Small Intestinal Bacterial Overgrowth (SIBO) and Twelve Groups of Related Diseases-Current State of Knowledge.

The human gut microbiota creates a complex microbial ecosystem, characterized by its high population density, wide diversity, and complex interactions. Any imbalance of the intestinal microbiome, whether qualitative or quantitative, may have serious consequences for human health, including small intestinal bacterial overgrowth (SIBO). SIBO is defined as an increase in the number of bacteria (103-105 CFU/mL), an alteration in the bacterial composition, or both in the small intestine. The PubMed, Science Direct, Web of Science, EMBASE, and Medline databases were searched for studies on SIBO and related diseases. These diseases were divided into 12 groups: (1) gastrointestinal disorders; (2) autoimmune disease; (3) cardiovascular system disease; (4) metabolic disease; (5) endocrine disorders; (6) nephrological disorders; (7) dermatological diseases; (8) neurological diseases (9); developmental disorders; (10) mental disorders; (11) genetic diseases; and (12) gastrointestinal cancer. The purpose of this comprehensive review is to present the current state of knowledge on the relationships between SIBO and these 12 disease groups, taking into account risk factors and the causal context. This review fills the evidence gap on SIBO and presents a biological-medical approach to the problem, clearly showing the groups and diseases having a proven relationship with SIBO, as well as indicating groups within which research should continue to be expanded.

MicroRNAs participate in the regulation of apoptosis and oxidative stress-related gene expression in rabbits infected with Lagovirus europaeus GI.1 and GI.2 genotypes.

MicroRNAs (miRs) are a group of small, 17-25 nucleotide, non-coding RNA that regulate gene expression at the post-transcriptional level. To date, little is known about the molecular signatures of regulatory interactions between miRs and apoptosis and oxidative stress in viral diseases. Lagovirus europaeus is a virus that causes severe disease in rabbits (Oryctolagus cuniculus) called Rabbit Hemorrhagic Disease (RHD) and belongs to the Caliciviridae family, Lagovirus genus. Within Lagovirus europaeus associated with RHD, two genotypes (GI.1 and GI.2) have been distinguished, and the GI.1 genotype includes four variants (GI.1a, GI.1b, GI.1c, and GI.1d). The study aimed to assess the expression of miRs and their target genes involved in apoptosis and oxidative stress, as well as their potential impact on the pathways during Lagovirus europaeus-two genotypes (GI.1 and GI.2) infection of different virulences in four tissues (liver, lung, kidneys, and spleen). The expression of miRs and target genes related to apoptosis and oxidative stress was determined using quantitative real-time PCR (qPCR). In this study, we evaluated the expression of miR-21 (PTEN, PDCD4), miR-16b (Bcl-2, CXCL10), miR-34a (p53, SIRT1), and miRs-related to oxidative stress-miR-122 (Bach1) and miR-132 (Nfr-2). We also examined the biomarkers of both processes (Bax, Bax/Bcl-2 ratio, Caspase-3, PARP) and HO-I as biomarkers of oxidative stress. Our report is the first to present the regulatory effects of miRs on apoptosis and oxidative stress genes in rabbit infection with Lagovirus europaeus-two genotypes (GI.1 and GI.2) in four tissues (liver, lungs, kidneys, and spleen). The regulatory effect of miRs indicates that, on the one hand, miRs can intensify apoptosis (miR-16b, miR-34a) in the examined organs in response to a viral stimulus and, on the other hand, inhibit (miR-21), which in both cases may be a determinant of the pathogenesis of RHD and tissue damage. Biomarkers of the Bax and Bax/Bcl-2 ratio promote more intense apoptosis after infection with the Lagovirus europaeus GI.2 genotype. Our findings demonstrate that miR-122 and miR-132 regulate oxidative stress in the pathogenesis of RHD, which is associated with tissue damage. The HO-1 biomarker in the course of rabbit hemorrhagic disease indicates oxidative tissue damage. Our findings show that miR-21, miR-16b, and miR-34a regulate three apoptosis pathways. Meanwhile, miR-122 and miR-132 are involved in two oxidative stress pathways.

