Biomimetic nanoplatform with microbiome modulation and antioxidant functions ameliorating insulin resistance and pancreatic ß-cell dysfunction for T2DM management.

Insulin resistance and pancreatic ß-cell dysfunction are the main pathogenesis of type 2 diabetes mellitus (T2DM). However, insulin therapy and diabetes medications do not effectively solve the two problems simultaneously. In this study, a biomimetic oral hydrogen nanogenerator that leverages the benefits of edible plant-derived exosomes and hydrogen therapy was constructed to overcome this dilemma by modulating gut microbiota and ameliorating oxidative stress and inflammatory responses. Hollow mesoporous silica (HMS) nanoparticles encapsulating ammonia borane (A) were used to overcome the inefficiency of H2 delivery in traditional hydrogen therapy, and exosomes originating from ginger (GE) were employed to enhance biocompatibility and regulate intestinal flora. Our study showed that HMS/A@GE not only considerably ameliorated insulin resistance and liver steatosis, but inhibited the dedifferentiation of islet ß-cell and enhanced pancreatic ß-cell proportion in T2DM model mice. In addition to its antioxidant and anti-inflammatory effects, HMS/A@GE augmented the abundance of Lactobacilli spp. and tryptophan metabolites, such as indole and indole acetic acid, which further activated the AhR/IL-22 pathway to improve intestinal-barrier function and metabolic impairments. This study offers a potentially viable strategy for addressing the current limitations of diabetes treatment by integrating gut-microbiota remodelling with antioxidant therapies.

Metabolomic and gut-microbial responses of earthworms exposed to microcystins and nano zero-valent iron in soil.

The earthworm-based vermiremediation facilitated with benign chemicals such as nano zero-valent iron (nZVI) is a promising approach for the remediation of a variety of soil contaminants including cyanotoxins. As the most toxic cyanotoxin, microcystin-LR (MC-LR) enter soil via runoff, irrigated surface water and sewage, and the application of cyanobacterial biofertilizers as part of the sustainable agricultural practice. Earthworms in such remediation systems must sustain the potential risk from both nZVI and MC-LR. In the present study, earthworms (Eisenia fetida) were exposed up to 14 days to MC-LR and nZVI (individually and in mixture), and the toxicity was investigated at both the organismal and metabolic levels, including growth, tissue damage, oxidative stress, metabolic response and gut microbiota. Results showed that co-exposure of MC-LR and nZVI is less potent to earthworms than that of separate exposure. Histological observations in the co-exposure group revealed only minor epidermal brokenness, and KEGG enrichment analysis showed that co-exposure induced earthworms to regulate glutathione biosynthesis for detoxification and reduced adverse effects from MC-LR. The combined use of nZVI promoted the growth and reproduction of soil and earthworm gut bacteria (e.g., Sphingobacterium and Acinetobacter) responsible for the degradation of MC-LR, which might explain the observed antagonism between nZVI and MC-LR in earthworm microcosm. Our study suggests the beneficial use of nZVI to detoxify pollutants in earthworm-based vermiremediation systems where freshwater containing cyanobacterial blooms is frequently used to irrigate soil and supply water for the growth and metabolism of earthworms.

RG-I pectic polysaccharides and hesperidin synergistically modulate gut microbiota: An in vitro study targeting the proportional relationship.

In this study, we investigated how different proportions blends of Rhamnogalacturonan-I pectic polysaccharides and hesperidin impact the gut microbiota and metabolites using an in vitro simulated digestion and fermentation model. The results indicated that both of them could modulate the gut microbiota and produce beneficial metabolites. However, their blends in particular proportions (such as 1:1) exhibited remarkable synergistic effects on modulating the intestinal microenvironment, surpassing the effects observed with individual components. Specifically, these blends could benefit the host by increasing short-chain fatty acids production (such as acetate), improving hesperidin bioavailability, producing more metabolites (such as hesperetin, phenolic acids), and promoting the growth of beneficial bacteria. This synergistic and additive effect was inseparable from the role of gut microbiota. Certain beneficial bacteria, such as Blautia, Faecalibacterium, and Prevotella, exhibited strong preferences for those blends, thereby contributing to host health through participating in carbohydrate and flavonoid metabolism.

