Search Results (29)

Mutations in the human patatin-like lysophospholipase domain containing the 6 gene PNPLA6 encode an evolutionarily conserved (lyso)phospholipase, leading to the development of a complex hereditary spastic paraplegia 39 (SPG 39) and a number of rare severe syndromes in humans. Diseases disrupt the functioning of the nervous and reproductive systems and the gastrointestinal tract. The study aims to investigate the role of the Drosophila melanogaster swiss cheese gene, an ortholog of the human PNPLA6 gene, in gut function. We showed that the swiss cheese gene knockout leads to changes in the morphology of the midgut, disruption of the septate junction structure and the intestinal barrier permeability, and a decrease in the lipid droplet number in enterocytes. As a result of such disturbances, intestinal stem cells (ISCs) proliferation is activated, and the gut microbiome is altered. Ectopic expression of human PNPLA6 leads to the recovery of the intestinal barrier in the fly gut. The example of Drosophila demonstrates the important role of evolutionarily conserved (lyso)phospholipase in intestinal homeostasis. Full article

Mycotoxins are toxic secondary metabolites produced by filamentous fungi that contaminate agricultural commodities, posing risks to food safety, animal productivity, and human health. The gastrointestinal tract is the first and most critical site of exposure, where the intestinal epithelium functions as both a physical and immunological barrier against luminal toxins and pathogens. While extensive research has demonstrated that mycotoxins disrupt epithelial integrity through tight junction impairment, oxidative stress, apoptosis, and inflammation, their effects on the intestinal stem cell (ISC) compartment and epithelial regeneration remain insufficiently understood. This review integrates recent findings from in vivo, cell culture, and advanced 3D intestinal organoid and gut-on-chip models to elucidate how mycotoxins such as deoxynivalenol and zearalenone impair ISC proliferation, alter Wnt/Notch signaling, and compromise mucosal repair. We also discuss dose relevance, species differences, and the modulatory roles of the microbiome and short-chain fatty acids, as well as emerging evidence of additive or synergistic toxicity under co-exposure conditions. By bridging well-established mechanisms of barrier disruption with the emerging concept of ISC-driven regenerative failure, this review identifies a critical knowledge gap in mycotoxin toxicology and highlights the need for integrative models that link epithelial damage to impaired regeneration. Collectively, these insights advance understanding of mycotoxin-induced intestinal dysfunction and provide a foundation for developing nutritional, microbial, and pharmacological strategies to preserve gut integrity and repair. Full article

Radiation-induced intestinal injury (RIII), a severe complication of abdominopelvic radiotherapy, causes intestinal ischemia, ulcers, and necrosis, severely impacting patients’ quality of life. Currently, effective treatments are limited, and a specific cure remains elusive. Our previous research showed that lactoferrin (LF) can promote intestinal stem cell (ISC) proliferation and tissue repair; however, its oral administration is limited by rapid degradation in the gastric environment. In this study, we developed LF-loaded liposomal nanoparticles (Lip-LF) using a simple ethanol injection method. The optimal formulation (cholesterol/egg yolk lecithin ratio 2:8, LF concentration 12.5 mg/mL) achieved a drug-loading capacity of 6.8% and a narrow size distribution (0.2 < PDI < 0.4). In vitro experiments demonstrated that Lip-LF protected LF from pepsin degradation in simulated gastric fluid (SGF), retaining over 80% integrity after 120 min, while releasing in simulated intestinal fluid (SIF). In vivo imaging revealed prolonged gastrointestinal retention of Lip-LF compared to free LF. In a murine model of RIII (12 Gy whole-body irradiation), Lip-LF significantly restored villus counts, increased crypt height, and promoted goblet-cell regeneration. Immunohistochemical and qPCR analyses revealed enhanced ISCs proliferation and upregulation of repair-associated genes, including Pcna and Olfm4. These findings demonstrate that Lip-LF protects LF from gastric degradation and enhances its targeted delivery to the intestine, improving its therapeutic efficacy in repairing RIII. Lip-LF thus offers a promising strategy for managing RIII. Full article

