment strategies. Given the substantial health and socioeconomic burden associated with ME/CFS, urgent attention and research efforts are needed to define causative treatment approaches.

Source: Rohrhofer, J.; Hauser, L.; Lettenmaier, L.; Lutz, L.; Koidl, L.; Gentile, S.A.; Ret, D.; Stingl, M.; Untersmayr, E. Immunological Patient Stratification in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Preprints 2023, 2023112007. https://doi.org/10.20944/preprints202311.2007.v1 https://www.preprints.org/manuscript/202311.2007/v1 (Full text available as PDF file)

Olmesartan alleviates symptoms of chronic fatigue syndrome in mice

Abstract:

Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is a lifestyle-related ailment that affects physical and mental abilities.

The etiology is largely unidentified but there are certain multifactorial mechanisms responsible such as mitochondrial aerobic pathways aberrations, hypothalamic-pituitary-adrenal (HPA) axis deregulation, immune hyperactivation, free radicals, pathogen infections, and central neurohumoral alterations.

Olmesartan is an antihypertensive drug that acts on the angiotensin 1 (AT1 ) receptor. The present research evaluated the efficiency of Olmesartanagainst CFS.

CFS was induced by lipopolysaccharide (LPS, 1mg/kg, i.p.) once on day 1 trailed by a forced swim (10 minutes) continued for 21 consecutive times once each day. Olmesartan (1and 3mg/kg, p.o.) and dexamethasone (standard drug, 0.5mg/kg, i.p.) were given from the 1 st to 21 st day.

Immobility time was noted in the forced swim test (FST). Elevated plus maze, raised zero maze, and open field tests were employed to assess animal behavior. Plasma glucose and cortisol, lipid peroxidation, and GSH levels were determined in the whole brain. LPS and repeated forced swim sessions instigated symptoms of CFS such as memory deficit and depression and anxiety-like symptoms.

Findings suggested that Olmesartan shortened the immobility period of mice against CFS in FST. Olmesartan reduced memory deficits, increased ambulation, and exerted an anxiolytic effect. Olmesartan treatment reduced blood cortisol levels, brain TBARS, and enhanced brain GSHin the CFS mouse model.

Hence, Olmesartan may prove to be an effective treatment for CFS and related behavioral discrepancies.

Source:

Development of a Mouse Model for Chronic Fatigue Syndrome

Abstract:

The purpose of this study was to develop a clinically relevant mouse model of CFS to allow for the testing of underlying mechanisms and development of novel treatment interventions.

Mice were injected with either lipopolysaccharide (LPS) or Poly I:C systemically (0.1- 1.0 mg/kg LPS, i.p. or 0.6-6mg/kg Poly I:C) and compared to a vehicle control injection.

To test for fatigue-like behaviors, we examined voluntary wheel running (VWR) and open field activity.

To test for pain-like behaviors, muscle withdrawal thresholds (MWT) and mechanical sensitivity of the paw.

Measurements were assessed before and up to 1 week after injection of LPS or Poly I:C.

Differences in voluntary running wheel data were assessed using mixed model analysis for differences between dose, time and an interaction between dose and time.

Differences in open field parameters, MWT, and paw sensitivity between groups were assessed using repeated measures ANOVAs.

Running wheel activity was reduced after injection of either LPS or Poly I:C (χ2=15.4; p=0.003).

LPS reduced running wheel activity on days 1-3 for the 1.0 mg/kg dose of LPS and on Day 1 for Poly I:C when compared to vehicle (p<0.001).

Lower doses of LPS showed faster recovery to baseline.

For the open field testing, LPS reduced in distance travelled (F=9.1; p<0.001), increase in time standing still (F=6.5, p=0.001) but not time in center (F= 1.1, p=0.36) 24h after infection.

Post-hoc testing (Tukey’s test) showed a significant difference between the vehicle and the 1.0 mg/kg group of LPS (p=0.001).

Similar reductions were observed for the 6 mg/kg group of Poly I:C (p<0.001). For pain behaviors, there was no difference between groups in the MWT or paw sensitivity (p>0.05) for either LPS or Poly I:C.

These results show that a single injection of an infectious agent reduces physical activity and exploratory behavior, but does not produce pain behaviors.

Source: Adam Janowski, Joseph Lesnak, Ashley Plumb, Lynn Rasmussen, Kathleen Sluka. Development of a Mouse Model for Chronic Fatigue Syndrome. The Journal of Pain 23 (5): 12. https://www.sciencedirect.com/science/article/abs/pii/S152659002200092X

Inflammation-type dysbiosis of the oral microbiome associates with the duration of COVID-19 symptoms and long-COVID

Abstract:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the pandemic Coronavirus Disease 2019 (COVID-19) and now many face the burden of prolonged symptoms-long-lasting COVID-19 symptoms or “long-COVID”. Long-COVID is thought to be linked to immune dysregulation due to harmful inflammation, with the exact causes being unknown. Given the role of the microbiome in mediating inflammation, we aimed to examine the relationship between the oral microbiome and the duration of long-COVID symptoms. Tongue swabs were collected from patients presenting with symptoms concerning for COVID-19. Confirmed infections were followed until resolution of all symptoms.