Uncovering the pharmacological mechanisms of Patchouli essential oil for treating ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Pogostemonis Herba has long been used in traditional Chinese medicine to treat inflammatory disorders. Patchouli essential oil (PEO) is the primary component of Pogostemonis Herba, and it has been suggested to offer curative potential when applied to treat ulcerative colitis (UC). However, the pharmacological mechanisms of PEO for treating UC remain to be clarified. AIM OF THE STUDY: To elucidate the pharmacological mechanisms of PEO for treating UC. METHODS AND RESULTS: In the present study, transcriptomic and network pharmacology approaches were combined to clarify the mechanisms of PEO for treating UC. Our results reveal that rectal PEO administration in UC model mice significantly alleviated symptoms of UC. In addition, PEO effectively suppressed colonic inflammation and oxidative stress. Mechanistically, PEO can ameliorate UC mice by modulating gut microbiota, inhibiting inflammatory targets (OPTC, PTN, IFIT3, EGFR, and TLR4), and inhibiting the PI3K-AKT pathway. Next, the 11 potential bioactive components that play a role in PEO's anti-UC mechanism were identified, and the therapeutic efficacy of the pogostone (a bioactive component) in UC mice was partially validated. CONCLUSION: This study highlights the mechanisms through which PEO can treat UC, providing a rigorous scientific foundation for future efforts to develop and apply PEO for treating UC.

Uncovering the mechanisms of Zhubi decoction against rheumatoid arthritis through an integrated study of network pharmacology, metabolomics, and intestinal flora.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhubi Decoction (ZBD) is a modified formulation derived from the classic traditional Chinese medicine prescription "Er-Xian Decoction" documented in the esteemed "Clinical Manual of Chinese Medical Prescription". While the utilization of ZBD has exhibited promising clinical outcomes in treating rheumatoid arthritis (RA), the precise bioactive chemical constituents and the underlying mechanisms involved in its therapeutic efficacy remain to be comprehensively determined. AIM OF THE STUDY: This study aims to systematically examine ZBD's pharmacological effects and molecular mechanisms for RA alleviation. MATERIALS AND METHODS: Utilizing the collagen-induced arthritis (CIA) rat model, we comprehensively evaluated the anti-rheumatoid arthritis effects of ZBD in vivo through various indices, such as paw edema, arthritis index, ankle diameter, inflammatory cytokine levels, pathological conditions, and micro-CT analysis. The UPLC-MS/MS technique was utilized to analyze the compounds of ZBD. The potential therapeutic targets and signaling pathways of ZBD in the management of RA were predicted using network pharmacology. To analyze comprehensive metabolic profiles and identify underlying metabolic pathways, we conducted a serum-based widely targeted metabolomics analysis utilizing LC-MS technology. Key targets and predicted pathways were further validated using immunofluorescent staining, which integrated findings from serum metabolomics and network pharmacology analysis. Additionally, we analyzed the gut microbiota composition in rats employing 16 S rDNA sequencing and investigated the effects of ZBD on the microbiota of CIA rats through bioinformatics and statistical methods. RESULTS: ZBD exhibited remarkable efficacy in alleviating RA symptoms in CIA rats without notable side effects. This included reduced paw redness and swelling, minimized joint damage, improved the histopathology of cartilage and synovium, mitigated the inflammatory state, and lowered serum concentrations of cytokines TNF-α, IL-1ß and IL-6. Notably, the effectiveness of ZBD was comparable to MTX. Network pharmacology analysis revealed inflammation and immunity-related signaling pathways, such as PI3K/AKT, MAPK, IL-17, and TNF signaling pathways, as vital mediators in the effectual mechanisms of ZBD. Immunofluorescence analysis validated ZBD's ability to inhibit PI3K/AKT pathway proteins. Serum metabolomics studies revealed that ZBD modulates 170 differential metabolites, partially restored disrupted metabolic profiles in CIA rats. With a notable impact on amino acids and their metabolites, and lipids and lipid-like molecules. Integrated analysis of metabolomics and network pharmacology identified 6 pivotal metabolite pathways and 3 crucial targets: PTGS2, GSTP1, and ALDH2. Additionally, 16 S rDNA sequencing illuminated that ZBD mitigated gut microbiota dysbiosis in the CIA group, highlighting key genera such as Ligilactobacillus, Prevotella_9, unclassified_Bacilli, and unclassified_rumen_bacterium_JW32. Correlation analysis disclosed a significant link between 47 distinct metabolites and specific bacterial species. CONCLUSION: ZBD is a safe and efficacious TCM formulation, demonstrates efficacy in treating RA through its multi-component, multi-target, and multi-pathway mechanisms. The regulation of inflammation and immunity-related signaling pathways constitutes a crucial mechanism of ZBD's efficacy. Furthermore, ZBD modulates host metabolism and intestinal flora. The integrated analysis presents experimental evidence of ZBD for the management of RA.