The objective of our study was to verify the intervention effect of Bacillus amyloliquefaciens SC06 on NE by constructing a C. perfringens-induced intestinal damage mouse model. A total of 40 mice were randomly assigned to four treatments: CON (basal diet), CP (basal diet + C. perfringens), SC06 + CP (basal diet + SC06 + C. perfringens) and SC06 (basal diet + SC06). Our findings indicated that SC06 supplementation was effective in maintaining the integrity of the intestinal barrier, enhancing the antioxidant capacity of the intestine, reducing the generation of an inflammatory response, and suppressing enterocyte apoptosis in the presence of C. perfringens. Furthermore, SC06 supplementation enhanced the prefoliation of intestinal stem cells (ISC) and prompted their differentiation into goblet cells and Paneth cells. Moreover, our findings indicate that SC06 promotes the proliferation of C. perfringens-induced jejunum organoids and the expression of genes and proteins associated with ISC differentiation and regeneration. The mechanism by which SC06 modulates ISCs has been validated, and the results align with those obtained in vivo. In conclusion, the findings demonstrated that SC06 stimulates the proliferation and differentiation of ISCs through the activation of the Wnt/β-catenin signaling pathway, thereby accelerating epithelial regeneration and repair. Full article

Intestinal regeneration is essential for maintaining epithelial integrity and repairing mucosal damage caused by inflammation, infections, or injuries. Traditional Chinese Medicine (TCM) has long utilized herbal remedies for gastrointestinal disorders, and accumulating evidence highlights that natural compounds derived from TCM possess significant regenerative potential. This review summarizes the multifaceted mechanisms by which these bioactive compounds promote intestinal healing. Key actions include the stimulation of intestinal stem cell (ISC) proliferation and differentiation, the modulation of inflammatory responses, the reinforcement of epithelial barrier integrity, the attenuation of oxidative stress, and the reshaping of the gut microbiota. Representative compounds such as Astragalus polysaccharides, berberine, curcumin, puerarin, and flavonoids like quercetin exhibit these effects through signaling pathways, including HIF-1, Wnt/β-catenin, NF-κB, Nrf2, and IL-22. Evidence from in vitro organoid models and in vivo studies in colitis, radiation injury, antibiotic-associated diarrhea, and intestinal dysmotility and diarrhea models demonstrates that these compounds enhance crypt villus regeneration, preserve tight junctions, and improve clinical outcomes. The holistic, multi-target actions of Chinese medicine-derived natural products make them promising candidates for therapeutic strategies aimed at intestinal repair. Further clinical validation and mechanistic studies are warranted to facilitate their integration into modern gastrointestinal medicine. Full article

Enteroendocrine cells (EECs) are specialized secretory cells in the gut epithelium that differentiate from intestinal stem cells (ISCs). Mature EECs secrete incretin hormones that stimulate pancreatic insulin secretion and regulate appetite. Decreased EEC numbers and impaired secretion of the incretin glucagon-like peptide-1 (GLP1) have been implicated in obesity-associated metabolic complications. Gut microbial metabolites of dietary tryptophan (TRP) were recently shown to modulate ISC proliferation and differentiation. However, their specific effects on EEC differentiation are not known. We hypothesized that the gut microbial metabolites of dietary tryptophan counteract impaired GLP1 production and function in obesity by stimulating EEC differentiation from ISCs. We utilized complementary models of human and rat intestines to determine the effects of obesity or TRP metabolites on EEC differentiation. EEC differentiation was assessed by the EEC marker chromogranin A (CHGA) levels in the intestinal mucosa of normal versus obese rats. The effects of TRP metabolites on EEC differentiation were determined in human intestinal organoids treated with indole, a primary TRP metabolite, or the culture supernatant of Lactobacillus acidophilus grown in TRP media (LA-CS-TRP). Our results showed that the mRNA and protein levels of CHGA, the EEC marker, were significantly decreased (~60%) in the intestinal mucosa of high-fat-diet-induced obese rat intestines. The expression of the transcription factors that direct the ISC differentiation towards the EEC lineage was also decreased in obesity. In human organoids, treatment with indole or LA-CS-TRP significantly increased (more than 2-fold) CHGA levels, which were blocked by the aryl hydrocarbon receptor (AhR) antagonist CH-223191. Thus, the stimulation of EEC differentiation by colonic microbial metabolites highlights a novel therapeutic role of TRP metabolites in obesity and associated metabolic disorders. Full article

