Search Results (22)

Phosphodiesterase 4 (PDE4) serves as a crucial regulator of cyclic adenosine monophosphate (cAMP) signaling and has been identified as a significant therapeutic target for inflammatory and metabolic disorders impacting the gastrointestinal (GI) tract and liver. Although pan-PDE4 inhibitors hold therapeutic promise, their clinical use has been constrained by dose-dependent adverse effects. Recent progress in the development of isoform-specific PDE4 inhibitors, such as those selective for PDE4B/D, alongside targeted delivery systems like liver-targeting nanoparticles and probiotic-derived vesicles, is reshaping the therapeutic landscape. This review consolidates the latest insights into PDE4 biology, highlighting how the structural characterization of isoforms informs drug design. We conduct a critical evaluation of preclinical and clinical data across various diseases, including inflammatory bowel diseases (IBDs), alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, and digestive tract tumors, with an emphasis on mechanisms extending beyond cAMP modulation, such as microbiota remodeling and immune reprogramming. Additionally, we address challenges in clinical translation, including biomarker discovery and the heterogeneity of trial outcomes, and propose a roadmap for future research directions. Full article

The discovery of profound differences in the brain microbiota of Alzheimer’s disease (AD) patients and age-matched controls (AMCs) raised questions of postmortem contamination and bacterial transport processes which could be informed by microspatial heterogeneities. We performed semiquantitative species-specific bacterial analyses on multiple micro biopsies from each of the 30 brain specimens (AD and controls). We trimmed ~1 mm of each specimen’s edges for surface contaminants and made multiple sterile biopsy punches of the resultant core of each specimen. To identify species-specific abundances, we used our validated, semiquantitative, full-length 16S rRNA gene pan-domain amplification protocol followed by high-fidelity circular consensus sequencing performed on a Pacific Biosciences Sequel IIe instrument. Statistical analyses showed no significant increase in bacterial abundance on trimmed surfaces compared to core specimens, including C. acnes, the most abundant species previously identified in AD. We did find evidence of substantial bacterial species abundance differences among micro-biopsies obtained from within individual tissue blocks supporting our hypothesis of microspatial heterogeneities. The autopsy brain specimens used in our analyses in this study and our previous publication were not contaminated prior to or postharvesting but we suggest that future microbiological analyses of brain specimens include similar types of edge-core comparison analyses. Further, the species-level bacterial abundance heterogeneities among specimens of the same tissue suggest that multiple symbiotic processes may be occurring. Full article

Background/Objectives: The role of the gut microbiome in cancer biology has become an increasingly prominent area of research, particularly regarding the role of microbial metabolites and their receptors (MMRs). These metabolites, through the various gut–organ axes, have been proven to influence several pathogenetic mechanisms. This study conducted a comprehensive pan-cancer analysis of MMR transcriptomic profiles across twenty-three cancer types, exploring the mechanisms through which they can influence cancer development and progression. Methods: Utilizing both cancer cell lines from CCLE (Cancer Cell Line Encyclopedia) and human tumor samples from TCGA (The Cancer Gene Atlas), we analyzed 107 MMRs interacting with microbial metabolites such as short-chain fatty acids, bile acids, indole derivatives, and others while studying their interactions with key known cancer genes. Results: Our results revealed that certain MMRs, such as GPR84 and serotonin receptors, are consistently upregulated in various malignancies, while others, like ADRA1A, are frequently downregulated, suggesting diverse roles in cancer pathophysiology. Furthermore, we identified significant correlations between MMR expression and cancer hallmark genes and pathways, including immune evasion, proliferation, and metastasis. Conclusions: These findings suggest that the interactions between microbial metabolites and MMRs may serve as potential biomarkers for cancer diagnosis, prognosis, and therapy, highlighting their therapeutic potential. This study underscores the significance of the microbiota–cancer axis and provides novel insights into microbiome-based strategies for cancer treatment. Full article

