Microplastic (1 μm - 5 mm) and nanoplastic (<1 μm) pollution is a heightening global challenge affecting the environment and the health of living creatures within. As primary precursors for plastic manufacturing, microplastics predominantly get into the environment through plastic product degradation and integrate into water, food chain and consumer products leading to potential health consequences. The mammalian system is equipped with several blood-tissue barriers with exclusive tight junctions that selectively regulate material transfer and protect vulnerable and functionally important organs. Nonetheless, emerging evidence indicates microplastics interact, traverse and compromise the integrity of these complex barriers. This review summarises the known and potential impact of microplastics on human health, focusing on specific organ barrier breaches. Evidence of microplastic traversal and deposition in distal mammalian organs are discussed. We further highlight current challenges facing both researchers and clinicians and provide an outlook for expanding our understanding of the impact of microplastic on health.

Eosinophilic oesophagitis (EoE) is a chronic inflammatory disease afflicting the oesophagus and causing lifelong morbidity. Over the last few decades, EoE has significantly increased in prevalence with oral corticosteroids, such as budesonide, being the current mainstay of therapy. Tacrolimus is an immunomodulatory drug with anti-inflammation properties that is not on the conventional therapeutic regimen for EoE but offers a promising alternative non-steroidal treatment for patients who do not respond to diet elimination, proton pump inhibitors (PPIs), or corticosteroids. This study aims to investigate and compare the accumulation between locally delivered budesonide and tacrolimus, using an ex vivo porcine oesophageal model of EoE, over a range of contact times up to 30 min. Budesonide and tacrolimus were solubilised in a cosolvent and surfactant formulation to maintain solvation capacity in artificial saliva. Injured and non-injured (control) porcine oesophageal mucosa were used as surrogates to represent EoE and healthy oesophageal mucosa in humans, respectively, due to the highly similar physiological architecture of the oesophagus. EoE-mimicking oesophageal damage was chemically induced by pancreatic enzymes and bile salts known to dilate intercellular spaces typically observed in EoE pathophysiology where tight junction damage was represented by an irreversible drop in transepithelial electrical resistance (TEER). Whole tissue and basolateral accumulation of budesonide and tacrolimus were quantified after 30 min using liquid chromatography tandem mass spectrometry (LC-MS/MS). Tacrolimus yielded a significant increase (p < 0.05) in injured tissue accumulation (approximately two-fold) in comparison to non-injured tissue, while budesonide yielded no significant difference (p > 0.05) in tissue accumulation between the two. Considering the significant accumulation of tacrolimus in this ex vivo porcine model of EoE, using injury-induced porcine oesophageal mucosa, this study suggests the use of tacrolimus as a targeted local therapy for the treatment of EoE.

Intraluminal causes of small bowel obstruction (SBO) are less common than mural or extrinsic etiologies. This review categorizes intraluminal causes of SBO into four broad categories to provide a diagnostic framework for radiologic interpretation: 1) ingested contents, 2) bowel stasis, 3) inflammatory causes, and 4) neoplasms. Ingested materials can result in SBO when individual or accumulated contents are too large to pass, such as in the case of foreign bodies or bezoars. Bowel stasis causing SBO can be secondary to abnormal bowel function, such as in cystic fibrosis, reduced transit of contents at sites of narrowing such as surgical anastomoses, or the formation of enteroliths in diverticula which may subsequently dislodge and result in luminal obstruction. Inflammatory causes of SBO include strictures or fistulas that allow foreign bodies (such as gallstones) formed outside the bowel to enter the bowel lumen and cause obstruction. Finally, neoplasms can present as endophytic masses that occlude the bowel lumen through a ball-valve mechanism or serve as a lead point for intussusception. Recognizing the imaging features that are suggestive of intraluminal SBO is critical for accurate diagnosis and timely patient care.

A micro-physiological model of the human small intestinal barrier incorporating mucus-generating cells has been developed. The established barrier was utilized to assess the absorption kinetics of three selected therapeutic compounds: Doxycycline, Ganciclovir, and its prodrug Valganciclovir, following the implementation of a thorough LC-MS/MS validation protocol. The co-culture of Caco-2 cells, representing absorptive enterocytes, and HT-29 MTX cells, modeling goblet cells, enabled the in-situ generation of a sufficiently thick mucus layer covering the entire cell monolayer. The presence of HT-29 MTX cells, which exhibit weaker tight junctions than enterocytes, contributed to the observed lower transepithelial electrical resistance (TEER) and higher FITC-dextran flux. The permeability of all the compounds was higher when tested in the co-culture system containing mucus-generating cells, compared to the Caco-2 monoculture, demonstrating the impact of mucus on intestinal drug transport kinetics. The permeability of ganciclovir following its generation from the prodrug valganciclovir was significantly higher than the permeability of ganciclovir itself, as the active metabolite ganciclovir exhibited an enhanced transport rate compared to when administered without metabolic activation. The developed microfluidic-based intestinal barrier model has demonstrated the capability to reliably simulate drug absorption and prodrug metabolism, and its impact on drug permeation kinetics across the small intestine.

Acute radiation gastrointestinal syndrome (GI-ARS) develops when the intestine is rapidly exposed to large doses of ionizing radiation. In humans, GI-ARS occurs at radiation doses of 6 Gy, with doses of ≥10 Gy typically resulting in death within 10 days. This condition can be caused by various factors, including war, terrorism, nuclear power plant accidents, and cancer therapy-associated adverse events. Developing effective approaches for treating GI-ARS requires a comprehensive understanding of the syndrome. This review summarizes the current body of literature that defines GI-ARS as a consequence of intestinal irradiation. It highlights the paradigm shift in understanding which intestinal stem cells contribute to homeostasis, the critical role of vascular injury in the development of GI-ARS, and recent advances in research on crypt-villus regeneration following radiation injury.

The development of an effective drug delivery system for the treatment of HIV/AIDS is a global challenge. The conventional drug delivery approach, namely highly active antiretroviral therapy (HAART), has increased the lifespan of HIV/AIDS patients. While antiretroviral drugs are critical for managing HIV/AIDS, they are not considered curative treatments and require additional supportive treatments depending on the clinical condition. Theoretically, all steps in the life cycle of HIV are potential targets for antiretroviral therapy. However, the eradication of HIV is still not possible with these approaches on account of some limitations. Lipid nanoparticles are effective in the delivery of antiretrovirals (ARVs) as they primarily lower the toxicity of ARVs and ease of scaling up and manufacturing, and also offer functionalization capabilities, targeted drug delivery, controlled release profiles and increased load capacity.