Potential interventions and interactions of bioactive polyphenols and functional polysaccharides to alleviate inflammatory bowel disease - A review.

Inflammatory bowel disease is a multifaceted condition that is influenced by nutritional, microbial, environmental, genetic, psychological, and immunological factors. Polyphenols and polysaccharides have gained recognition for their therapeutic potential. This review emphasizes the biological effects of polyphenols and polysaccharides, and explores their antioxidant, anti-inflammatory, and microbiome-modulating properties in the management of inflammatory bowel disease (IBD). However, polyphenols encounter challenges, such as low stability and low bioavailability in the colon during IBD treatment. Hence, polysaccharide-based encapsulation is a promising solution to achieve targeted delivery, improved bioavailability, reduced toxicity, and enhanced stability. This review also discusses the significance of covalent and non-covalent interactions, and simple and complex encapsulation between polyphenols and polysaccharides. The administration of these compounds in appropriate quantities has proven beneficial in preventing the development of Crohn's disease and ulcerative colitis, ultimately leading to the management of IBD. The use of polyphenols and polysaccharides has been found to reduce histological scores and colon injury associated with IBD, increase the abundance of beneficial microbes, inhibit the development of colitis-associated cancer, promote the production of microbial end-products, such as short-chain fatty acids (SCFAs), and improve anti-inflammatory properties. Despite the combined effects of polyphenols and polysaccharides observed in both in vitro and in vivo studies, further human clinical trials are needed to comprehend their effectiveness on inflammatory bowel disease.

Postbióticos: un nuevo miembro en la familia de los bióticos / Postbiotics: A new member in the biotics family

Los postbióticos fueron definidos en 2021 por la Asociación Científica Internacional de Probióticos y Prebióticos (ISAPP) como "una preparación de microorganismos inanimados y/o sus componentes celulares capaces de conferir un efecto benéfico al hospedador". El campo de los postbióticos es un área nueva dentro de la familia de los bióticos; se han desarrollado ya numerosos productos con aplicaciones clínicas, como la estimulación inmunológica, el manejo de diarreas en niños y adultos, el abordaje del intestino irritable, además de tres fórmulas infantiles. En particular, las fórmulas infantiles con postbióticos obtenidos a partir de la fermentación de la leche con Bifidobacterium breve C50 y Streptococcus thermophilus O65, y sus metabolitos, incluido el oligosacárido 3'-GL, han demostrado seguridad y contribución al desarrollo de la microbiota intestinal y el sistema inmune asociado al intestino. Estas modificaciones contribuyen a la prevención y el manejo de los trastornos funcionales digestivos del lactante.

Postbiotics were defined in 2021 by the International Scientific Association for Probiotics and Prebiotics (ISAPP) as a "preparation of inanimate microorganisms and/or their cellular components that confers a health benefit to the host." The field of postbiotics is a new area within the biotics family; numerous products have already been developed for clinical applications, such as immune stimulation, the management of diarrhea in children and adults, the management of irritable bowel syndrome, and 3 infant formulas. In particular, infant formulas with postbiotics obtained from milk fermented with Bifidobacterium breve C50 and Streptococcus thermophilus O65 ­and their metabolites­, including the oligosaccharide 3'-GL, have demonstrated to be safe and to contribute to the development of the gut microbiota and the gutassociated immune system. These modifications help to prevent and manage functional gastrointestinal disorders in infants.