The economic significance of ruminants in agriculture underscores the need for advanced research methodologies to enhance their traits. This review aims to elucidate the transformative role of pan-omics technologies in ruminant research, focusing on their application in uncovering the genetic mechanisms underlying complex traits such as growth, reproduction, production performance, and rumen function. Pan-omics analysis not only helps in identifying key genes and their regulatory networks associated with important economic traits but also reveals the impact of environmental factors on trait expression. By integrating genomics, epigenomics, transcriptomics, metabolomics, and microbiomics, pan-omics enables a comprehensive analysis of the interplay between genetics and environmental factors, offering a holistic understanding of trait expression. We explore specific examples of economic traits where these technologies have been pivotal, highlighting key genes and regulatory networks identified through pan-omics approaches. Additionally, we trace the historical evolution of each omics field, detailing their progression from foundational discoveries to high-throughput platforms. This review provides a critical synthesis of recent advancements, offering new insights and practical recommendations for the application of pan-omics in the ruminant industry. The broader implications for modern animal husbandry are discussed, emphasizing the potential for these technologies to drive sustainable improvements in ruminant production systems. Full article

Fructilactobacillus sanfranciscensis is a significant and dominant bacterial species of sourdough microbiota from ecological and functional perspectives. Despite the remarkable prevalence of different strains of this species in sourdoughs worldwide, the drivers behind the genetic diversity of this species needed to be clarified. In this research, 14 F. sanfranciscensis strains were isolated from sourdough samples to evaluate the genetic diversity and variation in metabolic traits. These 14 and 31 other strains (obtained from the NCBI database) genomes were compared. The values for genome size and GC content, on average, turned out to 1.31 Mbp and 34.25%, respectively. In 45 F. sanfranciscensis strains, there were 162 core genes and 0 to 51 unique genes present in each strain. The primary functions of core genes were related to nucleotide, lipid transport, and amino acid, as well as carbohydrate metabolism. The size of core genes accounted for 41.18% of the pan-genome size in 14 F. sanfranciscensis strains, i.e., 0.70 Mbp of 1.70 Mbp. There were genetic variations among the 14 strains involved in carbohydrate utilization and antibiotic resistance. Moreover, exopolysaccharides biosynthesis-related genes were annotated, including epsABD, wxz, wzy. The Type IIA & IE CRISPR-Cas systems, pediocin PA-1 and Lacticin_3147_A1 bacteriocins operons were also discovered in F. sanfranciscensis. These findings can help to select desirable F. sanfranciscensis strains to develop standardized starter culture for sourdough fermentation, and expect to provide traditional fermented pasta with a higher quality and nutritional value for the consumers. Full article

Bovine respiratory disease (BRD) is an economically important disease in feedyards influencing both animal welfare and antimicrobial utilization. Major pathogens associated with BRD have been identified in previous research, but little information is available on the relationship between nasopharyngeal microbiota and health outcomes. The objective of this study was to identify potential associations between nasopharyngeal microbiota and antimicrobial resistance patterns of clinical cases that lived or died compared to non-diseased controls. Enrolled animals were subdivided based on clinical disease status and case outcome (subsequent mortality). Deep nasopharyngeal swabs were collected on enrolled animals and submitted for bacterial isolation, antimicrobial susceptibility determination, and metagenomics analysis. Enrolled cattle were represented in three groups: animals at first treatment for BRD that subsequently died (BRDM, n = 9), animals at first treatment for BRD that subsequently lived (BRDL, n = 15), and animals that were never treated for BRD during the feeding phase (CONT, n = 11). Antimicrobial resistance patterns for Pasteurella multocida illustrated cattle in each outcome category had isolates that were pan-susceptible or only showed resistance to oxytetracycline. The relative abundance of species and genera illustrated few differences among the three outcomes. Higher alpha diversity was identified in BRDL compared to CONT at the species level, and both BRDL and BRDM showed increased alpha diversity compared to CONT at the general level. Overall, this work illustrated nasopharyngeal microbiota showed relatively few differences among BRD cases that lived or died compared to animals without BRD. Full article

The gastrointestinal microbiota consists of trillions of microorganisms that live symbiotically in the human body. The main factor influencing the formation of the gastrointestinal microbiota is lifestyle, particularly the diet of people from different geographic regions. As described in several reports, the gut microbiota composition of healthy adults can be stable for years. However, the relative abundance of each microbe fluctuates over time, and it varies between individuals and within individuals over the course of their lives depending on many factors such as diet and gender. The study aimed to define the basic profile of the oral and gut microbiota in healthy people of Polish ethnicity under the Western diet, showing the stability under one type of diet and dependence on gender. The study group included 144 healthy adults. The research materials were swabs and stool samples. The KomPAN questionnaire was used to examine eating habits. Bacterial 16S rRNA genes were sequenced using the next-generation sequencing (NGS) technology. The respondents followed a typical Western diet. There were no statistically significant differences in alpha species diversity in the oral and gut microbiota between the female and male groups. Statistically significant differences were found in the beta diversity between gut microbiota composition in women and men (p < 0.048). The oral microbiota was dominated by Firmicutes and Proteobacteria, and Firmicutes dominated the gut microbiota. According to the received results, it was found that in healthy adults of Polish origin, there is a basic profile of the oral and gut microbiota ensuring good health condition. Full article