Data were retrieved from various online electronic resources, including PubMed, Google Scholar and Scopus among others. Keywords such as 'lipid nanoparticles', 'antiretroviral therapy', 'HIV/AIDS' and 'nanomedicine' were used to formulate search strategies across approximately 106 research and review articles.

Lipid-based nanoparticles, including liposomes, solid lipid nanoparticles, nanostructured lipid carriers and hybrid lipid nanoparticles, have been reported as being an effective strategy for the delivery of anti-HIV drugs.

This review discusses how lipidic nanoparticles can be used to deliver drugs to their target sites in an effective manner and considers the fate of lipid nanoparticles within the animal body.

The mucosal barrier serves as a crucial defense against external pathogens and allergens, being widely distributed across the respiratory, gastrointestinal, urogenital tracts, and oral cavity. Its disruption can lead to various diseases, including inflammatory bowel disease, asthma, urinary tract infections, and oral inflammation. Current mainstream treatments for mucosa-associated diseases primarily involve glucocorticoids and immunosuppressants, but their long-term use may cause adverse effects. Therefore, the development of safer and more effective therapeutic strategies has become a focus of research. Natural products, with their multi-target and multi-system regulatory advantages, offer a promising avenue for the treatment of mucosal diseases. This review summarizes the potential applications of natural products in diseases of mucosal barrier dysfunction through mechanisms such as immune modulation, inflammation inhibition, tight junction protein restoration, and gut microbiota regulation, with the aim of providing insights for the exploration of novel therapeutic strategies.

The objective of this study is to develop an artificial intelligence-physiologically based pharmacokinetic (AI-PBPK) model to predict the pharmacokinetic (PK) and pharmacodynamic (PD) properties of aldosterone synthase inhibitors (ASIs), enabling selection of the right candidate with high potency and good selectivity at the drug discovery stage. On a web-based platform, an AI-PBPK model, integrating machine learning and a classical PBPK model for the PK simulation of ASIs, was developed. Baxdrostat, with the most clinical data available, was selected as the model compound. Following calibration and validation using published data, the model was applied to estimate the PK parameters of Baxdrostat, Dexfadrostat, Lorundrostat, BI689648, and the 11β-hydroxylase inhibitor LCI699. The PD of all five compounds was predicted based on plasma free drug concentrations. The results demonstrated that the PK/PD properties of an ASI could be inferred from its structural formula within a certain error range, providing a reference for early ASI lead compounds screening and optimization. Further validation and refinement of this model will enhance its predictive accuracy and expand its application in drug discovery.

The role of the human microbiome in cancer has been extensively studied, focusing mainly on bacteria-host interactions and their impact on tumor development and treatment response. However, fungi, an immune-active component of the human microbiome, have received less attention regarding their roles in cancer. Recent studies have identified the widespread and specific colonization and distribution of fungi in multiple sites in patients across various cancer types. Importantly, host-fungal immune interactions significantly influence immune regulation within the tumor microenvironment. The rapid advancement of immune-checkpoint blockade (ICB)-based cancer immunotherapy creates an urgent need for effective biomarkers and synergistic therapeutic targets. Cancer-associated fungi and their associated antifungal immunity demonstrate significant potential and efficacy in enhancing cancer immunotherapy. This review summarizes and discusses the growing evidence of the functions and mechanisms of commensal and pathogenic cancer-associated fungi in cancer immunotherapy. Additionally, we emphasize the potential of fungi as predictive biomarkers and therapeutic targets in cancer immunotherapy.

Intestinal absorption is a key toxicokinetics parameter. Although the colon carcinoma cell line Caco-2 is the most used in vitro model to estimate human drug absorption, models representing other intestinal segments are available. We characterized the morphology, tissue-specific markers, and functionality of 3 human intestinal cell types: Caco-2, primary human enteroid-derived cells from jejunum (J2), and duodenum (D109) when cultured in the OrganoPlate 3-lane 40 microphysiological system (MPS) or static 24-well Transwells. In both conditions, J2 and D109 formed dome-like structures; Caco-2 formed uniform monolayers. In MPS, only Caco-2 formed tubules. Cells grown on Transwells formed a thicker monolayer. All cells and conditions exhibited expression of ZO-1 (tight junctions). Polarization markers Ezrin and Villin were highest in J2 and D109 in MPS, highest expression of Mucin was observed with J2. However, J2 and D109 exhibited poor barrier (70 kDa TRITC-dextran) in MPS, whereas robust barrier was recorded in Transwells. Barrier function and drug transport were evaluated using caffeine, indomethacin, and propranolol. The gel lane in MPS acted as a blockade; only a small fraction crossed, even without cells. The permeability ratios were used to parameterize the probabilistic compartmental absorption model to determine whether in vitro data could reduce uncertainty. The most accurate prediction of the fraction absorbed was achieved with Transwell-derived data from Caco-2, combined with the experimentally derived segment-specific absorption ratios. The impact of this study includes demonstration that enteroid-derived cells cultured in MPS show most physiological morphology, but that studies of drug permeability in this MPS are challenging.

Postbiotics may help strengthen intestinal barrier function. This study assessed the effects of a postbiotic derived from Limosilactobacillus fermentum and Lactobacillus delbrueckii subsp. lactis on epithelial barrier and cytokine production. Human-derived colon tubules were cultured on chips for 15 days. On day 8, the epithelial barrier was disrupted with 0.7 μM afatinib. Postbiotic doses of 5, 10, or 20 mg/mL were added on days 6, 8, 11, and 13. Trans-epithelial electrical resistance (TEER) was measured on days 6, 8, 11, 13, and 15, along with phase contrast imaging. Cytokine levels were measured on day 13. All three postbiotic concentrations resulted in better TEER recovery on day 15 vs. the control (p < 0.001). On day 13, 10 and 20 mg/mL increased TEER (p < 0.001), but only 20 mg/mL did on day 11 (p < 0.05). Phase imaging confirmed the dose-dependent effect. The 20 mg/mL dose more effectively reduced CCL2, CX3CL1, CXCL1, CXCL5, IL-8, IL-11, and IL-4 than the other doses (p < 0.01), and 10 mg/mL more effectively reduced CCL2, CXCL1, CXCL10, IL-10, IL-11, and IL-23 than 5 mg/mL (p < 0.01). In a colonic organoid model, the Lactobacillaceae-derived postbiotic prevented drug-induced epithelial damage, enhanced recovery, and modulated cytokine secretion towards a more anti-inflammatory profile in a dose-dependent manner.