Intestinal stem cells (ISCs) maintain epithelial renewal through their proliferation and differentiation capabilities, responding to various intestinal insults. However, the impact of iturin A, a natural antimicrobial peptide, on ISC viability and its potential to mitigate heat-stable enterotoxin b (STb)-induced intestinal damage remains unclear. Our recent study demonstrated that oral administration of iturin A enhances tight junction protein expression, accelerates crypt-villus regeneration, and restores epithelial barrier integrity in STb-exposed mice. Furthermore, iturin A promotes ISC proliferation and differentiation, significantly increasing the numbers of goblet and Paneth cells in the jejunum following STb exposure. Notably, iturin A regulates intestinal homeostasis by scavenging reactive oxygen species (ROS), while elevating total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) levels in both serum and jejunal mucosa. Mechanistically, iturin A facilitates nuclear factor-erythroid 2- related factor 2 (Nrf2) release by disrupting Kelch-like ECH-associated protein 1 (Keap1), leading to the upregulation of the antioxidant enzyme glutathione peroxidase 4 (GPX4). In conclusion, our findings indicate that iturin A alleviates oxidative stress induced by STb through modulation of the Keap1/Nrf2 pathway and promotes ISC differentiation into goblet and Paneth cells, thereby enhancing resistance to STb-induced damage. Full article

As a prevalent mycotoxin found in cereal foods and feed, deoxynivalenol (DON) disrupts the orderly regeneration of intestinal epithelial tissue by interfering with the intracellular antioxidant defense system. However, the potential of mulberry leaf-derived Morin, a natural flavonoid active substance with clearing reactive oxygen species (ROS), to mitigate DON-induced intestinal oxidative damage remains unclear. Our investigation demonstrates that Morin effectively reverses the decline in growth performance and repairs damaged jejunal structures and barrier function under DON exposure. Furthermore, the proliferation and differentiation of intestinal stem cells (ISCs) is enhanced significantly after Morin intervention. Importantly, Morin increases the levels of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) in the serum and jejunal tissue, while reducing the accumulation of ROS and malondialdehyde (MDA). Molecular interaction analysis further confirms that Morin targets inhibition of Keap1 to activate the Nrf2-mediated antioxidant system. In summary, our results suggest that Morin alleviates the oxidative damage induced by DON by regulating the Keap1/Nrf2 pathway, thereby restoring the proliferation and differentiation activity of ISC, which provides new insights into Morin mitigating DON damage. Full article

Fermented feed is extensively used in animal production due to their improved palatability and efficient utilization. This study aimed to explore the effects of fermented feed on growth performance and gut health, particularly through the modulation of intestinal stem cells (ISCs). Twenty-four 28-day-old male weaned piglets were randomly assigned into two groups (n = 12): piglets in a control group fed a basal diet, and an experimental group fed a basal diet replaced with 6% fermented mixed feed (FMF) for 28 days. The results indicated that FMF significantly elevated the growth rate, feed intake, and nutrient digestibility of piglets (p < 0.05). Furthermore, FMF supplementation increased the jejunal villus height, transepithelial electrical resistance (TEER) values, and the expression of tight junction proteins (ZO-1 and Claudin1) (p < 0.05). Immunohistochemistry (IHC) analysis revealed that FMF increased the number of Olfm4⁺ ISCs and PCNA⁺ mitotic cells in jejunal crypts, facilitating the differentiation of ISCs into enterocytes (Villin), goblet cells (MUC2), and enteroendocrine cells (CHGA). Conversely, the protein expression of Cleaved Caspase-3 was decreased in the FMF group (p < 0.05). Notably, the Wnt/β-catenin signaling pathway, including FZD7 and Active β-catenin, was significantly upregulated in the jejunum after FMF supplementation. Consistent with these findings, intestinal organoids derived from jejunal crypts in the FMF group demonstrated enhanced growth and increased expression of Lgr5, PCNA, KRT20, and β-catenin (p < 0.05). These results suggest that fermented feed promotes intestinal development by enhancing ISC proliferation and differentiation via activation of the Wnt/β-catenin signaling pathway. Full article