Colorectal cancer (CRC) ranks third among all cancers in terms of prevalence. There is growing evidence that gut microbiota has a role in the development of colorectal cancer. Fusobacterium nucleatum is overrepresented in the gastrointestinal tract and tumor microenvironment of patients with CRC. This suggests the role of F. nucleatum as a potential risk factor in the development of CRC. Hence, we aimed to explore whole genomes of F. nucleatum strains related to CRC to predict potential therapeutic markers through a pan-genome integrated subtractive genomics approach. In the current study, we identified 538 proteins as essential for F. nucleatum survival, 209 non-homologous to a human host, and 12 as drug targets. Eventually, riboflavin synthase (RiS) was selected as a therapeutic target for further processing. Three different inhibitor libraries of lead-like natural products, i.e., cyanobactins (n = 237), streptomycins (n = 607), and marine bacterial secondary metabolites (n = 1226) were screened against it. After the structure-based study, three compounds, i.e., CMNPD3609 (−7.63) > Malyngamide V (−7.03) > ZINC06804365 (−7.01) were prioritized as potential inhibitors of F. nucleatum. Additionally, the stability and flexibility of these compounds bound to RiS were determined via a molecular dynamics simulation of 50 ns. Results revealed the stability of these compounds within the binding pocket, after 5 ns. ADMET profiling showed compounds as drug-like, non-permeable to the blood brain barrier, non-toxic, and HIA permeable. Pan-genomics mediated drug target identification and the virtual screening of inhibitors is the preliminary step towards inhibition of this pathogenic oncobacterium and we suggest mouse model experiments to validate our findings. Full article

Janus kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and filgotinib (Jyseleca), have been approved for treatment of ulcerative colitis with several other JAK inhibitors in late-stage clinical trials for inflammatory bowel disease (IBD). Despite their impressive efficacy, the risk of adverse effects accompanying the use of JAK inhibitors has brought the entire class under scrutiny, leading to them receiving an FDA black box warning. In this study we investigated whether ileocolonic-targeted delivery of a pan-JAK inhibitor, tofacitinib, can lead to increased tissue exposure and reduced systemic exposure compared to untargeted formulations. The stability of tofacitinib in the presence of rat colonic microbiota was first confirmed. Next, in vivo computed tomography imaging was performed in rats to determine the transit time and disintegration site of ileocolonic-targeted capsules compared to gastric release capsules. Pharmacokinetic studies demonstrated that systemic drug exposure was significantly decreased, and colonic tissue exposure increased at 10 mg/kg tofacitinib dosed in ileocolonic-targeted capsules compared to gastric release capsules and an oral solution. Finally, in a rat model of LPS-induced colonic inflammation, targeted tofacitinib capsules significantly reduced concentrations of proinflammatory interleukin 6 in colonic tissue compared to a vehicle-treated control (p = 0.0408), unlike gastric release tofacitinib capsules and orally administered dexamethasone. Overall, these results support further development of ileocolonic-targeted tofacitinib, and potentially other specific JAK inhibitors in pre-clinical and clinical development, for the treatment of IBD. Full article

Gilliamella and Snodgrassella, members of core gut microbiota in corbiculate bees, have high species diversity and adaptability to a wide range of hosts. In this study, we performed species taxonomy and phylogenetic analysis for Gilliamella and Snodgrassella strains that we isolated in our laboratory, in combination with published whole-genome. Functional effects of accessory and unique genes were investigated by KEGG category and pathway annotation in pan-genome analysis. Consequently, in Gilliamella, we inferred the importance of carbohydrate metabolism, amino acid metabolism, membrane transport, energy metabolism, and metabolism of cofactors and vitamins in accessory or unique genes. The pathway mentioned above, plus infectious disease, lipid metabolism, nucleotide metabolism as well as replication and repair exert a pivotal role in accessory or unique genes of Snodgrassella. Further analysis revealed the existence of functional differentiation of accessory and unique genes among Apis-derived genomes and Bombus-derived genomes. We also identified eight and four biosynthetic gene clusters in all Gilliamella and Snodgrassella genomes, respectively. Our study provides a good insight to better understand how host heterogeneity influences the bacterial speciation and affects the versatility of the genome of the gut bacteria. Full article

