PURPOSE: Dysregulation of the microbiota on different mucosal surfaces is associated with both immune-mediated and malignant diseases. Nevertheless, the involvement of different microbial communities is still poorly characterized. The aim of our study was to compare oral and gut microbiota composition between patients with uveitis, vitreoretinal lymphoma (VRL), and controls. METHODS: This study was designed as a prospective observational study. The inclusion criteria were treatment-naïve patients with immune-mediated uveitis or newly diagnosed VRL. The buccal swab and faecal samples were collected and bacterial 16S ribosomal RNA gene sequencing was used to identify the oral and gut microbiota. RESULTS: We enrolled 18 patients with uveitis, median age 39 years, 16 patients with VRL, median age 67.5 years, and 16 controls, median age 63 years. In the oral microbiota, the patients suffering from uveitis showed significant enrichment of genera Pseudomonas (p < 0.0001 and p < 0.0001), and Diaphorobacter (p = 0.007 and 0.013) and reduction of Streptococcus (p < 0.0001 and p < 0.0001) when compared to patients with VRL and control subjects, respectively. In addition, these patients had also significantly higher relative abundance of the genus Enhydrobacter (p = 0.029) and lower abundance of the genera Gemella (p = 0.002), Neisseria (p = 0.008), and Prevotella (p = 0.011) when compared to patients with VRL. We found only minor changes in the gut microbiota. CONCLUSION: Our study, as the first one, highlighted significant differences in the composition of oral microbiota among patients with uveitis, VRL, and control subjects.

• Keywords
• Microbiome, Microbiota, Sequencing, Uveitis, Vitreoretinal lymphoma,
• Publication type
• Journal Article MeSH

The impairment of intestinal barrier function is implicated in primary sclerosing cholangitis, but the clinical evidence is scarce. Therefore, we performed a cross-sectional study to evaluate serological markers of inflammation and intestinal permeability (Reg3a, iFABP, Zonulin, Calprotectin) in patients after liver transplantation (LT) for PSC. The cohort included 26 subjects with PSC recurrence (rPSC), 87 subjects without PSC recurrence (non-rPSC), and a unique control group consisting of post-LT patients (n = 113) transplanted due to alcohol cirrhosis. Generalized Linear Models were calculated to assess the association between serological markers of intestinal barrier function or inflammation (IP_Models) and PSC diagnosis per se (IP_Model_1), non-rPSC (IP_Model_2) or rPSC incidence (IP_Model_3) and compared with models (ST_Models) based on validated PSC markers (ALP, GGT, bilirubin). The increased probability of PSC occurrence (IP_Model_1, p < 0.001, AIC = 182) was associated with higher serum Reg3a concentration, while a negative association was found for iFABP, BMI, and age. The probability of non-recurrence (IP_Model_2, p < 0.001, AIC = 167) was associated with lower Reg3a concentration, older age, and BMI. The performance of IP_Models_1,2 and ST_models_1,2 was comparable. rPSC prediction was less precise by both models (IP_Model_3 p = 0.063, AIC = 92; ST_Model_3 p < 0.001, AIC = 108). rPSC incidence was positively associated with fecal calprotectin and serum zonulin concentrations, while it was independent of Reg3a, iFABP, age or BMI. In conclusion, this pilot study suggests that impaired intestinal permeability is associated with the pathophysiology of rPSC. Our data could serve as a basis for testing in a larger independent validation cohort and, if confirmed, help to explain the mechanisms underlying the pathophysiology of PSC and the recurrence of this disease after transplantation.

• Keywords
• Reg3a, iFABP, liver transplantation, recurrence of primary sclerosing cholangitis, zonulin,
• Publication type
• Journal Article MeSH

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree, leading to significant liver function impairment over time. There is a strong association with inflammatory bowel diseases (IBD), together representing a distinct and complex medical condition. Patients with PSC-IBD face a heightened risk of various cancers, particularly colorectal carcinoma (CRC) and cholangiocarcinoma (CCA) as the most common types. In this review, we aim to characterize the distinctive features of PSC-IBD-associated carcinomas. Cancer pathogenesis in PSC-IBD is shaped by various factors including dysregulated bile acid metabolism, gut dysbiosis, and unique immune responses. PSC-IBD-associated CRC is often right-sided and warrants vigilant monitoring due to its higher incidence and unique morphological features compared to CRC arising in the terrain of IBD alone. CCA shares substantial genetic similarities with extrahepatic CCA and poses diagnostic challenges since it is frequently detected at advanced stages due to symptom overlap with PSC. Besides, reliable predictive biomarkers for targeted therapy remain largely unexplored. The distinct molecular, genetic, and histopathological profiles of CRC and CCA in PSC-IBD underscore the complexity of these malignancies and highlight the need for continued research to develop precise therapeutic strategies.