The gut has long been hypothesized to be the "motor" of critical illness, propagating inflammation and playing a key role in multiple organ dysfunction. However, the exact mechanisms through which impaired gut integrity potentially contribute to worsened clinical outcome remain to be elucidated. Critical elements of gut dysregulation including intestinal hyperpermeability and a perturbed microbiome are now recognized as potential therapeutic targets in critical care.

The gut is a finely tuned ecosystem comprising ~ 40 trillion microorganisms, a single cell layer intestinal epithelia that separates the host from the microbiome and its products, and the mucosal immune system that actively communicates in a bidirectional manner. Under basal conditions, these elements cooperate to maintain a finely balanced homeostasis benefitting both the host and its internal microbial community. Tight junctions between adjacent epithelial cells selectively transport essential molecules while preventing translocation of pathogens. However, critical illness disrupts gut barrier function leading to increased gut permeability, epithelial apoptosis, and immune activation. This disruption is further exacerbated by a shift in the microbiome toward a "pathobiome" dominated by pathogenic microbes with increased expression of virulence factors, which intensifies systemic inflammation and accelerates organ dysfunction. Research has highlighted several potential therapeutic targets to restore gut integrity in the host, including the regulation of epithelial cell function, modulation of tight junction proteins, and inhibition of epithelial apoptosis. Additionally, microbiome-targeted therapies, such as prebiotics, probiotics, fecal microbiota transplantation, and selective decontamination of the digestive tract have also been extensively investigated to promote restoration of gut homeostasis in critically ill patients. Future research is needed to validate the potential efficacy of these interventions in clinical settings and to determine if the gut can be targeted in an individualized fashion.

Increased gut permeability and a disrupted microbiome are common in critical illness, potentially driving dysregulated systemic inflammation and organ dysfunction. Therapeutic strategies to modulate gut permeability and restore the composition of microbiome hold promise as novel treatments for critically ill patients.

The intestinal epithelium represents a critical interface between the host and external environment, serving as the second largest surface area in the human body after the lungs. This dynamic barrier is sustained by specialized epithelial cell types and their complex interactions with the gut microbiota. This review comprehensively examines the recent advances in understanding the bidirectional communication between intestinal epithelial cells and the microbiome. We briefly highlight the role of various intestinal epithelial cell types, such as Paneth cells, goblet cells, and enteroendocrine cells, in maintaining intestinal homeostasis and barrier function. Gut microbiota-derived metabolites, particularly short-chain fatty acids and bile acids, influence epithelial cell function and intestinal barrier integrity. Additionally, we highlight emerging evidence of the sophisticated cooperation between different epithelial cell types, with special emphasis on the interaction between tuft cells and Paneth cells in maintaining microbial balance. Understanding these complex interactions has important implications for developing targeted therapeutic strategies for various gastrointestinal disorders, including inflammatory bowel disease, metabolic disorders, and colorectal cancer.

The gut-brain axis plays a crucial role in the regulation and development of psychological and physical processes. The first year of life is a critical period for the development of the gut microbiome, which parallels important milestones in establishing sleep rhythm and brain development. Growing evidence suggests that the gut microbiome influences sleep, cognition and early neurodevelopment. For term-born and preterm-born infants, difficulties in sleep regulation may have consequences on health. Identifying effective interventions on the gut-brain axis in early life is likely to have long-term implications for the health and development of at-risk infants.

In this multicentre, four-group, double-blinded, placebo (PLC)-controlled randomised trial with a factorial design, 120 preterm-born and 260 term-born infants will be included. The study will investigate whether the administration of daily synbiotics or PLC for a duration of 3 months improves sleep patterns and neurodevelopmental outcomes up to 2 years of age. The trial will also: (1) determine the association between gut microbiota, sleep patterns and health outcomes in children up to 2 years of age; and (2) leverage the interactions between gut microbiota, brain and sleep to develop new intervention strategies for at-risk infants.

The NapBiome trial has received ethical approval by the Committee of Northwestern and Central Switzerland and Canton Vaud, Switzerland (#2024-01681). Outcomes will be disseminated through publication and will be presented at scientific conferences. Metagenomic data will be shared through the European Nucleotide Archive.

The US National Institutes of Health NCT06396689.

Permeability is an important molecular property in drug discovery, as it co-determines pharmacokinetics whenever a drug crosses the phospholipid bilayer, e.g., into the cell, in the gastrointestinal tract, or across the blood-brain barrier. Many methods for the determination of permeability have been developed, including cell line assays (CACO-2 and MDCK), cell-free model systems like parallel artificial membrane permeability assay (PAMPA) mimicking, e.g., gastrointestinal epithelia or the skin, as well as the black lipid membrane (BLM) and submicrometer liposomes. Furthermore, many in silico approaches have been developed for permeability prediction: meta-analysis of publicly available databases for permeability data (MolMeDB and ChEMBL) was performed to establish their usability. Four experimental and two computational methods were evaluated. It was shown that repeatability of the reported permeability measurement is not great even for the same method. For the PAMPA method, two different permeabilities are reported: intrinsic and apparent. They can vary in degrees of magnitude; thus, we suggest being extra cautious using literature data on permeability. When we compared data for the same molecules using different methods, the best agreement was between cell-based methods and between BLM and computational methods. Existence of unstirred water layer (UWL) permeability limits the data agreement between cell-based methods (and apparent PAMPA) with data that are not limited by UWL permeability (computational methods, BLM, intrinsic PAMPA). Therefore, different methods have different limitations. Cell-based methods provide results only in a small range of permeabilities (-8 to -4 in cm/s), and computational methods can predict a wider range of permeabilities beyond physical limitations, but their precision is therefore limited. BLM with liposomes can be used for both fast and slow permeating molecules, but its usage is more complicated than standard transwell techniques. To sum up, when working with in-house measured or published permeability data, we recommend caution in interpreting and combining them.