Bacterial composition was determined by metagenomic sequencing. We used random forest modeling to identify microbiota and clinical covariates that associated with long-COVID symptoms. Of the patients followed, 63% (17/27) developed ongoing symptomatic COVID-19 and 37% (10/27) went on to long-COVID. Patients with prolonged symptoms had significantly higher abundances of microbiota that induce inflammation, such as members of the genera Prevotella and Veillonella. Of note are species that produce lipopolysaccharides and the similarity of long-COVID patients’ oral microbiome to those of patients with chronic fatigue syndrome. All together, we our findings suggest an association with the oral microbiome and long-COVID revealing the possibility that dysfunction of the oral microbiome may contribute to this draining disease.

Source: Haran JP, Bradley E, Zeamer AL, Cincotta L, Salive MC, Dutta P, Mutaawe S, Anya O, Meza-Segura M, Moormann AM, Ward DV, McCormick BA, Bucci V. Inflammation-type dysbiosis of the oral microbiome associates with the duration of COVID-19 symptoms and long-COVID. JCI Insight. 2021 Aug 17:152346. doi: 10.1172/jci.insight.152346. Epub ahead of print. PMID: 34403368. https://pubmed.ncbi.nlm.nih.gov/34403368/

Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome is a serious illness of unknown etiology, characterized by debilitating exhaustion, memory impairment, pain and sleep abnormalities. Viral infections are believed to initiate the pathogenesis of this syndrome although the definite proof remains elusive. With the unfolding of COVID-19 pandemic, the interest in this condition has resurfaced as excessive tiredness, a major complaint of patients infected with the SARS-CoV-2 virus, often lingers for a long time, resulting in disability, and poor life quality.

In a previous article, we hypothesized that COVID-19-upregulated angiotensin II triggered premature endothelial cell senescence, disrupting the intestinal and blood brain barriers. Here, we hypothesize further that post-viral sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome, are promoted by the gut microbes or toxin translocation from the gastrointestinal tract into other tissues, including the brain. This model is supported by the SARS-CoV-2 interaction with host proteins and bacterial lipopolysaccharide. Conversely, targeting microbial translocation and cellular senescence may ameliorate the symptoms of this disabling illness.

Source: Sfera A, Osorio C, Zapata Martín Del Campo CM, Pereida S, Maurer S, Maldonado JC, Kozlakidis Z. Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis. Front Cell Neurosci. 2021 Jun 25;15:673217. doi: 10.3389/fncel.2021.673217. PMID: 34248502; PMCID: PMC8267916. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267916/ (Full study)

Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria

Abstract:

BACKGROUND: There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome(CFS).

METHODS: The present study examines the serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria, i.e. Hafnia Alvei; Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae in CFS patients both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, in conjunction with a leaky gut diet during 10-14 months. We measured the above immune variables as well as the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and 10-14 months after intake of NAIOSs.

RESULTS: Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years).

DISCUSSION: The results show that normalization of the IgA and IgM responses to translocated LPS may predict clinical outcome in CFS. The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific NAIOSs and a leaky gut diet.

 

Source: Maes M, Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008 Dec;29(6):902-10. https://www.ncbi.nlm.nih.gov/pubmed/19112401

 

Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is an idiopathic illness associated with a variety of immunologic abnormalities. To investigate potential pathogenetic mechanisms, we evaluated serum levels and peripheral blood mononuclear cell (PBMC) production of selected cytokines and immunoglobulins.

Serum bioactive transforming growth factor beta (TGF-beta) levels were higher (P less than 0.01) in patients with CFS (290 +/- 46 pg/mL) than in control subjects (104 +/- 18 pg/mL), but levels of other cytokines tested were not different. Lipopolysaccharide-stimulated release of interleukin 1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha was increased (P less than 0.05) in PBMC cultures from patients with CFS versus control subjects; enhanced (P less than 0.01) IL-6 release to phytohemagglutinin was also observed.

In contrast, TGF-beta release in response to lipopolysaccharide was depressed (P less than 0.01) in PBMC cultures derived from patients with CFS. No differences in IL-2 and IL-4 or immunoglobulin production were observed.

The enhanced release of inflammatory cytokines by stimulated PBMC from patients with CFS suggests that these cells are primed for an increased response to immune stimuli. These data also suggest an association between abnormal regulation of TGF-beta production in vivo and in vitro with the immunologic consequence of CFS.

 

Source: Chao CC1, Janoff EN, Hu SX, Thomas K, Gallagher M, Tsang M, Peterson PK. Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine. 1991 Jul;3(4):292-8. http://www.ncbi.nlm.nih.gov/pubmed/1873478