Akkermanisia muciniphila imparts important health benefits and is considered a next-generation probiotic. It is imperative to understand the genomic diversity and metabolic potential of the species for safer applications as probiotics. As it resides with both health-promoting and pathogenic bacteria, understanding the evolutionary patterns are crucial, but this area remains largely unexplored. Moreover, pan-genome has previously been established based on only a limited number of strains and without careful strain selection. The pan-genomics have become very important for understanding species diversity and evolution. In the current study, a systematic approach was used to find a refined pan-genome profile of A. muciniphila by excluding too-diverse strains based on average nucleotide identity-based species demarcation. The strains were divided into four phylogroups using a variety of clustering techniques. Horizontal gene transfer and recombination patterns were also elucidated. Evolutionary patterns revealed that different phylogroups were expanding differently. Furthermore, a comparative evaluation of the metabolic potential of the pan-genome and its subsections was performed. Lastly, the study combines functional annotation, persistent genome, and essential genes to devise an approach to determine a minimal genome that can systematically remove unwanted genes, including virulent factors. The selection of one strain to be used as a chassis for the prediction of a reduced genome was very carefully performed by analyzing several genomic parameters, including the number of unique genes and the resistance and pathogenic potential of the strains. The strategy could be applied to other microbes, including human-associated microbiota, towards a common goal of predicting a minimal or a reduced genome. Full article

Eighty-eight Bifidobacterium pseudocatenulatum strains, which were isolated from human, chicken and cow fecal samples from different niches of China, were compared genomically in this study to evaluate their diversity. It was found that B. pseudocatenulatum displayed a closed pan-genome, including abundant glycoside hydrolase families of the carbohydrate active enzyme (CAZy). A total of 30 kinds of glycoside hydrolases (GHs), 14 kinds of glycosyl transferases (GTs), 13 kinds of carbohydrate-binding modules (CBMs), 6 kinds of carbohydrate-esterases (CEs), and 2 kinds of auxiliary activities (AAs) gene families were identified across the genomes of the 88 B. pseudocatenulatum strains. Specifically, this showed that significant differences were also present in the number of 10 carbohydrate-active enzyme gene families (GT51, GH13_32, GH26, GH42, GH121, GH3, AA3, CBM46, CE2, and CE6) among the strains derived from the hosts of different age groups, particularly between strains from infants and those from other human age groups. Twelve different individuals of B. pseudocatenulatum from four main clusters were selected for further study to reveal the genetic diversity of carbohydrate metabolism-related genes within the same phylogenetics. The animal experiment showed that 3 weeks of oral administration and 1 week after cessation of administration of these strains did not markedly alter the serum routine inflammatory indicators in mice. Furthermore, the administration of these strains did not significantly cause adverse changes in the gut microbiota, as indicated by the α- and β-diversity indexes, relative to the control group (normal diet). Beyond that, FAHBZ9L5 significantly increased the abundance of B. pseudocatenulatum after 3 weeks and significantly increased the abundance of acetic acid and butyric acid in the host’s intestinal tract 3 and 4 weeks after the first administration, respectively, compared with the control group. Corresponding to this, comparative genomic analyses of 12 B. pseudocatenulatum suggest that FAHBZ9L5-specific genes were rich in ABC transporters and carbohydrate esterase. Combining the results of comparative genomics analyses and animal experiment, it is suggested that the strains containing certain gene clusters contribute to another competitive growth advantage of B. pseudocatenulatum, which facilitates its intestinal carbohydrate metabolism in a host. Full article

