Herpesvirus Antibodies, Vitamin D and Short-Chain Fatty Acids: Their Correlation with Cell Subsets in Multiple Sclerosis Patients and Healthy Controls

Domínguez-Mozo, María Inmaculada; Pérez-Pérez, Silvia; Villarrubia, Noelia; Costa‐Frossard, Lucienne; Fernández-Velasco, José Ignacio; Ortega‐Madueño, Isabel; García‐Martínez, Maria Ángel; García-Calvo, Estefanía; Estévez, Héctor; Garcia, Jose Luis Luque; Torrejón, María José; Arroyo, Rafael; Villar, Luisa María; Álvarez‐Lafuente, Roberto

doi:10.3390/cells10010119

Cited by 13 publications

(8 citation statements)

References 70 publications

(63 reference statements)

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“…In our study, the concentration of acetate, propionate and butyrate were higher compared with previous studies ( 14 , 19 , 42 ). This might be explained by the use of different extraction methods for the detection of SCFAs between the studies.…”

Section: Discussioncontrasting

confidence: 80%

Serum Short-Chain Fatty Acids and Associations With Inflammation in Newly Diagnosed Patients With Multiple Sclerosis and Healthy Controls

et al. 2021

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Multiple sclerosis (MS) is a chronic immune-mediated disease characterized by demyelination and neuroaxonal damage in the central nervous system. The etiology is complex and is still not fully understood. Accumulating evidence suggests that our gut microbiota and its metabolites influence the MS pathogenesis. Short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate, are metabolites produced by gut microbiota through fermentation of indigestible carbohydrates. SCFAs and kynurenine metabolites have been shown to have important immunomodulatory properties, and propionate supplementation in MS patients has been associated with long-term clinical improvement. However, the underlying mechanisms of action and its importance in MS remain incompletely understood. We analyzed serum levels of SCFAs and performed targeted metabolomics in relation to biomarkers of inflammation, and clinical and MRI measures in newly diagnosed patients with relapsing-remitting MS before their first disease modifying therapy and healthy controls (HCs). We demonstrated that serum acetate levels were nominally reduced in MS patients compared with HCs. The ratios of acetate/butyrate and acetate/(propionate + butyrate) were significantly lower in MS patients in a multivariate analysis (orthogonal partial least squares discriminant analysis; OPLS-DA). The mentioned ratios and acetate levels correlated negatively with the pro-inflammatory biomarker IFNG, indicating an inverse relation between acetate and inflammation. In contrast, the proportion of butyrate was found higher in MS patients in the multivariate analysis, and both butyrate and valerate correlated positively with proinflammatory cytokines (IFNG and TNF), suggesting complex bidirectional regulatory properties of SCFAs. Branched SCFAs were inversely correlated with clinical disability, at a nominal significance level. Otherwise SCFAs did not correlate with clinical variables or MRI measures. There were signs of an alteration of the kynurenine pathway in MS, and butyrate was positively correlated with the immunomodulatory metabolite 3-hydroxyanthranilic acid. Other variables that influenced the separation between MS and HCs were NfL, ARG1 and IL1R1, D-ribose 5-phosphate, pantothenic acid and D-glucuronic acid. In conclusion, we provide novel results in this rapidly evolving field, emphasizing the complexity of the interactions between SCFAs and inflammation; therefore, further studies are required to clarify these issues before supplementation of SCFAs can be widely recommended.

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Section: Discussioncontrasting

confidence: 80%

Serum Short-Chain Fatty Acids and Associations With Inflammation in Newly Diagnosed Patients With Multiple Sclerosis and Healthy Controls

et al. 2021

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“…By carrying stretches of telomeric repeats at their linear genome, the variants HHV-6A and HHV-6B are able to integrate into human chromosomes and become latent [ 160 ]. This virus has been found in several human diseases, including autoimmunity [ 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 ], ME/CFS [ 190 , 191 , 192 , 193 ], mitochondrial dysfunction [ 193 , 194 ], and in patients with moderate to critical COVID-19 [ 42 , 43 , 44 , 195 , 196 ]. Among the autoimmune diseases associated with HHV-6, the most frequently cited is multiple sclerosis (MS) [ 170 , 171 , 172 , 173 , 174 , 175 , 176 , …”

Section: Multiple Tissue Damage and Autoimmunitymentioning

confidence: 99%

“…This has been demonstrated by the direct detection of the HHV-6 genome and antigens in the blood and brain of patients with MS [ 176 , 177 , 178 , 181 , 182 , 183 ]. Furthermore, not only were higher levels of anti-HHV-6 A/B antibodies detected in the blood of MS patients, their titers also correlated with the severity of the disease [ 170 ] and in predicting risk of relapse [ 184 , 185 , 186 ]. Researchers further concluded that in addition to its potential etiologic role in MS, infection with HHV-6 or immune reaction against it may also have an effect on MS relapse and its progression [ 184 ].…”

Section: Multiple Tissue Damage and Autoimmunitymentioning

confidence: 99%

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID

Vojdani

Vojdani²,

Saidara

et al. 2023

Viruses

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A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein–Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.

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“…Virtually all (99.5%) patients with MS are seropositive for antibodies directed against EBV ( 22 ). A recent study analyzed multiple environmental factors that may contribute to MS risk, including VitD levels and EBV antibody titers ( 23 ). EBV antibody titers were significantly higher in MS patients and there was an inverse relationship between VitD levels and EDSS, yet no correlation between VitD levels and EBV antibody titers.…”

Section: Multiple Sclerosismentioning

confidence: 99%

Vitamin D as a Risk Factor for Multiple Sclerosis: Immunoregulatory or Neuroprotective?

et al. 2022

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Vitamin D insufficiency during childhood has been linked to the development of multiple sclerosis (MS), typically an adult-onset inflammatory demyelinating disease of the central nervous system (CNS). Since vitamin D was known to have immunoregulatory properties on both innate and adaptive immunity, it was hypothesized that low vitamin D resulted in aberrant immune responses and the development of MS. However, vitamin D receptors are present on many cell types, including neurons, oligodendrocytes, astrocytes and microglia, and vitamin D has profound effects on development and function of the CNS. This leads to the possibility that low vitamin D may alter the CNS in a manner that makes it vulnerable to inflammation and the development of MS. This review analysis the role of vitamin D in the immune and nervous system, and how vitamin D insufficiency in children may contribute to the development of MS.

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Herpesvirus Antibodies, Vitamin D and Short-Chain Fatty Acids: Their Correlation with Cell Subsets in Multiple Sclerosis Patients and Healthy Controls

Cited by 13 publications

References 70 publications

Serum Short-Chain Fatty Acids and Associations With Inflammation in Newly Diagnosed Patients With Multiple Sclerosis and Healthy Controls

Serum Short-Chain Fatty Acids and Associations With Inflammation in Newly Diagnosed Patients With Multiple Sclerosis and Healthy Controls

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID

Vitamin D as a Risk Factor for Multiple Sclerosis: Immunoregulatory or Neuroprotective?

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