Role of diet in development of non-communicable diseases: focus on gut microbiome.

OBJECTIVES: The dietary composition is able to rapidly and significantly influence the diversity of the gut microbiome. This article focuses on how various types of diet affect the composition of the gut microbiome and how dietary changes are able to prevent or slow down the development of non-communicable diseases including obesity, type 2 diabetes mellitus, cardiovascular diseases, and low-grade inflammation. METHODS: A review in PubMed and a hand search using references in identified articles were performed. Studies published in English from 2000 to 2024 were included. RESULTS: The studies showed the significant effect of diet on the development of non-communicable diseases dependent on the state of the gut microbiota and molecules it produces. The Western diet that continues to gain in popularity for Czech people, leads to dysbiosis and production of bacterial lipopolysaccharide or trimethylamine N-oxide causing systemic chronic inflammation in the body and thus promoting the development of non-communicable diseases. CONCLUSIONS: Findings from this review emphasize the importance of healthy eating habits in the prevention of intestinal dysbiosis and still increasing prevalence and incidence of obesity and other non-communicable diseases.

Role of ultra-processed foods in modulating the effect of Mediterranean diet on human and planet health-study protocol of the PROMENADE randomized controlled trial.

BACKGROUND: The Mediterranean diet (MD), globally recognized for its sustainability and health benefits, traditionally emphasizes the consumption of plant-based foods in raw or minimally processed forms. However, shifting lifestyles, even in Mediterranean regions, have led to an increasing consumption of ultra-processed foods (UPF). Epidemiological evidence suggests that UPF consumption may be detrimental to human health, but there is only one clinical trial on this topic which is largely debated in the scientific community. This study aims to investigate the impact of the inclusion of UPF within a Mediterranean-based dietary pattern on cardiometabolic markers, gut microbiota, and other markers of human and planet health. METHODS: Fifty clinically healthy individuals showing overweight and presenting a low-to-moderate cardiovascular risk profile will be recruited for a 7-month randomized, open, cross-over dietary trial. Eligible participants will be randomly assigned to a 3-month high-UPF MD (intervention group) or a low-UPF MD (control group), with a 1-month wash-out period. Both intervention diets will have identical food group compositions, with the intervention group consuming 5 servings/day of selected UPF items, and the control group consuming raw/minimally processed items from the same food group. Blood, urine, and fecal samples, alongside food/lifestyle diaries, will be collected from each participant before and after the dietary interventions. The primary endpoint will be the change in plasma LDL-cholesterol levels from baseline. Additional markers include blood pressure, anthropometric parameters, chemical parameters, glucose and lipid-related metabolic markers, incretins, inflammatory and oxidative stress markers, fecal microbiota composition, and short-chain fatty acids. Finally, food waste production will be evaluated through specific validated food diaries. The study has been approved by the Ethical Committee of the University of Milan and the Tuscany Regional Ethics Committee of the Azienda Ospedaliera Universitaria (AOU) - Careggi, Florence. DISCUSSION: Results from the PROMENADE study will improve knowledge about the impact of UPF consumption on human and planet health and will contribute to the scientific debate on this topic. TRIAL REGISTRATION: ClinicalTrials.gov NCT06314932. Registered on March 13, 2024.

Stratification of human gut microbiomes by succinotype is associated with inflammatory bowel disease status.