Acute-on-chronic liver failure (ACLF) is a severe condition in patients with decompensated liver cirrhosis, marked by high short-term mortality. Recent experimental and clinical evidence has linked intestinal dysfunction to both the initiation of ACLF as well as disease outcome. This review discusses the significant role of the gut-liver axis in ACLF pathogenesis, highlighting recent advances. Gut mucosal barrier disruption, gut dysbiosis, and bacterial translocation emerge as key factors contributing to systemic inflammation in ACLF. Different approaches of therapeutically targeting the gut-liver axis via farnesoid X receptor agonists, nonselective beta receptor blockers, antibiotics, and probiotics are discussed as potential strategies mitigating ACLF progression. The importance of understanding the distinct pathophysiology of ACLF compared with other stages of liver cirrhosis is highlighted. In conclusion, research findings suggest that disruption of intestinal integrity may be an integral component of ACLF pathogenesis, paving the way for novel diagnostic and therapeutic approaches to manage this syndrome more effectively.

Intestinal barrier function lies at a critical interface of a range of peripheral and central processes that influence disorders of gut-brain interactions (DGBI). Although rigorously tested, the role of barrier dysfunction in driving clinical phenotype of DGBI remains to be fully elucidated. In vitro, in vivo, and ex vivo strategies can test various aspects of the broader permeability and barrier mechanisms in the gut. Luminal mediators of host, bacterial, and dietary origin can influence the barrier function and a disrupted barrier can also influence the luminal milieu. Critical to our understanding is how barrier dysfunction is influenced by stress and other comorbidities that associate with DGBI and the crosstalk between barrier and neural, hormonal, and immune responses. Additionally, the microbiome's significant role in the communication between the brain and gut has led to the integrative model of a microbiome gut-brain axis with reciprocal interactions between brain networks and networks composed of multiple cells in the gut, including immune cells, enterochromaffin cells, gut microbiota and the derived luminal mediators. This review highlights the techniques for assessment of barrier function, appraises evidence for barrier dysfunction in DGBI including mechanistic studies in humans, as well as provides an overview of therapeutic strategies that can be used to directly or indirectly restore barrier function in DGBI patients.

Three-dimensional structural parameters correlate better with the intestinal function compared to two-dimensional structural parameters. The objective of the present study was to investigate the three-dimensional morphometrical features of the small intestine in rabbits using a design-based stereology. Five adult male New Zealand rabbits were used in this research. The total volume, volume fraction of different layers, internal surface area, villus and circular folds amplification factors were estimated in the whole and various segments of the small intestine. The small intestine volume was estimated to be 59.57 ± 8.57 cm3. The jejunum and ileum showed the most and the least total volumes, respectively (p < 0.05). The volume fractions of the tunica mucosa, tela submucosa and tunica muscularis were 62.57% ± 2.78%, 21.11% ± 2.01% and 16.25% ± 0.94%, respectively. The minimum volume of the tela submucosa was observed in the ileum (p < 0.05) and the fractional volume of the tunica muscularis in the ileum was significantly more than those of other segments (p < 0.05). The surface area of the entire small intestine was estimated to be 8302.31 ± 1872.39 cm2. The jejunum and ileum segments showed the most and the least surface areas, respectively. The increase in the intestinal surface area attributable to the presence of villi was estimated to be 6.82 ± 0.84, and that for circular folds was accounted for 1.36 ± 0.09. The largest amplification factors of villi and circular folds were observed in the duodenum and ileum, respectively. Our data presented the three-dimensional morphometry of the small intestine of the rabbit as a translational model and provided basic findings for the diagnosis and treatment of intestinal diseases in this species.

The human immune system is closely linked to microbiota such as a complex symbiotic relationship during the coevolution of vertebrates and microorganisms. The transfer of microorganisms from the mother's microbiota to the newborn begins before birth during gestation and is considered the initial phase of the intestinal microbiota (IM). The gut is an important site where microorganisms can establish colonies. The IM contains polymicrobial communities, which show complex interactions with diet and host immunity. The tendency towards dysbiosis of the intestinal microbiota is influenced by local but also extra-intestinal factors such as inflammatory processes, infections, or a septic state that can aggravate it. Pathogens could trigger an immune response, such as proinflammatory responses. In addition, changes in the host immune system also influence the intestinal community and structure with additional translocation of pathogenic and non-pathogenic bacteria. Finally, local intestinal inflammation has been found to be an important factor in the growth of pathogenic microorganisms, particularly in its role in sepsis. The aim of this article is to be able to detect the current knowledge of the mechanisms that can lead to dysbiosis of the intestinal microbiota and that can cause bacterial translocation with a risk of infection or septic state and vice versa.

Type 2 diabetes is a chronic disease characterized by insulin resistance and often worsened by obesity. Effective management involves the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to assist with glycemic control and weight management. However, these drugs must be administered subcutaneously due to their low oral bioavailability. We developed an oral liraglutide (LRG) formulation by electrostatic complexation of GLP-1 RA with bile acid derivatives and nanomicelle (NM) formation, with non-ionic surfactant n-dodecyl-β-d-maltoside (DDM). The optimized formulation, LDD[1:2:4]-NM, had a mean particle size of 75.9 ± 5.60 nm and a permeability 1347 % higher than that of unformulated LRG when tested in Caco-2/HT29-MTX-E12 cell monolayers. In rats, oral bioavailability was 4.63-fold higher than that of unformulated LRG (1.11 ± 0.20 % vs. 5.14 ± 0.63 %). The absorption mechanism included clathrin-mediated endocytosis, macropinocytosis, and an ASBT-mediated pathway. A 12-week oral treatment consisting of a daily dose of 20 mg LDD[1:2:4]-NM/kg significantly reduced glycohemoglobin levels, a marker of diabetic control, and the HOMA-IR index, a marker of insulin resistance. The weight of epididymal and inguinal white adipose tissue and brown adipose tissue (BAT) was also reduced. Moreover, LDD[1:2:4]-NM had a greater impact on BAT activation, pro-inflammatory gene expression, and lipid metabolism than subcutaneous LRG. This study showed that an oral NM formulation can efficiently deliver LRG. Long-term treatment led to improved hyperglycemic effects, insulin resistance, and modulated lipid metabolism. LDD[1:2:4]-NM is thus a promising oral therapeutic option for the management of type 2 diabetes, potentially transforming treatment paradigms based on the availability of a more convenient administration route.