• Keywords
• Cholangiocarcinoma, Colorectal carcinoma, Crohn’s disease, Inflammatory bowel disease, Primary sclerosing cholangitis, Ulcerative colitis,
• MeSH
• Cholangiocarcinoma * pathology   etiology   genetics   MeSH
• Inflammatory Bowel Diseases * complications   pathology   MeSH
• Colorectal Neoplasms * pathology   etiology   genetics   MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Bile Duct Neoplasms * pathology   etiology   genetics   MeSH
• Cholangitis, Sclerosing * complications   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Biomarkers, Tumor MeSH

PURPOSE OF THE REVIEW: The purpose of this Review was to summarize the evidence on the associations among estrogen status, cellular senescence, the gut microbiome and osteoporosis. RECENT FINDINGS: Indicate that osteoporosis is a global public health problem that impacts individuals and society. In postmenopausal women, a decrease in estrogen levels is associated with a decrease in gut microbial diversity and richness, as well as increased permeability of the gut barrier, which allows for low-grade inflammation. The direct effects of estrogen status on the association between bone and the gut microbiome were observed in untreated and treated ovariectomized women. In addition to the direct effects of estrogens on bone remodeling, estrogen therapy could reduce the risk of postmenopausal osteoporosis by preventing increased gut epithelial permeability, bacterial translocation and inflammaging. However, in studies comparing the gut microbiota of older women, there were no changes at the phylum level, suggesting that age-related comorbidities may have a greater impact on changes in the gut microbiota than menopausal status does. Estrogens modify bone health not only by directly influencing bone remodeling, but also indirectly by influencing the gut microbiota, gut barrier function and the resulting changes in immune system reactivity.

• Keywords
• Aging, Estrogen, Inflammation, Leaky gut, Microbiota, Osteoporosis, Ovariectomy,
• MeSH
• Estrogens * MeSH
• Humans MeSH
• Osteoporosis MeSH
• Osteoporosis, Postmenopausal * MeSH
• Bone Remodeling * MeSH
• Cellular Senescence MeSH
• Gastrointestinal Microbiome * MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Estrogens * MeSH

The human microbiota is a complex ecosystem that colonizes body surfaces and interacts with host organ systems, especially the immune system. Since the composition of this ecosystem depends on a variety of internal and external factors, each individual harbors a unique set of microbes. These differences in microbiota composition make individuals either more or less susceptible to various diseases, including cancer. Specific microbes are associated with cancer etiology and pathogenesis and several mechanisms of how they drive the typical hallmarks of cancer were recently identified. Although most microbes reside in the distal gut, they can influence cancer initiation and progression in distant tissues, as well as modulate the outcomes of established cancer therapies. Here, we describe the mechanisms by which microbes influence carcinogenesis and discuss their current and potential future applications in cancer diagnostics and management.

• Keywords
• Fecal microbiota transplantation, Gut microbiota, Hallmarks of cancer, Tumor microenvironment,
• Publication type
• Journal Article MeSH
• Review MeSH

The unique functionality of Akkermansia muciniphila in gut microbiota indicates it to be an indispensable microbe for human welfare. The importance of A. muciniphila lies in its potential to convert mucin into beneficial by-products, regulate intestinal homeostasis and maintain gut barrier integrity. It is also known to competitively inhibit other mucin-degrading bacteria and improve metabolic functions and immunity responses in the host. It finds a pivotal perspective in various diseases and their treatment. It has future as a promising probiotic, disease biomarker and therapeutic agent for chronic diseases. Disease-associated dysbiosis of A. muciniphila in the gut microbiome makes it a potential candidate as a biomarker for some diseases and can provide future theranostics by suggesting ways of diagnosis for the patients and best treatment method based on the screening results. Manipulation of A. muciniphila in gut microbiome may help in developing a novel personalized therapeutic action and can be a suitable next generation medicine. However, the actual pathway governing A. muciniphila interaction with hosts remains to be investigated. Also, due to the limited availability of products containing A. muciniphila, it is not exploited to its full potential. The present review aims at highlighting the potential of A. muciniphila in mucin degradation, contribution towards the gut health and host immunity and management of metabolic diseases such as obesity and type 2 diabetes, and respiratory diseases such as cystic fibrosis and COVID-19.