BACKGROUND: The human gut microbiome produces and consumes a variety of compounds that interact with the host and impact health. Succinate is of particular interest as it intersects with both host and microbiome metabolism. However, which gut bacteria are most responsible for the consumption of intestinal succinate is poorly understood. RESULTS: We build upon an enrichment-based whole fecal sample culturing approach and identify two main bacterial taxa that are responsible for succinate consumption in the human intestinal microbiome, Phascolarctobacterium and Dialister. These two taxa have the hallmark of a functional guild and are strongly mutual exclusive across 21,459 fecal samples in 94 cohorts and can thus be used to assign a robust "succinotype" to an individual. We show that they differ with respect to their rate of succinate consumption in vitro and that this is associated with higher concentrations of fecal succinate. Finally, individuals suffering from inflammatory bowel disease (IBD) are more likely to have the Dialister succinotype compared to healthy subjects. CONCLUSIONS: We identified that only two bacterial genera are the key succinate consumers in human gut microbiome, despite the fact that many more intestinal bacteria encode for the succinate pathway. This highlights the importance of phenotypic assays in functionally profiling intestinal microbiota. A stratification based on "succinotype" is to our knowledge the first function-based classification of human intestinal microbiota. The association of succinotype with IBD thus builds a bridge between microbiome function and IBD pathophysiology related to succinate homeostasis. Video Abstract.

Correlation between the neuroendocrine axis, microbial species, inflammatory response, and gastrointestinal symptoms in irritable bowel syndrome.

BACKGROUND: This study examines the complex relationships among the neuroendocrine axis, gut microbiome, inflammatory responses, and gastrointestinal symptoms in patients with irritable bowel syndrome (IBS). The findings provide new insights into the pathophysiology of IBS and suggest potential therapeutic targets for improving patient outcomes. AIM: To investigate the interactions between the neuroendocrine axis, gut microbiome, inflammation, and gastrointestinal symptoms in patients with IBS. METHODS: Patients diagnosed with IBS between January 2022 and January 2023 were selected for the study. Healthy individuals undergoing routine check-ups during the same period served as the control group. Data were collected on neuroendocrine hormone levels, gut microbiome profiles, inflammatory biomarkers, and gastrointestinal symptomatology to analyze their interrelations and their potential roles in IBS pathogenesis. RESULTS: IBS patients exhibited significant dysregulation of the neuroendocrine axis, with altered levels of cortisol, serotonin, and neuropeptides compared to healthy controls. The gut microbiome of IBS patients showed reduced diversity and specific alterations in bacterial genera, including Bifidobacterium, Lactobacillus, and Faecalibacterium, which were associated with neuroendocrine disturbances. Additionally, elevated levels of inflammatory markers, such as C-reactive protein, interleukin-6, and tumor necrosis factor-α, were observed and correlated with the severity of gastrointestinal symptoms like abdominal pain, bloating, and altered bowel habits. CONCLUSION: The findings suggest that targeting the neuroendocrine axis, gut microbiome, and inflammatory pathways may offer novel therapeutic strategies to alleviate symptoms and improve the quality of life in IBS patients.

Fusobacterium nucleatum: Unraveling its potential role in gastric carcinogenesis.

Fusobacterium nucleatum (F. nucleatum) is a Gram-negative anaerobic bacterium that plays a key role in the development of oral inflammation, such as periodontitis and gingivitis. In the last 10 years, F. nucleatum has been identified as a prevalent bacterium associated with colorectal adenocarcinoma and has also been linked to cancer progression, metastasis and poor disease outcome. While the role of F. nucleatum in colon carcinogenesis has been intensively studied, its role in gastric carcinogenesis is still poorly understood. Although Helicobacter pylori infection has historically been recognized as the strongest risk factor for the development of gastric cancer (GC), with recent advances in DNA sequencing technology, other members of the gastric microbial community, and F. nucleatum in particular, have received increasing attention. In this review, we summarize the existing knowledge on the involvement of F. nucleatum in gastric carcinogenesis and address the potential translational and clinical significance of F. nucleatum in GC.

Causal pathways in lymphoid leukemia: the gut microbiota, immune cells, and serum metabolites.