In recent decades, microplastics (MPs) have emerged as one of the biggest environmental challenges in aquatic environments. Ingestion and toxicity of MPs in seawater (SW) and freshwater (FW) fish have been studied extensively both in field and laboratory settings. However, the basic mechanism of how fish deal with MPs in SW and FW remains unclear, although physiological conditions of fish differ significantly in the two environments. In this study, using Javanese medaka (Oryzias javanicus), a euryhaline fish that adapts readily to both SW and FW, we investigated elimination of MPs in fish in SW and FW environments. We exposed O. javanicus larvae (21 days post-hatching) to 0.25 mg/L of fluorescent polystyrene microspheres (1 μm) for 24 hours and then conducted an elimination test for up to 5 days. Results showed that the gut retention time of MPs is longer in FW than in SW, indicating that MP elimination occurs more quickly in SW than in FW. However, higher numbers of MPs tended to be retained longer in SW larvae than FW larvae. Subsequently, using a fluorescent marker, gastrointestinal fluid was found to move more rapidly in the SW group. This finding indicates that water drinking accelerates gastrointestinal fluid movement, which moves MPs through the gut in SW larvae. Beside the difference in physiological conditions, MP elimination was faster when food was available, suggesting that feeding also affects MP elimination in fish. Internal factors such as body size and intestine length were also examined, but indicated no significant difference. Therefore, osmoregulation and feeding both influence MP elimination in fish.

Sheep are an important livestock species whose gastrointestinal tract is essential for overall health. Feed contaminants such as bacterial toxins and mycotoxins severely damage the sheep intestine, yet the mechanisms remain mostly elusive partially due to the lack of physiologically relevant in vitro models. Here, we investigated molecular mechanisms underlying deoxynivalenol (DON)-induced toxicity by developing intestinal organoids from isolated intestinal crypts of Hu sheep. The organoids had a central lumen and monolayer epithelium, and could be continuously passaged, cryopreserved, and resuscitated. Histological and transcriptomic analysis showed that the intestinal organoids recapitulate the cell lineages and gene expression characteristics of the original intestinal tissues. Statistical analysis indicated that DON exposure significantly inhibited organoid formation efficiency, as well as the proliferation and activity of intestinal organoid cells. RNA-seq and Western blotting analysis further revealed that DON exposure induces intestinal toxicity by inhibiting the PI3K/AKT/GSK3β/β-catenin signaling pathway. Our study provides a novel example of organoid application in toxicity studies and reveals the signaling pathway involved in DON-induced toxicity in sheep, which is of great significance for improving mitigation strategies for DON.

Parkinson's disease (PD) involves both the central nervous system (CNS) and enteric nervous system (ENS), and their interaction is important for understanding both the clinical manifestations of the disease and the underlying disease pathophysiology. Although the neuroanatomical distribution of pathology strongly suggests that the ENS is involved in disease pathophysiology, there are significant gaps in knowledge about the underlying mechanisms. In this article, we review the clinical presentation and management of gastrointestinal dysfunction in PD. In addition, we discuss the current understanding of disease pathophysiology in the gut, including controversies about early involvement of the gut in disease pathogenesis. We also review current knowledge about gut α-synuclein and the microbiome, discuss experimental models of PD-linked gastrointestinal pathophysiology, and highlight areas for further research. Finally, we discuss opportunities to use the gut-brain axis for the development of biomarkers and disease-modifying treatments.

Background/Objectives: The development of targeted drug delivery systems for active pharmaceutical ingredients with narrow absorption windows is crucial for improving their bioavailability. This study proposes a novel 3D-printed expandable drug delivery system designed to precisely administer drugs to the upper small intestine, where absorption is most efficient. The aim was to design, prototype, and evaluate the system's functionality for organ retention and targeted drug release. Methods: The system was created using 3D printing technologies, specifically FDM and SLA, with materials such as PLA and HPMC. The device was composed of matrices and springs, with different spring geometries (diameter, coil number, and cross-sectional shape) being tested for strength and flexibility. A gastro-resistant string was used to maintain the device in a compact configuration until it reached the neutral pH environment of the small intestine, where the string dissolved. The mechanical performance of the springs was evaluated using a texture analyzer, and the ability of the system to expand upon pH change was tested in simulated gastrointestinal conditions. Results: The results demonstrated that the system remained in the space-saving configuration for two hours under acidic conditions. Upon a pH change to 6.8, the system expanded as expected, with opening times of 5.5 ± 1.2 min for smaller springs and 2.5 ± 0.3 min for larger springs. The device was able to regain its expanded state, suggesting its potential for controlled drug release in the small intestine. Conclusions: This prototype represents a promising approach for targeted drug delivery to the upper small intestine, offering a potential alternative for drugs with narrow absorption windows. While the results are promising, further in vivo studies are necessary to assess the system's clinical potential and mechanical stability in real gastrointestinal conditions.

Small bowel tumors (SBTs) are a heterogeneous group of difficult-to-diagnose tumors that account for 2%-5% of all gastrointestinal tumors. Single-balloon enteroscopy greatly enhances the diagnosis and treatment of SBTs. However, few epidemiological studies have been conducted in Taiwan to determine the clinical profile of SBTs.

To investigate the clinical characteristics, managements and prognosis of SBTs in a medical center in Taiwan.

The study enrolled 51 patients aged 58.9 ± 8.8 years (range, 22-93) diagnosed with SBTs from November 2009 to July 2021. We retrospectively recorded clinical characteristics, indications, endoscopic findings, pathological results, management, and outcomes for further analysis.

A male preponderance was observed (56.8%). The most common indications were suspected small intestinal tumors (52.9%) and obscure gastrointestinal bleeding (39.2%). The most common tumor location was the ileum (41.2%). The performance of imaging studies (P = 0.004) and the types of findings (P = 0.005) differed significantly between malignant and benign SBTs. The most frequent imaging finding was a small intestinal mass (43.1%). The top three malignant tumor types were gastrointestinal stromal tumors (GISTs), adenocarcinomas, and lymphomas. Moreover, the proportions of benign and malignant tumors were 27.5% and 72.5%, respectively. The survival rates of patients with malignant tumors in the GIST and non-GIST groups differed significantly (P = 0.015). Kaplan-Meier survival analysis showed a significant difference in survival between patients in the malignant and benign groups (P = 0.04). All patients with lymphoma underwent chemotherapy (n = 7/8, 87.5%), whereas most patients with GISTs underwent surgery (n = 13/14, 92.8%).