The Pan-Okhotsk region, which is part of the western North Pacific Ocean, is famous for its active volcanoes, which are part of the Pacific Ring of Fire and that enrich the surrounding waters with essential chemicals. Therefore, this region, including the Sea of Okhotsk and the Sea of Japan, is characterized by rich biota. Bacterioplankton plays a significant part in biological communities and is an indicator of ecosystem function. Analyzing the adaptability of three representatives of the microbiota of the Pan-Okhotsk region was the goal of our investigation. Marinomonas primoryensis KMM3633^T (MP), Yersinia ruckeri KMM821 (YR), and Yersinia pseudotuberculosis 598 (YP) from the G.B. Elyakov Pacific Institute of Bioorganic Chemistry were studied by means of genomic and bioinformatic methods. The list of membrane translocator proteins, metabolism pathways, and cold shock and antifreeze proteins that were revealed in the genome of MP characterized this bacterium as being adaptable to free living in marine conditions, even at winter temperatures. The genomic potential of YR and YP makes not only survival in the environment of the Pan-Okhotsk region but also pathogenesis in eukaryotic organisms possible. The data obtained will serve as a basis for further ecosystem monitoring with the help of microbiota research. Full article

Neuroendocrine neoplasms (NENs) are rare neoplasms with heterogeneous clinical behavior. Alteration in human microbiota was reported in association with carcinogenesis in different solid tumors. However, few studies addressed the role of microbiota in NEN. We here aimed at evaluating the presence of bacterial infiltration in neuroendocrine tumoral tissue. To assess the presence of bacteria, 20 specimens from pancreatic NEN (pan-NEN) and 20 from intestinal NEN (I-NEN) were evaluated through Fluorescent In situ Hybridization and confocal microscopy. Demographic data, pre-operative investigations, operative findings, pathological diagnosis, follow-up, and survival data were evaluated. Among I-NEN, bacteria were detected in 15/20 (75%) specimens, with high variability in microbial distribution. In eight patients, a high infiltration of microorganisms was observed. Among pan-NEN, 18/20 (90%) showed microorganisms’ infiltration, with a homogeneous microbial distribution. Bacterial localization in pan-NEN was observed in the proximity of blood vessels. A higher bacterial infiltration in the tumoral specimen as compared with non-tumoral tissue was reported in 10/20 pan-NEN (50%). No significant differences were observed in mean bacterial count according to age, sex, ki67%, site, tumor stage. Mean bacterial count did not result to be a predictor of disease-specific survival. This preliminary study demonstrates the presence of a significant microbiota in the NEN microenvironment. Further research is needed to investigate the potential etiological or clinical role of microbiota in NEN. Full article

Lipocalin 2 (LCN2) mediates key roles in innate immune responses. It has affinity for many lipophilic ligands and binds various siderophores, thereby limiting bacterial growth by iron sequestration. Furthermore, LCN2 protects against obesity and metabolic syndrome by interfering with the composition of gut microbiota. Consequently, complete or hepatocyte-specific ablation of the Lcn2 gene is associated with higher susceptibility to bacterial infections. In the present study, we comparatively profiled microbiota in fecal samples of wild type and Lcn2 null mice and show, in contrast to previous reports, that the quantity of DNA in feces of Lcn2 null mice is significantly lower than that in wild type mice (p < 0.001). By using the hypervariable V4 region of the 16S rDNA gene and Next-Generation Sequencing methods, we found a statistically significant change in 16 taxonomic units in Lcn2^-/- mice, including eight gender-specific deviations. In particular, members of Clostridium, Escherichia, Helicobacter, Lactococcus, Prevotellaceae_UCG-001 and Staphylococcus appeared to expand in the intestinal tract of knockout mice. Interestingly, the proportion of Escherichia (200-fold) and Staphylococcus (10-fold) as well as the abundance of intestinal bacteria encoding the LCN2-sensitive siderphore enterobactin (entA) was significantly increased in male Lcn2 null mice (743-fold, p < 0.001). This was accompanied by significant higher immune cell infiltration in the ileum as demonstrated by increased immunoreactivity against the pan-leukocyte protein CD45, the lymphocyte transcription factor MUM-1/IRF4, and the macrophage antigen CD68/Macrosialin. In addition, we found a higher expression of mucosal mast cell proteases indicating a higher number of those innate immune cells. Finally, the ileum of Lcn2 null mice displayed a high abundance of segmented filamentous bacteria, which are intimately associated with the mucosal cell layer, provoking epithelial antimicrobial responses and affecting T-helper cell polarization. Full article