Background: We employed Mendelian randomization (MR) to investigate the causal relationship between the gut microbiota and lymphoid leukemia, further exploring the causal relationships among immune cells, lymphoid leukemia, and potential metabolic mediators. Methods: We utilized data from the largest genome-wide association studies to date, encompassing 418 species of gut microbiota, 713 types of immune cells, and 1,400 serum metabolites as exposures. Summary statistics for lymphoid leukemia, acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL) were obtained from the FinnGen database. We performed bidirectional Mendelian analyses to explore the causal relationships among the gut microbiota, immune cells, serum metabolites, and lymphoid leukemia. Additionally, we conducted a two-step mediation analysis to identify potential intermediary metabolites between immune cells and lymphoid leukemia. Results: Several gut microbiota were found to have causal relationships with lymphoid leukemia, ALL, and CLL, particularly within the Firmicutes and Bacteroidetes phyla. In the two-step MR analysis, various steroid hormone metabolites (such as DHEAS, pregnenolone sulfateprogestogen derivatives, and androstenediol-related compounds) were identified as potential intermediary metabolites between lymphoid leukemia and immune cells. In ALL, the causal relationship between 1-palmitoyl-2-docosahexaenoyl-GPE (16:0/22:6) and ALL was mediated by CD62L-plasmacytoid DC%DC (mediated proportion=-2.84%, P=0.020). In CLL, the causal relationship between N6,n6,n6-trimethyllysine and CLL was mediated by HLA DR+ CD8br AC (mediated proportion=4.07%, P=0.021). Conclusion: This MR study provides evidence supporting specific causal relationships between the gut microbiota and lymphoid leukemia, as well as between certain immune cells and lymphoid leukemia with potential intermediary metabolites.

Age-associated changes in innate and adaptive immunity: role of the gut microbiota.

Aging is generally regarded as an irreversible process, and its intricate relationship with the immune system has garnered significant attention due to its profound implications for the health and well-being of the aging population. As people age, a multitude of alterations occur within the immune system, affecting both innate and adaptive immunity. In the realm of innate immunity, aging brings about changes in the number and function of various immune cells, including neutrophils, monocytes, and macrophages. Additionally, certain immune pathways, like the cGAS-STING, become activated. These alterations can potentially result in telomere damage, the disruption of cytokine signaling, and impaired recognition of pathogens. The adaptive immune system, too, undergoes a myriad of changes as age advances. These include shifts in the number, frequency, subtype, and function of T cells and B cells. Furthermore, the human gut microbiota undergoes dynamic changes as a part of the aging process. Notably, the interplay between immune changes and gut microbiota highlights the gut's role in modulating immune responses and maintaining immune homeostasis. The gut microbiota of centenarians exhibits characteristics akin to those found in young individuals, setting it apart from the microbiota observed in typical elderly individuals. This review delves into the current understanding of how aging impacts the immune system and suggests potential strategies for reversing aging through interventions in immune factors.

Beyond bacteria: Role of non-bacterial gut microbiota species in inflammatory bowel disease and colorectal cancer progression.

This letter emphasizes the need to expand discussions on gut microbiome's role in inflammatory bowel disease (IBD) and colorectal cancer (CRC) by including the often-overlooked non-bacterial components of the human gut flora. It highlights how viral, fungal and archaeal inhabitants of the gut respond towards gut dys-biosis and contribute to disease progression. Viruses such as bacteriophages target certain bacterial species and modulate the immune system. Other viruses found associated include Epstein-Barr virus, human papillomavirus, John Cunningham virus, cytomegalovirus, and human herpes simplex virus type 6. Fungi such as Candida albicans and Malassezia contribute by forming tissue-invasive filaments and producing inflammatory cytokines, respectively. Archaea, mainly metha-nogens are also found altering the microbial fermentation pathways. This corres-pondence, thus underscores the significance of considering the pathological and physiological mechanisms of the entire spectrum of the gut microbiota to develop effective therapeutic interventions for both IBD and CRC.

Metabolic mediators: microbial-derived metabolites as key regulators of anti-tumor immunity, immunotherapy, and chemotherapy.