Patients with GISTs have a significantly higher survival rate than those with other malignant SBTs. Therefore, a large-scale nationwide study is warranted to evaluate the population-based epidemiology of SBTs.

Antibiotics are safe, effective drugs and continue to save millions of lives and prevent long-term illness worldwide. A large body of epidemiological, interventional and experimental evidence shows that exposure to antibiotics has long-term negative effects on human health. We reviewed the literature data on the links between antibiotic exposure, gut dysbiosis, and chronic disease (notably with regard to the "developmental origins of health and disease" ("DOHaD") approach). Molecular biology studies show that the systemic administration of antibiotic to infants has a rapid onset but also often a long-lasting impact on the microbial composition of the gut. Along with other environmental factors (e.g., an unhealthy "Western" diet and sedentary behavior), antibiotics induce gut dysbiosis, which can be defined as the disruption of a previously stable, functionally complete microbiota. Gut dysbiosis many harmful long-term effects on health. Associations between early-life exposure to antibiotics have been reported for chronic diseases, including inflammatory bowel disease, celiac disease, some cancers, metabolic diseases (obesity and type 2 diabetes), allergic diseases, autoimmune disorders, atherosclerosis, arthritis, and neurodevelopmental, neurodegenerative and other neurological diseases. In mechanistic terms, gut dysbiosis influences chronic disease through direct effects on mucosal immune and inflammatory pathways, plus a wide array of direct or indirect effects of short-chain fatty acids, the enteric nervous system, peristaltic motility, the production of hormones and neurotransmitters, and the loss of intestinal barrier integrity (notably with leakage of the pro-inflammatory endotoxin lipopolysaccharide into the circulation). To mitigate dysbiosis, the administration of probiotics in patients with chronic disease is often (but not always) associated with positive effects on clinical markers (e.g., disease scores) and biomarkers of inflammation and immune activation. Meta-analyses are complicated by differences in probiotic composition, dose level, and treatment duration, and large, randomized, controlled clinical trials are lacking in many disease areas. In view of the critical importance of deciding whether or not to prescribe antibiotics (especially to children), we suggest that the DOHaD concept can be logically extended to "gastrointestinal origins of health and disease" ("GOHaD") or even "microbiotic origins of health and disease" ("MOHaD").

Engineered nanoparticles (NPs) are extensively used in the food industry, yet safety concerns remain. The lack of validated methodologies is a bottleneck towards resolving this uncertainty. Hence, the current study aims to compare two cell models by examining the toxicological impacts of two food-relevant NPs (SiO2 and Ag) on intestinal epithelia using monolayer Caco-2 cells and full-thickness 3D tissue models of human small intestines (EpiIntestinal™). Comprehensive characterization and dosimetric analysis of the NPs were performed to determine effective doses and model realistic exposures. Neither genotoxicity nor cytotoxicity were detected in the 3D tissues after NP treatment, while the 2D cultures exhibited cytotoxic response from Ag NP treatment for 24 h at 1 μg/ml. Hyperspectral imaging and transmission electron microscopy confirmed uptake of both NPs by cells in both 2D and 3D culture models. Ag NPs caused an increase in autophagy, whereas SiO2 NPs induced increased cytoplasmic vacuolization. Based on realistic exposure levels studied, the 3D small intestinal tissue model was found to be more resilient to NP treatment compared to 2D cell monolayers. This comparative approach towards toxicological assessment of food relevant NPs could be used as a framework for future analysis of NP behavior and nanotoxicity in the gut.

Enteroendocrine cells (EECs) are well-known for their systemic hormonal effects, especially in the regulation of appetite and glycemia. Much less is known about how the products made by EECs regulate their local environment within the intestine. Here, we focus on paracrine interactions between EECs and other intestinal cells as they regulate three essential aspects of intestinal homeostasis and physiology: 1) intestinal stem cell function and proliferation; 2) nutrient absorption; and 3) mucosal barrier function. We also discuss the ability of EECs to express multiple hormones, describe in vitro and in vivo models to study EECs, and consider how EECs are altered in GI disease.

Whey protein emulsion gel is an ideal model food for revealing how the multilength scale food structures affect food digestion, as their structure and mechanical properties can be precisely manipulated by controlling the type and intensity of intermolecular interactions between protein molecules. However, there are still significant understanding gaps among intermolecular interactions, protein aggregation and gelation, emulsion gel formation, gel breakdown in the gastrointestinal tract (GIT), and the practical use of whey protein emulsion gels, which limits their GIT-targeted applications. In this regard, the relationship between the structure and digestion behavior of heat-set whey protein emulsion gels is reviewed and discussed mainly from the following aspects: (1) structural characteristics of whey protein molecules; (2) how different types of intermolecular interactions influence heat-induced aggregation and gelation of whey protein in the aqueous solutions and the oil-in-water emulsions, and the mechanical properties of the final gels; (3) functions of the mouth, the stomach, and the small intestine in processing of solid foods, and how different types of intermolecular interactions influence the breakdown properties of heat-set whey protein emulsion gels in GIT (i.e., their respective role in controlling gel digestion). Finally, the implications of knowledge derived from the formation and gastrointestinal breakdown of heat-set whey protein emulsion gels for developing controlled delivery vehicles, human satiety enhancers, and sensory modifiers are highlighted.