Biomarkers of the Complement System Activation (C3a, C5a, sC5b-9) in Serum of Patients before and after Liver Transplantation.

The liver has a huge impact on the functioning of our body and the preservation of homeostasis. It is exposed to many serious diseases, which may lead to the chronic failure of this organ, which is becoming a global health problem today. Currently, the final form of treatment in patients with end-stage (acute and chronic) organ failure is transplantation. The proper function of transplanted organs depends on many cellular processes and immune and individual factors. An enormous role in the process of acceptance or rejection of a transplanted organ is attributed to, among others, the activation of the complement system. The aim of this study was the evaluation of the concentration of selected biomarkers' complement system activation (C3a, C5a, and sC5b-9 (terminal complement complex)) in the serum of patients before and after liver transplantation (24 h, two weeks). The study was conducted on a group of 100 patients undergoing liver transplantation. There were no complications during surgery and no transplant rejection in any of the patients. All patients were discharged home 2-3 weeks after the surgery. The levels of all analyzed components of the complement system were measured using the ELISA method. Additionally, the correlations of the basic laboratory parameters-C-reactive protein (CRP), hemoglobin (Hb), total bilirubin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGTP), and albumin-with the parameters of the complement system (C3a, C5a, and sC5b-9) were determined. In our study, changes in the concentrations of all examined complement system components before and after liver transplantation were observed, with the lowest values before liver transplantation and the highest concentration two weeks after. The direct increase in components of the complement system (C3a, C5a, and sC5b-9) 24 h after transplantation likely affects liver damage after ischemia-reperfusion injury (IRI), while their increase two weeks after transplantation may contribute to transplant tolerance. Increasingly, attention is being paid to the role of C3a and CRP as biomarkers of damage and failure of various organs. From the point of view of liver transplantation, the most interesting correlation in our own research was found exactly between CRP and C3a, 24 h after the transplantation. This study shows that changes in complement activation biomarkers and the correlation with CRP in blood could be a prognostic signature of liver allograft survival or rejection.

Digital PCR (dPCR) Quantification of miR-155-5p as a Potential Candidate for a Tissue Biomarker of Inflammation in Rabbits Infected with Lagovirus europaeus/Rabbit Hemorrhagic Disease Virus (RHDV).

MicroRNAs (miRNAs, miRs) are a group of small, 17-25 nucleotide, non-coding RNA sequences that, in their mature form, regulate gene expression at the post-transcriptional level. They participate in many physiological and pathological processes in both humans and animals. One such process is viral infection, in which miR-155 participates in innate and adaptive immune responses to a broad range of inflammatory mediators. Recently, the study of microRNA has become an interesting field of research as a potential candidate for biomarkers for various processes and disease. To use miRNAs as potential biomarkers of inflammation in viral diseases of animals and humans, it is necessary to improve their detection and quantification. In a previous study, using reverse transcription real-time quantitative PCR (RT-qPCR), we showed that the expression of ocu-miR-155-5p in liver tissue was significantly higher in rabbits infected with Lagovirus europaeus/Rabbit Hemorrhagic Disease Virus (RHDV) compared to healthy rabbits. The results indicated a role for ocu-miR-155-5p in Lagovirus europaeus/RHDV infection and reflected hepatitis and the impairment/dysfunction of this organ during RHD. MiR-155-5p was, therefore, hypothesized as a potential candidate for a tissue biomarker of inflammation and examined in tissues in Lagovirus europaeus/RHDV infection by dPCR. The objective of the study is the absolute quantification of ocu-miR-155-5p in four tissues (liver, lung, kidney, and spleen) of rabbits infected with Lagovirus europaeus/RHDV by digital PCR, a robust technique for the precise and direct quantification of small amounts of nucleic acids, including miRNAs, without standard curves and external references. The average copy number/µL (copies/µL) of ocu-miRNA-155-5p in rabbits infected with Lagovirus europaeus GI.1a/Rossi in the liver tissue was 12.26 ± 0.14, that in the lung tissue was 48.90 ± 9.23, that in the kidney tissue was 16.92 ± 2.89, and that in the spleen was 25.10 ± 0.90. In contrast, in the tissues of healthy control rabbits, the average number of copies/µL of ocu-miRNA-155-5p was 5.07 ± 1.10 for the liver, 23.52 ± 2.77 for lungs, 8.10 ± 0.86 for kidneys, and 42.12 ± 3.68 for the spleen. The increased expression of ocu-miRNA-155-5p in infected rabbits was demonstrated in the liver (a fold-change of 2.4, p-value = 0.0003), lung (a fold-change of 2.1, p-value = 0.03), and kidneys (a fold-change of 2.1, p-value = 0.01), with a decrease in the spleen (a fold-change of 0.6, p-value = 0.002). In the study of Lagovirus europaeus/RHDV infection and in the context of viral infections, this is the first report that shows the potential use of dPCR for the sensitive and absolute quantification of microRNA-155-5p in tissues during viral infection. We think miR-155-5p may be a potential candidate for a tissue biomarker of inflammation with Lagovirus europaeus/RHDV infection. Our report presents a new path in discovering potential candidates for the tissue biomarkers of inflammation.