The intestinal area is composed of diverse cell types that harmonize gut homeostasis, which is influenced by both endogenous and exogenous factors. Notably, the environment of the intestine is exposed to several types of mechanical forces, including shear stress generated by fluid flow, compression and stretch generated by luminal contents and peristaltic waves of the intestine, and stiffness attributed to the extracellular matrix. These forces play critical roles in the regulation of cell proliferation, differentiation, and migration. Many efforts have been made to simulate the actual intestinal environment in vitro. The three-dimensional organoid culture system has emerged as a powerful tool for studying the mechanism of the intestinal epithelial barrier, mimicking rapidly renewing epithelium from intestinal stem cells (ISCs) in vivo. However, many aspects of how mechanical forces, such as shear stress, stiffness, compression, and stretch forces, influence the intestinal area remain unresolved. Here, we review the recent studies elucidating the impact of mechanical forces on intestinal immunity, interaction with the gut microbiome, and intestinal diseases. Full article

Understanding the regulation of somatic stem cells, both during homeostasis and in response to environmental challenges like injury, infection, chemical exposure, and nutritional changes, is critical because their dysregulation can result in tissue degeneration or tumorigenesis. The use of models such as the Drosophila and mammalian adult intestines offers valuable insights into tissue homeostasis and regeneration, advancing our knowledge of stem cell biology and cancer development. This review highlights significant findings from recent studies, unveiling the molecular mechanisms that govern self-renewal, proliferation, differentiation, and regeneration of intestinal stem cells (ISCs). These insights not only enhance our understanding of normal tissue maintenance but also provide critical perspectives on how ISC dysfunction can lead to pathological conditions such as colorectal cancer (CRC). Full article

The intestines are in a constant state of motion and self-renewal. The mechanical breakdown of food facilitates intestinal movement and aids digestion. It is believed that mechanical stimulation, triggered by changes in osmotic pressure within the intestines, plays a crucial role in regulating gastrointestinal motility. While TRPs and PIEZO1/2 have been identified as mechanosensitive ion channels involved in this process, there still exist numerous unidentified channels with similar properties. In this study, we demonstrate that the TMEM63B expressed in intestinal stem cells contributes to the regulation of intestinal motility and digestion. The deletion of TMEM63B in intestinal stem cells not only decelerates intestinal motility and impairs digestion but also attenuates the proliferation of intestinal stem cells and exacerbates DSS-induced colitis in mice. Collectively, our findings unveil the pivotal role of TMEM63B in governing optimal digestive function and modulating intestinal motility. Full article

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestines without a cure. Current therapies suppress inflammation to prevent further intestinal damage. However, healing already damaged intestinal epithelia is still an unmet medical need. Under physiological conditions, Lgr5⁺ intestinal stem cells (ISCs) in the intestinal crypts replenish the epithelia every 3–5 days. Therefore, understanding the regulation of Lgr5⁺ ISCs is essential. Previous data suggest vitamin D signaling is essential to maintain normal Lgr5⁺ ISC function in vivo. Our recent data indicate that to execute its functions in the intestines optimally, 1,25(OH)₂D requires high concentrations that, if present systemically, can cause hypercalcemia (i.e., blood calcium levels significantly higher than physiological levels), leading to severe consequences. Using 5-bromo-2′-deoxyuridine (BrdU) to label the actively proliferating ISCs, our previous data suggested that de novo synthesized locally high 1,25(OH)₂D concentrations effectively enhanced the migration and differentiation of ISCs without causing hypercalcemia. However, although sparse in the crypts, other proliferating cells other than Lgr5⁺ ISCs could also be labeled with BrdU. This current study used high-purity Lgr5⁺ ISC lines and a mouse strain, in which Lgr5⁺ ISCs and their progeny could be specifically tracked, to investigate the effects of de novo synthesized locally high 1,25(OH)₂D concentrations on Lgr5⁺ ISC function. Our data showed that 1,25(OH)₂D at concentrations significantly higher than physiological levels augmented Lgr5⁺ ISC differentiation in vitro. In vivo, de novo synthesized locally high 1,25(OH)₂D concentrations significantly elevated local 1α-hydroxylase expression, robustly suppressed experimental colitis, and promoted Lgr5⁺ ISC differentiation. For the first time, this study definitively demonstrated 1,25(OH)₂D’s role in Lgr5⁺ ISCs, underpinning 1,25(OH)₂D’s promise in IBD therapy. Full article