Inflammatory bowel disease (IBD) encompasses chronic inflammatory conditions of the distal gastrointestinal tract, including Crohn's disease and ulcerative colitis. This chapter explores the potential of Dendritic cell-associated C-type lectin-1 (Dectin-1), a pattern recognition receptor, as a therapeutic target for IBD. We delve into the multifaceted roles of Dectin-1 in immune response modulation, focusing on its interactions with the gut microbiota and immune system. Key sections include an examination of intestinal dysbiosis and its impact on IBD, highlighting the critical role of fungal dysbiosis and immune responses mediated by Dectin-1. The chapter discusses the dual functions of Dectin-1 in maintaining gut homeostasis and its contribution to disease pathogenesis through interactions with the gut's fungal community. Furthermore, the genetic and molecular mechanisms underpinning Dectin-1's role in IBD susceptibility are explored, alongside its signaling pathways and their effects on immune modulation. We also present therapeutic strategies targeting Dectin-1, including innovative drug delivery systems that leverage its natural binding affinity for β-glucans, enhancing targeted delivery to inflamed tissues. The chapter underscores the potential of dietary modulation of Dectin-1 pathways to restore gut microbiota balance and suggests future research directions to fully exploit Dectin-1's therapeutic potential in managing IBD. By elucidating the complex interplay between Dectin-1 and the gut microbiota, this chapter provides insights into novel therapeutic approaches aimed at mitigating IBD symptoms and improving patient outcomes.

Little is known about the biogeography of the mucosa associated microbiome (MAM) in patients with inflammatory bowel disease (IBD) versus controls in different segments of the gastrointestinal tract, as well as the links between the MAM, gastrointestinal symptoms, and use of proton pump inhibitors (PPI).

We recruited 59 controls (without structural abnormalities and gastrointestinal symptoms), 44 patients with ulcerative colitis (UC) and 31 with Crohn's disease (CD). Biopsies from various segments of the upper and lower gastrointestinal tract were collected. Microbial composition was assessed via 16S rRNA gene amplicon analysis and the bacterial load of the mucosal biopsies were assessed via qPCR. The MAM was examined in the context of disease status, PPI usage, the severity of gastrointestinal symptoms, and the symptom response to a standardised nutrient challenge (SNC).

Microbial communities of the MAM in the upper and lower gastrointestinal tract differed. IBD patients were characterised by relative and absolute depletion of numerous genera known to produce butyrate and/or propionate, with the largest differentiation being the depletion of Faecalibacterium in the lower gastrointestinal tract of CD patients. Notably, PPI users exhibited an enrichment of Faecalibacterium in the lower gastrointestinal tract. The severity of gastrointestinal symptoms, as well as the symptom response to the SNC, were significantly associated with MAM composition in the gastrointestinal tract.

The absolute and relative composition of the MAM is variable across different segments of the gastrointestinal tract. These quantitative changes indicates that MAM can be targeted in specific segments of the GI tract to improve patient outcomes.

The intricate connection between the gut and the brain involves multiple routes. Several viral families begin their infection cycle in the intestinal tract. However, amongst the long list of viral intestinal pathogens, picornaviruses, and astroviruses stand out for their ability to transition from the intestinal epithelia to central or peripheral nervous system cells. In immunocompromised, neonates and young children, these viral infections can manifest as severe diseases, such as encephalitis, meningitis, and acute flaccid paralysis. What confers this remarkable plasticity and makes them efficient in infecting cells of the gut and the brain axes? Here, we review the current understanding of the virus infection along the gut-brain axis for some enteric viruses and discuss the molecular mechanisms of their attenuation.

Ingestible microdevices represent a breakthrough in non-invasive sampling of the human gastrointestinal (GI) tract. By capturing the native spatiotemporal microbiome and intricate biochemical gradients, these devices allow a non-invasive multi-omic access to the unperturbed host-microbiota crosstalk, immune/nutritional landscapes and gut-organ connections. We present the current progress of GI sampling microdevices towards personalized metabolism and fostering collaboration among clinicians, engineers, and data scientists.

Interferon lambdas (IFN-λs) are crucial to control virus infections at mucosal surfaces. Interleukin-22 (IL-22) was reported to help IFN-λ control rotavirus infection in the intestinal epithelium of mice either by aiding in the induction of interferon-stimulated genes (ISGs) or by increasing cell proliferation thereby clearing virally infected cells. We investigated whether IL-22 and IFN-λs exhibit similar synergistic effects in human intestinal epithelial cells (IECs) models. Our results showed that co-treatment of IL-22 and IFN-λ induced more phosphorylation of STAT1 than either cytokine used alone. However, this increased STAT1 activation did not translate to increased ISGs production or antiviral protection. Transcriptomics analysis revealed that despite sharing a common subunit (IL-10Rb) within their heterodimeric receptors and activating similar STATs, the signaling generated by IL-22 and IFN-λs is independent, with IFN-λ signaling inducing ISGs and IL-22 signaling inducing cell proliferation genes. Using human intestinal organoids, we confirmed that IL-22 increased the size of the organoids through increased cell proliferation and expression of the stem cell marker (OLFM4). These findings suggest that in human intestinal cells, IFN-λs and IL-22 act independently to clear virus infections. IFN-λs induce ISGs to control virus replication and spread, whereas IL-22 increases cell proliferation to eliminate infected cells and repair the damage epithelium. Although these two cytokines do not act synergistically, each plays a key function in the protection of human IECs.

Intensive care unit-acquired weakness (ICU-AW) is a syndrome characterized by a long-term muscle weakness often observed in sepsis-surviving patients during the chronic phase. Although ICU-AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death-1 (PD-1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU-AW remains to be elucidated. Here, we study how PD-1 deficiency affects sepsis-induced skeletal muscle dysfunction in a preclinical sepsis model.

Chronic sepsis model was developed by treating wild-type (WT) and PD-1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15-17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL-13) and PD-1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow-twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). In an in vitro study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL-13 followed by gene expression measurements.

WT septic mice exhibited decreased muscle weight (quadriceps, P < 0.01; gastrocnemius, P < 0.05; and tibialis anterior, P < 0.01) and long-term muscle weakness (P < 0.0001), whereas PD-1 KO septic mice did not exhibit any reduction in muscle weights and strengths. Slow-twitch specific mRNAs, including myoglobin (Mb), troponin I type 1 (Tnni1), and myosin heavy chain 7 (Myh7) were decreased in WT skeletal muscle (Mb, P < 0.0001; Tnni1, P < 0.05; and Myh7, P < 0.05) after sepsis induction, but mRNA expressions of Tnni1 and Myh7 were increased in PD-1 KO septic mice (Mb, not significant; Tnni1, P < 0.0001; and Myh7, P < 0.05). Treatment of C2C12 myotube cells with LPS decreased the expression of slow-twitch mRNAs, which was restored by IL-13 (Mb, P < 0.0001; Tnni1, P < 0.001; and Myh7, P < 0.05). IL-13 production was significantly higher in ILC2s compared to T cells in skeletal muscle (P < 0.05). IL-13-producing ILC2s in skeletal muscle were examined and found to increase in PD-1 KO septic mice, compared with WT septic mice (P < 0.05). ILC2-derived IL-13 was increased by PD-1 KO septic mice and thought to protect the muscles from experimental ICU-AW.