Micro-Players of Great Significance-Host microRNA Signature in Viral Infections in Humans and Animals.

Over time, more and more is becoming known about micro-players of great significance. This is particularly the case for microRNAs (miRNAs; miR), which have been found to participate in the regulation of many physiological and pathological processes in both humans and animals. One such process is viral infection in humans and animals, in which the host miRNAs-alone or in conjunction with the virus-interact on two levels: viruses may regulate the host's miRNAs to evade its immune system, while the host miRNAs can play anti- or pro-viral roles. The purpose of this comprehensive review is to present the key miRNAs involved in viral infections in humans and animals. We summarize the data in the available literature, indicating that the signature miRNAs in human viral infections mainly include 12 miRNAs (i.e., miR-155, miR-223, miR-146a, miR-122, miR-125b, miR-132, miR-34a, miR -21, miR-16, miR-181 family, let-7 family, and miR-10a), while 10 miRNAs are commonly found in animals (i.e., miR-155, miR-223, miR-146a, miR-145, miR-21, miR-15a/miR-16 cluster, miR-181 family, let-7 family, and miR-122) in this context. Knowledge of which miRNAs are involved in different viral infections and the biological functions that they play can help in understanding the pathogenesis of viral diseases, facilitating the future development of therapeutic agents for both humans and animals.

New Insights into the Role of the Complement System in Human Viral Diseases.

The complement system (CS) is part of the human immune system, consisting of more than 30 proteins that play a vital role in the protection against various pathogens and diseases, including viral diseases. Activated via three pathways, the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP), the complement system leads to the formation of a membrane attack complex (MAC) that disrupts the membrane of target cells, leading to cell lysis and death. Due to the increasing number of reports on its role in viral diseases, which may have implications for research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), this review aims to highlight significant progress in understanding and defining the role of the complement system in four groups of diseases of viral etiology: (1) respiratory diseases; (2) acute liver failure (ALF); (3) disseminated intravascular coagulation (DIC); and (4) vector-borne diseases (VBDs). Some of these diseases already present a serious global health problem, while others are a matter of concern and require the collaboration of relevant national services and scientists with the World Health Organization (WHO) to avoid their spread.