The human microbiome has recently emerged as a focal point in cancer research, specifically in anti-tumor immunity, immunotherapy, and chemotherapy. This review explores microbial-derived metabolites, emphasizing their crucial roles in shaping fundamental aspects of cancer treatment. Metabolites such as short-chain fatty acids (SCFAs), Trimethylamine N-Oxide (TMAO), and Tryptophan Metabolites take the spotlight, underscoring their diverse origins and functions and their profound impact on the host immune system. The focus is on SCFAs' remarkable ability to modulate immune responses, reduce inflammation, and enhance anti-tumor immunity within the intricate tumor microenvironment (TME). The review critically evaluates TMAO, intricately tied to dietary choices and gut microbiota composition, assessing its implications for cancer susceptibility, progression, and immunosuppression. Additionally, the involvement of tryptophan and other amino acid metabolites in shaping immune responses is discussed, highlighting their influence on immune checkpoints, immunosuppression, and immunotherapy effectiveness. The examination extends to their dynamic interaction with chemotherapy, emphasizing the potential of microbial-derived metabolites to alter treatment protocols and optimize outcomes for cancer patients. A comprehensive understanding of their role in cancer therapy is attained by exploring their impacts on drug metabolism, therapeutic responses, and resistance development. In conclusion, this review underscores the pivotal contributions of microbial-derived metabolites in regulating anti-tumor immunity, immunotherapy responses, and chemotherapy outcomes. By illuminating the intricate interactions between these metabolites and cancer therapy, the article enhances our understanding of cancer biology, paving the way for the development of more effective treatment options in the ongoing battle against cancer.

Berberine alleviates ETEC-induced intestinal inflammation and oxidative stress damage by optimizing intestinal microbial composition in a weaned piglet model.

Introduction: Enterotoxigenic Escherichia coli (ETEC) is the main diarrhea-causing pathogen in children and young animals and has become a global health concern. Berberine is a type of "medicine and food homology" and has a long history of use in China, particularly in treating gastrointestinal disorders and bacterial diarrhea. Methods: In this study, we explored the effects of berberine on growth performance, intestinal inflammation, oxidative damage, and intestinal microbiota in a weaned piglet model of ETEC infection. Twenty-four piglets were randomly divided into four groups-a control group (fed a basal diet [BD] and infused with saline), a BD+ETEC group (fed a basal diet and infused with ETEC), a LB+ETEC group (fed a basal diet with 0.05% berberine and infused with ETEC infection), and a HB+ETEC group (fed a basal diet with 0.1% berberine and infused with ETEC). Results: Berberine significantly improved the final body weight (BW), average daily gain (ADG), and average daily feed intake (ADFI) (P<0.05) of piglets, and effectively decreased the incidence of diarrhea among the animals (P<0.05). Additionally, berberine significantly downregulated the expression levels of the genes encoding TNF-α, IL-1ß, IL-6, IL-8, TLR4, MyD88, NF-κB, IKKα, and IKKß in the small intestine of piglets (P<0.05). ETEC infection significantly upregulated the expression of genes coding for Nrf2, CAT, SOD1, GPX1, GST, NQO1, HO-1, GCLC, and GCLM in the small intestine of the animals (P<0.05). Berberine significantly upregulated 12 functional COG categories and 7 KEGG signaling pathways. A correlation analysis showed that berberine significantly increased the relative abundance of beneficial bacteria (Gemmiger, Pediococcus, Levilactobacillus, Clostridium, Lactiplantibacillus, Weissella, Enterococcus, Blautia, and Butyricicoccus) and decreased that of pathogenic bacteria (Prevotella, Streptococcus, Parabacteroides, Flavonifractor, Alloprevotella) known to be closely related to intestinal inflammation and oxidative stress in piglets. In conclusion, ETEC infection disrupted the intestinal microbiota in weaned piglets, upregulating the TLR4/MyD88/NF-κB and Nrf2 signaling pathways, and consequently leading to intestinal inflammation and oxidative stress-induced damage. Discussion: Our data indicated that berberine can optimize intestinal microbiota balance and modulate the TLR4/MyD88/NF-κB and Nrf2 signaling pathways, thus helping to alleviate intestinal inflammation and oxidative damage caused by ETEC infection in weaned piglets.

