The gammaretroviral human endogenous retrovirus (HERV) families MRSV/HERV-W and HERV-H (including the closely related HERV-Fc1) are associated with an increased risk of multiple sclerosis (MS). Complete HERV sequences betray their endogenous retroviral origin, with open reading frames in gag, pro, pol and env being flanked by two long terminal repeats containing promoter and enhancer sequences with the capacity to regulate HERV transactivation and the activity of host genes in spite of endogenous epigenetic repression mechanisms. HERV virions, RNA, cDNA, Gag and Env, and antibodies to HERV transcriptional products, have variously been found in the blood and/or brain and/or cerebrospinal fluid of MS patients, with the HERV expression level being associated with disease status. Furthermore, some HERV-associated single nucleotide polymorphisms (SNPs), such as rs662139 T/C in a 3-kb region of Xq22.3 containing a HERV-W env locus, and rs391745, upstream of the HERV-Fc1 locus on the X chromosome, are associated with MS susceptibility, while a negative association has been reported with SNPs in the tripartite motif-containing (TRIM) protein-encoding genes TRIM5 and TRIM22. Factors affecting HERV transcription include immune activation and inflammation, since HERV promoter regions possess binding sites for related transcription factors; oxidative stress, with oxidation of guanine to 8-oxoguanine and conversion of cytosine to 5-hydroxymethylcytosine preventing binding of methyl groups transferred by DNA methyltransferases; oxidative stress also inhibits the activity of deacetylases, thereby favouring the acetylation of histone lysine residues favouring gene expression; interferon beta; natalizumab treatment; impaired epigenetic regulation; and the sex of patients.

Background: Increased intestinal permeability with heightened translocation of Gramnegative bacteria, also known as “leaky gut”, is associated with the pathophysiology of neuroimmune disorders, such as Major Depressive Disorder (MDD), Chronic Fatigue Syndrome (CSF) and (deficit) schizophrenia, as well as with general medical disorders, including irritable bowel syndrome. This review aims to summarize clinical biochemistry and molecular immunology tests that may aid in the recognition of leaky gut in clinical practice. Methods: We searched online libraries, including PubMed/MEDLINE, Google Scholar and Scopus, with the key words “diagnosis” or “biomarkers” and “leaky gut”, “bacterial translocation”, and “intestinal permeability” and focused on papers describing tests that may aid in the clinical recognition of leaky gut. Results: To evaluate tight junction barrier integrity, serum IgG/IgA/IgM responses to occludin and zonulin and IgA responses to actomyosin should be evaluated. The presence of cytotoxic bacterial products in serum can be evaluated using IgA/IgM responses to sonicated samples of common Gram-negative gut commensal bacteria and assays of serum lipopolysaccharides (LPSs) and other bacterial toxins, including cytolethal distenting toxin, subunit B. Major factors associated with increased gut permeability, including gut dysbiosis and yeast overgrowth, use of NSAIDs and alcohol, food hypersensitivities (IgE-mediated), food intolerances (IgG-mediated), small bacterial overgrowth (SIBO), systemic inflammation, psychosocial stressors, some infections (e.g., HIV) and dietary patterns, should be assessed. Stool samples can be used to assay gut dysbiosis, gut inflammation and decreased mucosal defenses using assays of fecal growth of bacteria, yeast and fungi and stool assays of calprotectin, secretory IgA, β-defensin, α- antitrypsin, lysozyme and lactoferrin. Blood and breath tests should be used to exclude common causes of increased gut permeability, namely, food hypersensitivities and intolerances, SIBO, lactose intolerance and fructose malabsorption. Discussion: Here, we propose strategies to recognize “leaky gut” in a clinical setting using the most adequate clinical chemistry and molecular immunology assays.

Cytokines as intercellular signal molecules are responsible to a great extent for the pathological processes in Salmonella infection, as well as for the development of protective mechanisms in the disease. The present study aimed to reveal the correlation between serum levels of IFN-γ, IL-12, TNF-α and IL-10, measured by enzyme-immunoassay, and clearance of bacteria in stool of patients with gastroenteric Salmonella infection. The study included 36 patients with culture confirmed gastroenteric Salmonella infection. At discharge from hospital, 20 patients recovered with bacteriological negative stool culture for Salmonella and 16 were Salmonella excretors. Mean serum concentrations of IFN-γ, IL-12, TNF-α and IL-10 in the acute stage were compared between the 2 groups of patients and with those of healthy controls. Serum levels of examined cytokines were increased (p<0.001) in the patients in comparison with the healthy controls. In patients with early bacterial clearance mean serum concentrations of IFN-γ, IL-12 and TNF-α in the acute stage were significantly (p<0.05) higher than in the non-clearance group. IL-10 serum level showed an opposite correlation (p<0.01) and higher values in Salmonella excretors. The accumulated data imply that Th1 type cytokines probably participate in protective immunity and early bacterial clearance in patients with gastroenteric Salmonella infection.

Deregulated cytokines' production is found in depressed patients. Salidroside and curcumin both have been described with potential antidepressant-like activities. The present study investigated the effect of pure salidroside, curcumin and their combination on the immunoreactivity of animals, subjected to a chronic mild stress (CMS) model, followed by lipopolysaccharide (LPS)-induced inflammation. Wistar male rats were separated in the following six groups: control, CMS model, fluoxetine (2.5 mg/kg, oral), salidroside (5 mg/kg, oral), curcumin (20 mg/kg, oral) and salidroside + curcumin (5 mg/kg + 20 mg/kg, oral). Changes in glucose preference, spatial learning and exploratory behavior were recorded. The IL-6 levels in the rats' sera and of the TNF-α levels in the rats' sera and the brain tissue homogenate were evaluated. The groups exposed to stress and treated with fluoxetine, salidroside, curcumin or salidroside + curcumin showed increase in the glucose preference and locomotor activity, as well as, decrease in the escape latency and the cytokines' levels compared to the CMS model group. The chronic stress induced behavioral alternations and increased cytokines' levels in rats which were reversed by administration of salidroside and curcumin, suggesting antidepressant-like effects comparable to that of fluoxetine and potential synergistic interaction regarding the anti-inflammatory and anti-stress effects.