Role of miR-506 in ulcerative colitis associated with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is commonly accompanied by ulcerative colitis (UC). MicroRNA-506 modulates expression of genes which are essential for sphingosine-mediated signaling pathway and intestinal mucosa protection. We investigated whether miR-506 and its target genes are involved in phenotypic presentations of colonic inflammation and/or neoplasia. We analyzed serum and colon tissue samples collected from patients with PSC, PSC with concurrent UC (PSC + UC), UC alone, and healthy controls (n = 10 each). MiR-506 was substantially upregulated in ascending colons of PSC and PSC + UC patients, in contrast to sigmoid colons of PSC and UC patients. Upregulation of miR-506 was associated with inhibition of SPHK1, AE2, InsP3R3, and p53. Colonic suppression of miR-506 presented in UC was accompanied by substantially increased DNMT1, SPHK1, and S1P lyase expressions. A functional in vitro analysis in Caco-2 cells showed that the induction of miR-506 activity by miR-506 mimic or GDCDA bile acid suppressed, whereas inhibition of miR-506 by miR-506 inhibitor or lipopolysaccharide (LPS) upregulated the expression of the examined target genes. A different phenotypic presentation of colitis may be related to miR-506 expression. In ascending colons with PSC + UC, upregulation of miR-506 may result in failure of bicarbonate secretion and inhibition of p53, which predisposes to pro-tumorigenic transformation. In contrast, downregulation of miR-506 enhances S1P production, leading to pro-inflammatory signaling.

Melatonin Protects Cholangiocytes from Oxidative Stress-Induced Proapoptotic and Proinflammatory Stimuli via miR-132 and miR-34.

Biosynthesis of melatonin by cholangiocytes is essential for maintaining the function of biliary epithelium. However, this cytoprotective mechanism appears to be impaired in primary biliary cholangitis (PBC). MiR-132 has emerged as a mediator of inflammation in chronic liver diseases. The effect of melatonin on oxidative stress and bile acid-induced apoptosis was also examined in cholangiocyes overexpressing miR506, as a PBC-like cellular model. In PBC patients the serum levels of melatonin were found increased in comparison to healthy controls. Whereas, in cholangiocytes within cirrhotic PBC livers the melatonin biosynthetic pathway was substantially suppressed even though the expressions of melatonin rate-limiting enzyme aralkylamine N-acetyltransferase (AANAT), and CK-19 (marker of cholangiocytes) were enhanced. In cholangiocytes exposed to mitochondrial oxidative stress melatonin decreased the expression of proapoptotic stimuli (PTEN, Bax, miR-34), which was accompanied by the inhibition of a pivotal mediator of inflammatory response Nf-κB-p65 and the activation of antiapoptotic signaling (miR-132, Bcl2). Similarly, melatonin reduced bile acid-induced proapoptotic caspase 3 and Bim levels. In summary, the insufficient hepatic expression of melatonin in PBC patients may predispose cholangiocytes to oxidative stress-related damage. Melatonin, via epigenetic modulation, was able to suppress NF-κB signaling activation and protect against biliary cells apoptotic signaling.

A Circadian Rhythm in both Complement Cascade (ComC) Activation and Sphingosine-1-Phosphate (S1P) Levels in Human Peripheral Blood Supports a Role for the ComC-S1P Axis in Circadian Changes in the Number of Stem Cells Circulating in Peripheral Blood.

The number of hematopoietic stem/progenitor cells (HSPCs) circulating in peripheral blood (PB) is regulated by a circadian rhythm, and more HSPCs circulate in PB in the morning hours than at night. Different mechanisms have been proposed that might regulate this process, including changes in tonus of ß-adrenergic innervation of bone marrow (BM) tissue. Our group reported that in mice circadian changes in the number of HSPCs circulating in PB correlates with diurnal activation of the complement cascade (ComC) and that the mice deficient in C5 component of ComC (C5-KO mice) do not show circadian changes in the number of circulating HSPCs in PB. We also reported the existence of a gradient between PB and BM of a bioactive phosphosphingolipid, sphingosine-1-phosphate (S1P), which is a major PB chemottractant for BM-residing HSPCs. Based on these observations, we investigated activation of the ComC and the level of S1P in the PB of 66 healthy volunteers. We found that both ComC activation and the S1P level undergo changes in a circadian cycle. While the ComC becomes highly activated during deep sleep at 2 am, S1P becomes activated later, and its highest level is observed at 8 am, which precedes circadian egress of HSPCs from BM into PB. In sum, circadian activation of the ComC-S1P axis releases HSPCs from BM into PB.