• Keywords
• Akkermansia muciniphila, Biomarker, COVID-19, Gut microbiome, Host immunity, Mucus degradation, Obesity, Probiotic, Therapeutic, Type 2 diabetes,
• MeSH
• COVID-19 * MeSH
• Diabetes Mellitus, Type 2 * MeSH
• Dysbiosis therapy   MeSH
• Mucus MeSH
• Humans MeSH
• Mucins metabolism   MeSH
• Gastrointestinal Microbiome * MeSH
• Verrucomicrobia metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Mucins MeSH

Crohn's disease (CD) and ulcerative colitis (UC) are two forms of inflammatory bowel disease (IBD), where the role of gut but not skin dysbiosis is well recognized. Inhibitors of TNF have been successful in IBD treatment, but up to a quarter of patients suffer from unpredictable skin adverse events (SkAE). For this purpose, we analyzed temporal dynamics of skin microbiota and serum markers of inflammation and epithelial barrier integrity during anti-TNF therapy and SkAE manifestation in IBD patients. We observed that the skin microbiota signature of IBD patients differs markedly from healthy subjects. In particular, the skin microbiota of CD patients differs significantly from that of UC patients and healthy subjects, mainly in the retroauricular crease. In addition, we showed that anti-TNF-related SkAE are associated with specific shifts in skin microbiota profile and with a decrease in serum levels of L-FABP and I-FABP in IBD patients. For the first time, we showed that shifts in microbial composition in IBD patients are not limited to the gut and that skin microbiota and serum markers of the epithelium barrier may be suitable markers of SkAE during anti-TNF therapy.

• Keywords
• 16S RNA sequencing, IBD, TNF-alpha antagonist, serum biomarker, skin adverse events, skin microbiota,
• MeSH
• Biomarkers MeSH
• Crohn Disease * MeSH
• Inflammatory Bowel Diseases * drug therapy   MeSH
• Tumor Necrosis Factor Inhibitors MeSH
• Humans MeSH
• Microbiota * MeSH
• Colitis, Ulcerative * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers MeSH
• Tumor Necrosis Factor Inhibitors MeSH

Plectin, a highly versatile cytolinker protein, provides tissues with mechanical stability through the integration of intermediate filaments (IFs) with cell junctions. Here, we hypothesize that plectin-controlled cytoarchitecture is a critical determinant of the intestinal barrier function and homeostasis. Mice lacking plectin in an intestinal epithelial cell (IEC; PleΔIEC) spontaneously developed colitis characterized by extensive detachment of IECs from the basement membrane (BM), increased intestinal permeability, and inflammatory lesions. Moreover, plectin expression was reduced in the colons of ulcerative colitis (UC) patients and negatively correlated with the severity of colitis. Mechanistically, plectin deficiency in IECs led to aberrant keratin filament (KF) network organization and the formation of dysfunctional hemidesmosomes (HDs) and intercellular junctions. In addition, the hemidesmosomal α6β4 integrin (Itg) receptor showed attenuated association with KFs, and protein profiling revealed prominent downregulation of junctional constituents. Consistent with the effects of plectin loss in the intestinal epithelium, plectin-deficient IECs exhibited remarkably reduced mechanical stability and limited adhesion capacity in vitro. Feeding mice with a low-residue liquid diet that reduced mechanical stress and antibiotic treatment successfully mitigated epithelial damage in the PleΔIEC colon.

• MeSH
• Desmosomes genetics   metabolism   MeSH
• Adult MeSH
• Keratins metabolism   MeSH
• Colitis metabolism   prevention & control   MeSH
• Colon pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Disease Models, Animal MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Plectin genetics   metabolism   MeSH
• Aged MeSH
• Intestinal Mucosa metabolism   pathology   MeSH
• Colitis, Ulcerative metabolism   prevention & control   MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Mice MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Keratins MeSH
• Plectin MeSH