Long-term muscle weakness in experimental ICU-AW was ameliorated in PD-1 KO mice. ILC2-derived IL-13 production in skeletal muscles was increased in PD-1 KO mice, thereby suggesting that IL-13 alleviates muscle weakness during sepsis. This study demonstrates the effects of PD-1 blockade in preserving muscle strength during sepsis through an increase in ILC2-derived IL-13 and may be an attractive therapeutic target for sepsis-induced ICU-AW.

Messenger RNA (mRNA) therapeutics have been widely employed as strategies for the treatment and prevention of diseases. Amid the global outbreak of COVID-19, mRNA vaccines have witnessed rapid development. Generally, in the case of mRNA vaccines, the initiation of the innate immune system serves as a prerequisite for triggering subsequent adaptive immune responses. Critical cells, cytokines, and chemokines within the innate immune system play crucial and beneficial roles in coordinating tailored immune reactions towards mRNA vaccines. Furthermore, immunostimulators and delivery systems play a significant role in augmenting the immune potency of mRNA vaccines. In this comprehensive review, we systematically delineate the latest advancements in mRNA vaccine research, present an in-depth exploration of strategies aimed at amplifying the immune effectiveness of mRNA vaccines, and offer some perspectives and recommendations regarding the future advancements in mRNA vaccine development.

Drug metabolism in the intestinal wall affects bioavailability of orally administered drugs and is influenced by age. Hence, it is important to fully understand the drug metabolizing capacity of the gut to predict systemic exposure. The aim of this study was to investigate the potential of enteroids as a tool to study CYP3A4/5 -mediated metabolism in both children and adults. Bioconversion of midazolam, a CYP3A4/5 model substrate, was studied using enteroid monolayers as well as tissue explants in the Ussing chamber, both derived from pediatric [median (range age): 54 weeks (2 days - 13 years), n = 21] and adult (n = 5) tissue. Caco-2 cellular monolayers were employed as controls. In addition, mRNA expression of CYP3A4 was determined in enteroid monolayers (n = 11), tissue (n = 23) and Caco-2 using RT-qPCR. Midazolam metabolism was successfully detected in all enteroid monolayers, as well as in all tissue explants studied in the Ussing chamber, whereas Caco-2 showed no significant metabolite formation. The extracted fraction of midazolam was similar between enteroid monolayers and tissue. The fraction of midazolam extracted increased with age in enteroid monolayers derived from 0 to 70 week old donors. No statistically significant correlation was observed in tissue likely due to high variability observed and the smaller donor numbers included in the study. At the level of gene expression, CYP3A4 increased with age in tissues (n = 32), while this was not reflected in enteroid monolayers (n = 16). Notably, asymmetric metabolite formation was observed in enteroids and tissue, with higher metabolite formation on the luminal side of the barrier. In summary, we demonstrated that enteroids can be used to measure CYP3A4/5 midazolam metabolism, which we show is similar as observed in fresh isolated tissue. This was the case both in children and adults, indicating the potential of enteroids to predict intestinal metabolism. This study provides promising data to further develop enteroids to study drug metabolism in vitro and potentially predict oral absorption for special populations as an alternative to using fresh tissue.

While approved vaccines for COVID-19 provide protection against severe disease and death, they have limited efficacy in the prevention of infection and virus transmission. Mucosal immunity is preferred over systemic immunity to provide protection at the point of entry against pathogens such as SARS-CoV-2. VaxForm has developed an oral vaccine delivery platform that elicits mucosal and systemic immune responses by targeting immune cells in the gut through C-type lectin receptors. The technology consists of microencapsulating the vaccine with an enteric polymer, which also results in enhanced thermostability. This article describes the formulation development and in vivo testing of a novel protein-based oral COVID-19 vaccine using this technology. Results demonstrate successful induction of immune response in mice and showed that the particle size of the vaccines following administration can impact the ratio of mucosal to systemic response. Immunogenicity and thermostability of liquid suspension and dry powder versions of the vaccine were compared in mice. The liquid suspension vaccine showed excellent heat resistance by maintaining immunogenicity after 14 days of storage at 60 °C. While further investigation is needed to determine correlates of protection and duration of response for mucosal immunity, this study demonstrates the vaccine's potential as a COVID-19 booster to enhance mucosal protection in humans and improve global access by lowering the cost of production, removing cold-chain requirements, and allowing self-administration.

To review what intestinal permeability is and how it is measured, and to summarise the current evidence linking altered intestinal permeability with the development of hypertension.

Increased gastrointestinal permeability, directly measured in vivo, has been demonstrated in experimental and genetic animal models of hypertension. This is consistent with the passage of microbial substances to the systemic circulation and the activation of inflammatory pathways. Evidence for increased gut permeability in human hypertension has been reliant of a handful of blood biomarkers, with no studies directly measuring gut permeability in hypertensive cohorts. There is emerging literature that some of these putative biomarkers may not accurately reflect permeability of the gastrointestinal tract. Data from animal models of hypertension support they have increased gut permeability; however, there is a dearth of conclusive evidence in humans. Future studies are needed that directly measure intestinal permeability in people with hypertension.

Tea is a highly popular beverage, primarily due to its unique flavor and aroma as well as its perceived health benefits. The impact of tea on the gut microbiome could be an important means by which tea exerts its health benefits since the link between the gut microbiome and health is strong. This review provided a discussion of the bioactive compounds in tea and the human gut microbiome and how the gut microbiome interacts with tea polyphenols. Importantly, studies were compiled on the impact of differently processed tea, which contains different polyphenol profiles, on the gut microbiota from in vivo animal feeding trials, in vitro human fecal fermentation experiments, and in vivo human feeding trials from 2004-2024. The results were discussed in terms of different tea types and how their impacts are related to or different from each other in these three study groups.