Dual-targeted treatment for inflammatory bowel disease: Whether fecal microbiota transplantation can be an important part of it.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disease. With the emergence of biologics and other therapeutic methods, two biologics or one biologic combined with a novel small-molecule drug has been proposed in recent years to treat IBD. Although treatment strategies for IBD are being optimized, their efficacy and risks still warrant further consideration. This editorial explores the current risks associated with dual-targeted treatment for IBD and the great potential that fecal microbiota transplantation (FMT) may have for use in combination therapy for IBD. We are focused on addressing refractory IBD or biologically resistant IBD based on currently available dual-targeted treatment by incorporating FMT as part of this dual-targeted treatment. In this new therapy regimen, FMT represents a promising combination therapy.

SpLitteR: diploid genome assembly using TELL-Seq linked-reads and assembly graphs.

Background: Recent advances in long-read sequencing technologies enabled accurate and contiguous de novo assemblies of large genomes and metagenomes. However, even long and accurate high-fidelity (HiFi) reads do not resolve repeats that are longer than the read lengths. This limitation negatively affects the contiguity of diploid genome assemblies since two haplomes share many long identical regions. To generate the telomere-to-telomere assemblies of diploid genomes, biologists now construct their HiFi-based phased assemblies and use additional experimental technologies to transform them into more contiguous diploid assemblies. The barcoded linked-reads, generated using an inexpensive TELL-Seq technology, provide an attractive way to bridge unresolved repeats in phased assemblies of diploid genomes. Results: We developed the SpLitteR tool for diploid genome assembly using linked-reads and assembly graphs and benchmarked it against state-of-the-art linked-read scaffolders ARKS and SLR-superscaffolder using human HG002 genome and sheep gut microbiome datasets. The benchmark showed that SpLitteR scaffolding results in 1.5-fold increase in NGA50 compared to the baseline LJA assembly and other scaffolders while introducing no additional misassemblies on the human dataset. Conclusion: We developed the SpLitteR tool for assembly graph phasing and scaffolding using barcoded linked-reads. We benchmarked SpLitteR on assembly graphs produced by various long-read assemblers and have demonstrated that TELL-Seq reads facilitate phasing and scaffolding in these graphs. This benchmarking demonstrates that SpLitteR improves upon the state-of-the-art linked-read scaffolders in the accuracy and contiguity metrics. SpLitteR is implemented in C++ as a part of the freely available SPAdes package and is available at https://github.com/ablab/spades/releases/tag/splitter-preprint.

Gut microbiota and metabolomic profile changes play critical roles in tacrolimus-induced diabetes in rats.

Aims: Hyperglycemia is one of the adverse effects of tacrolimus (TAC), but the underlying mechanism is not fully identified. We used multi-omics analysis to evaluate the changes in the gut microbiota and metabolic profile of rats with TAC-induced diabetes. Methods: To establish a diabetic animal model, Sprague Dawley rats were divided randomly into two groups. Those in the TAC group received intraperitoneal injections of TAC (3 mg/kg) for 8 weeks, and those in the CON group served as the control. 16S rRNA sequencing was used to analyze fecal microbiota. The metabolites of the two groups were detected and analyzed by nontargeted and targeted metabolomics, including amino acids (AAs), bile acids (BAs), and short-chain fatty acids (SCFAs). Results: The rats treated with TAC exhibited hyperglycemia as well as changes in the gut microbiota and metabolites. Specifically, their gut microbiota had significantly higher abundances of Escherichia-Shigella, Enterococcus, and Allobaculum, and significantly lower abundances of Ruminococcus, Akkermansia, and Roseburia. In addition, they had significantly reduced serum levels of AAs including asparagine, aspartic acid, glutamic acid, and methionine. With respect to BAs, they had significantly higher serum levels of taurocholic acid (TCA), and glycochenodeoxycholic acid (GCDCA), but significantly lower levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA). There were no differences in the levels of SCFAs between the two groups. Correlations existed among glucose metabolism indexes (fasting blood glucose and fasting insulin), gut microbiota (Ruminococcus and Akkermansia), and metabolites (glutamic acid, hydroxyproline, GCDCA, TDCA, and TUDCA). Conclusions: Both AAs and BAs may play crucial roles as signaling molecules in the regulation of TAC-induced diabetes.