Diet is a strong modifier of microbiome and mucosal microenvironment in the gut. Recently, components of western-type diets have been associated with metabolic and immune diseases. Here, we studied how high-sugar diet (HSD) consumption influences gut mucosal barrier and immune response under steady state conditions and in a mouse model of acute colitis. We found that HSD significantly increased gut permeability, spleen weight, and neutrophil levels in spleens of healthy mice. Subsequent dextran sodium sulfate administration led to severe colitis. In colon, HSD significantly promoted neutrophil infiltration and increased the levels of IL-6, IL-1β, and TNF-α. Moreover, HSD-fed mice had significantly higher abundance of pathobionts, such as Escherichia coli and Candida, in fecal samples. Although germ-free mice colonized with microbiota of conventionally reared mice that consumed different diets had equally severe colitis, mice colonized with HSD microbiota showed markedly increased infiltration of neutrophils to the gut. The induction of colitis in Toll-like receptor 4 (TLR4)-deficient HSD-fed mice led to significantly milder colitis than in wild-type mice. In conclusion, our results suggested a significant role of HSD in disruption of barrier integrity and balanced mucosal and systemic immune response. In addition, these processes seemed to be highly influenced by resident potentially pathogenic microbiota or metabolites via the TLR4 signaling pathway.

• Keywords
• high-sugar diet, inflammatory bowel diseases, metabolites, microbiome, mucosal barrier, neutrophils,
• MeSH
• Chronic Disease MeSH
• Diet * MeSH
• DNA-Binding Proteins deficiency   metabolism   MeSH
• Feces MeSH
• Colitis genetics   immunology   pathology   MeSH
• Monosaccharides adverse effects   MeSH
• Mice, Inbred BALB C MeSH
• Permeability MeSH
• Gene Expression Regulation MeSH
• Signal Transduction * MeSH
• Dextran Sulfate MeSH
• Immunity, Mucosal MeSH
• Intestines pathology   MeSH
• Gastrointestinal Microbiome * MeSH
• Severity of Illness Index MeSH
• T-Lymphocytes immunology   MeSH
• Toll-Like Receptor 4 metabolism   MeSH
• Inflammation microbiology   pathology   MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA-Binding Proteins MeSH
• Monosaccharides MeSH
• Rag2 protein, mouse MeSH Browser
• Dextran Sulfate MeSH
• Toll-Like Receptor 4 MeSH

Oxidative stress with subsequent premutagenic oxidative DNA damage has been implicated in colorectal carcinogenesis. The repair of oxidative DNA damage is initiated by lesion-specific DNA glycosylases (hOGG1, NTH1, MUTYH). The direct evidence of the role of oxidative DNA damage and its repair is proven by hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome), where germline mutations cause loss-of-function in glycosylases of base excision repair, thus enabling the accumulation of oxidative DNA damage and leading to the adenoma-colorectal cancer transition. Unrepaired oxidative DNA damage often results in G:C>T:A mutations in tumor suppressor genes and proto-oncogenes and widespread occurrence of chromosomal copy-neutral loss of heterozygosity. However, the situation is more complicated in complex and heterogeneous disease, such as sporadic colorectal cancer. Here we summarized our current knowledge of the role of oxidative DNA damage and its repair on the onset, prognosis and treatment of sporadic colorectal cancer. Molecular and histological tumor heterogeneity was considered. Our study has also suggested an additional important source of oxidative DNA damage due to intestinal dysbiosis. The roles of base excision repair glycosylases (hOGG1, MUTYH) in tumor and adjacent mucosa tissues of colorectal cancer patients, particularly in the interplay with other factors (especially microenvironment), deserve further attention. Base excision repair characteristics determined in colorectal cancer tissues reflect, rather, a disease prognosis. Finally, we discuss the role of DNA repair in the treatment of colon cancer, since acquired or inherited defects in DNA repair pathways can be effectively used in therapy.

• Keywords
• DNA repair, base excision repair (BER)glycosylases, colorectal cancer, oxidative DNA damage,
• MeSH
• Cellular Microenvironment MeSH
• Molecular Targeted Therapy MeSH
• DNA Glycosylases metabolism   MeSH
• Colorectal Neoplasms etiology   metabolism   pathology   therapy   MeSH
• Humans MeSH
• Disease Susceptibility * MeSH
• Cell Transformation, Neoplastic genetics   metabolism   MeSH
• DNA Repair MeSH
• Oxidative Stress * MeSH
• DNA Damage * MeSH
• Intestinal Mucosa metabolism   microbiology   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• DNA Glycosylases MeSH