Exposure to the space microenvironment has been found to disrupt the homeostasis of intestinal epithelial cells and alter the composition of the microbiota. To investigate this in more detail and to examine the impact of ginsenoside Rb1, we utilized a mouse model of hindlimb unloading (HU) for four weeks to simulate the effects of microgravity. Our findings revealed that HU mice had ileum epithelial injury with a decrease in the number of intestinal stem cells (ISCs) and the level of cell proliferation. The niche functions for ISCs were also impaired in HU mice, including a reduction in Paneth cells and Wnt signaling, along with an increase in oxidative stress. The administration of Rb1 during the entire duration of HU alleviated the observed intestinal defects, suggesting its beneficial influence on epithelial cell homeostasis. Hindlimb unloading also resulted in gut dysbiosis. The supplementation of Rb1 in the HU mice or the addition of Rb1 derivative compound K in bacterial culture in vitro promoted the growth of beneficial probiotic species such as Akkermansia. The co-housing experiment further showed that Rb1 treatment in ground control mice alone could alleviate the defects in HU mice that were co-housed with Rb1-treated ground mice. Together, these results underscore a close relationship between dysbiosis and impaired ISC functions in the HU mouse model. It also highlights the beneficial effects of Rb1 in mitigating HU-induced epithelial injury by promoting the expansion of intestinal probiotics. These animal-based insights provide valuable knowledge for the development of improved approaches to maintaining ISC homeostasis in astronauts. Full article

Cadmium (Cd) is a highly toxic and cumulative environmental pollutant. Siderophores are heavy metal chelators with high affinity to heavy metals, such as Cd. Ryegrass (Lolium perenne L.) has a potential remediation capacity for soils contaminated by heavy metals. Consequently, using ryegrass alongside beneficial soil microorganisms that produce siderophores may be an effective means to remediate soils contaminated with Cd. In this study, the Bacillus strains WL1210 and CD303, which were previously isolated from the rhizospheres of Nitraria tangutorum in Wulan and Peganum harmala L. in Dachaidan, Qinghai, China, respectively, both arid and sandy environments, were evaluated for heavy metal pollution mitigation. Our quantitative analyses have discerned that the two bacterial strains possess commendable attributes of phosphorus (P) solubilization and potassium (K) dissolution, coupled with the capacity to produce phytohormones. To assess the heavy metal stress resilience of these strains, they were subjected to a cadmium concentration gradient, revealing their incremental growth despite cadmium presence, indicative of a pronounced tolerance threshold. The subsequent phylogenetic analysis, bolstered by robust genomic data from conserved housekeeping genes, including 16S rDNA, gyr B gene sequencing, as well as dnaK and recA, delineated a species-level phylogenetic tree, thereby confirming the strains as Bacillus atrophaeus. Additionally, we identified the types of iron-carrier-producing strains as catechol (WL1210) and carboxylic acid ferrophilin (CD303). A genomic analysis uncovered functional genes in strain CD303 associated with plant growth and iron carrier biosynthesis, such as fnr and iscA. Ryegrass seed germination assays, alongside morphological and physiological evaluations under diverse heavy metal stress, underscored the strains’ potential to enhance ryegrass growth under high cadmium stress when treated with bacterial suspensions. This insight probes the strains’ utility in leveraging alpine microbial resources and promoting ryegrass proliferation. Full article