Gut microbiota dysbiosis has recently been reported in a number of clinical states, including neurological, psychiatric, cardiovascular, metabolic and autoimmune disorders. Yet, it is not completely understood how colonizing microorganisms are implicated in their pathophysiology and molecular pathways. There are a number of suggested mechanisms of how gut microbiota dysbiosis triggers or sustains extraintestinal diseases; however, none of these have been widely accepted as part of the disease pathogenesis. Recent studies have proposed that gut microbiota and its metabolites could play a pivotal role in the modulation of immune system responses and the development of autoimmunity in diseases such as rheumatoid arthritis, multiple sclerosis or type 1 diabetes. Fecal microbiota transplantation (FMT) is a valuable tool for uncovering the role of gut microbiota in the pathological processes. This review aims to summarize the current knowledge about gut microbiota dysbiosis and the potential of FMT in studying the pathogeneses and therapies of autoimmune diseases. Herein, we discuss the extraintestinal autoimmune pathologies with at least one published or ongoing FMT study in human or animal models.

Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the gastrointestinal tract, encompassing two main disorders: Crohn’s disease (CD) and ulcerative colitis (UC). In both these pathologies, excessive and local immune response against luminal antigens promotes a pathological process leading to various degrees of gut damage. Matrix metalloproteinases (MMPs) are a family of neutral proteases with the ability to degrade all components of extracellular matrix. In physiological conditions, MMPs are produced at very low level and generally in the latent form and are involved in the normal tissue turnover. Their function is inhibited by tissue inhibitors of metalloproteinases (TIMPs). However, in inflamed tissue of IBD patients, MMPs are produced in excess and/or the activity of TIMPs is not sufficient to block MMPs, thereby making a major contribution to the IBD-related mucosal degradation. In this review, we summarize the available evidence on the expression and role of MMPs in IBD.

Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their incidence continues to increase. Despite major efforts aimed at discovering and validating novel and effective drugs against these malignancies, the process of developing such drugs remains lengthy and costly, with high attrition rates. Drug repositioning (also known as drug repurposing), that is, the process of finding new uses for approved drugs, has been gaining popularity in oncological drug development as it provides the opportunity to expedite promising anti-cancer agents into clinical trials. Among the drugs considered for repurposing in oncology, compounds belonging to some classes of anthelmintics—a group of agents acting against infections caused by parasitic worms (helminths) that colonize the mammalian intestine—have shown pronounced anti-tumor activities and attracted particular attention due to their ability to target key oncogenic signal transduction pathways. In this review, we summarize and discuss the available experimental and clinical evidence about the use of anthelmintic drugs for the treatment of cancers of the digestive system.

Inflammatory bowel diseases (IBDs) are a group of chronic autoinflammatory diseases including Crohn’s disease and ulcerative colitis. Although the molecular mechanisms governing the pathogenesis of gastrointestinal inflammation are not completely clear, the main factors are presumed to be genetic predisposition, environmental exposure, and the intestinal microbiome. Hitherto, most of the studies focusing on the role of the microbiome studied the action and effect of bacteria. However, the intestinal microbiome comprises other members of the microbial community as well, namely, fungi, protozoa, and viruses. We believe that bacteriophages are among the main orchestrators of the effect of microbiota on the gut mucosa. Therefore, this review aims to summarize the knowledge of the role of intestinal phageome in IBD and to discuss the concept of phage therapy and its future applications.

Circulating extracellular DNA (ecDNA) is known to worsen the outcome of many diseases. ecDNA released from neutrophils during infection or inflammation is present in the form of neutrophil extracellular traps (NETs). It has been shown that higher ecDNA concentration occurs in a number of inflammatory diseases including inflammatory bowel disease (IBD). Enzymes such as peptidyl arginine deiminases (PADs) are crucial for NET formation. We sought to describe the dynamics of ecDNA concentrations and fragmentation, along with NETosis during a mouse model of chemically induced colitis. Plasma ecDNA concentration was highest on day seven of dextran sulfate sodium (DSS) intake and the increase was time-dependent. This increase correlated with the percentage of cells undergoing NETosis and other markers of disease activity. Relative proportion of nuclear ecDNA increased towards more severe colitis; however, absolute amount decreased. In colon explant medium, the highest concentration of ecDNA was on day three of DSS consumption. Early administration of PAD4 inhibitors did not alleviate disease activity, but lowered the ecDNA concentration. These results uncover the biological characteristics of ecDNA in IBD and support the role of ecDNA in intestinal inflammation. The therapeutic intervention aimed at NETs and/or nuclear ecDNA has yet to be fully investigated.

The human virome, which is a collection of all the viruses that are present in the human body, is increasingly being recognized as an essential part of the human microbiota. The human gastrointestinal tract and related organs (e.g., liver, pancreas, and gallbladder)—composing the gastrointestinal (or digestive) system—contain a huge number of viral particles which contribute to maintaining tissue homeostasis and keeping our body healthy. However, perturbations of the virome steady-state may, both directly and indirectly, ignite/sustain oncogenic mechanisms contributing to the initiation of a dysplastic process and/or cancer progression. In this review, we summarize and discuss the available evidence on the association and role of viruses in the development of cancers of the digestive system.