Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.

Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.

Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity.

Group 3 innate lymphoid cells (ILC3s) sense environmental signals that are critical for gut homeostasis and host defense. However, the metabolite-sensing G-protein-coupled receptors that regulate colonic ILC3s remain poorly understood. We found that colonic ILC3s expressed Ffar2, a microbial metabolite-sensing receptor, and that Ffar2 agonism promoted ILC3 expansion and function. Deficiency of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived interleukin-22 (IL-22) production. This led to impaired gut epithelial function characterized by altered mucus-associated proteins and antimicrobial peptides and increased susceptibility to colonic injury and bacterial infection. Ffar2 increased IL-22+ CCR6+ ILC3s and influenced ILC3 abundance in colonic lymphoid tissues. Ffar2 agonism differentially activated AKT or ERK signaling and increased ILC3-derived IL-22 via an AKT and STAT3 axis. Our findings suggest that Ffar2 regulates colonic ILC3 proliferation and function, and they identify an ILC3-receptor signaling pathway modulating gut homeostasis and pathogen defense.

The Environmental Sensor AHR Protects from Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity.

The epithelium and immune compartment in the intestine are constantly exposed to a fluctuating external environment. Defective communication between these compartments at this barrier surface underlies susceptibility to infections and chronic inflammation. Environmental factors play a significant, but mechanistically poorly understood, role in intestinal homeostasis. We found that regeneration of intestinal epithelial cells (IECs) upon injury through infection or chemical insults was profoundly influenced by the environmental sensor aryl hydrocarbon receptor (AHR). IEC-specific deletion of Ahr resulted in failure to control C. rodentium infection due to unrestricted intestinal stem cell (ISC) proliferation and impaired differentiation, culminating in malignant transformation. AHR activation by dietary ligands restored barrier homeostasis, protected the stem cell niche, and prevented tumorigenesis via transcriptional regulation of of Rnf43 and Znrf3, E3 ubiquitin ligases that inhibit Wnt-ß-catenin signaling and restrict ISC proliferation. Thus, activation of the AHR pathway in IECs guards the stem cell niche to maintain intestinal barrier integrity.

Autophagy-mediated plasma membrane removal promotes the formation of epithelial syncytia.

Epithelial wound healing in Drosophila involves the formation of multinucleate cells surrounding the wound. We show that autophagy, a cellular degradation process often deployed in stress responses, is required for the formation of a multinucleated syncytium during wound healing, and that autophagosomes that appear near the wound edge acquire plasma membrane markers. In addition, uncontrolled autophagy in the unwounded epidermis leads to the degradation of endo-membranes and the lateral plasma membrane, while apical and basal membranes and epithelial barrier function remain intact. Proper functioning of TORC1 is needed to prevent destruction of the larval epidermis by autophagy, in a process that depends on phagophore initiation and expansion but does not require autophagosomes fusion with lysosomes. Autophagy induction can also affect other sub-cellular membranes, as shown by its suppression of experimentally induced laminopathy-like nuclear defects. Our findings reveal a function for TORC1-mediated regulation of autophagy in maintaining membrane integrity and homeostasis in the epidermis and during wound healing.

Role of the intestinal microbiota in contributing to weight disorders and associated comorbidities.

SUMMARYThe gut microbiota is a major factor contributing to the regulation of energy homeostasis and has been linked to both excessive body weight and accumulation of fat mass (i.e., overweight, obesity) or body weight loss, weakness, muscle atrophy, and fat depletion (i.e., cachexia). These syndromes are characterized by multiple metabolic dysfunctions including abnormal regulation of food reward and intake, energy storage, and low-grade inflammation. Given the increasing worldwide prevalence of obesity, cachexia, and associated metabolic disorders, novel therapeutic strategies are needed. Among the different mechanisms explaining how the gut microbiota is capable of influencing host metabolism and energy balance, numerous studies have investigated the complex interactions existing between nutrition, gut microbes, and their metabolites. In this review, we discuss how gut microbes and different microbiota-derived metabolites regulate host metabolism. We describe the role of the gut barrier function in the onset of inflammation in this context. We explore the importance of the gut-to-brain axis in the regulation of energy homeostasis and glucose metabolism but also the key role played by the liver. Finally, we present specific key examples of how using targeted approaches such as prebiotics and probiotics might affect specific metabolites, their signaling pathways, and their interactions with the host and reflect on the challenges to move from bench to bedside.

How dietary advanced glycation end products could facilitate the occurrence of food allergy.

BACKGROUND: Food allergy (FA) is one of the most common chronic conditions in children with an increasing prevalence facilitated by the exposure to environmental factors in predisposed individuals. It has been hypothesized that the increased consumption of ultra-processed foods, containing high levels of dietary advanced glycation end products (AGEs), could facilitate the occurrence of FA. OBJECTIVE: We sought to provide preclinical and clinical evidence on the potential role of AGEs in facilitating the occurrence of FA. METHODS: Human enterocytes, human small intestine organ culture, and PBMCs from children at risk for allergy were used to investigate the direct effect of AGEs on gut barrier, inflammation, TH2 cytokine response, and mitochondrial function. Intake of the 3 most common glycation products in Western diet foods, Nε-(carboxymethyl) lysine, Nε-(1-carboxyethyl) lysin, and Nδ-(5-hydro-5- methyl-4-imidazolone-2-yl)-ornithine (MG-H1), and the accumulation of AGEs in the skin were comparatively investigated in children with FA and in age-matched healthy controls. RESULTS: Human enterocytes exposed to AGEs showed alteration in gut barrier, AGE receptor expression, reactive oxygen species production, and autophagy, with increased transepithelial passage of food antigens. Small intestine organ cultures exposed to AGEs showed an increase of CD25+ cells and proliferating crypt enterocytes. PBMCs exposed to AGEs showed alteration in proliferation rate, AGE receptor activation, release of inflammatory and TH2 cytokines, and mitochondrial metabolism. Significant higher dietary AGE intake and skin accumulation were observed children with FA (n = 42) compared with age-matched healthy controls (n = 66). CONCLUSIONS: These data, supporting a potential role for dietary AGEs in facilitating the occurrence of FA, suggest the importance of limiting exposure to AGEs children as a potential preventive strategy against this common condition.

Akkermansia muciniphila MucT attenuates sodium valproate-induced hepatotoxicity and upregulation of Akkermansia muciniphila in rats.

In the previous study, we found that the oral sodium valproate (SVP) increased the relative abundance of Akkermansia muciniphila (A. muciniphila) in rats, and plasma aspartate transaminase (AST) and alanine aminotransferase (ALT) activities were positively correlated with A. muciniphila levels. This study aimed to further investigate the role of A. muciniphila in SVP-induced hepatotoxicity by orally supplementing rats with the representative strain of A. muciniphila, A. muciniphila MucT. Additionally, the fresh faeces were incubated anaerobically with SVP to investigate the effect of SVP on faecal A. muciniphila in the absence of host influence. Results showed that A. muciniphila MucT ameliorated the hepatotoxicity and upregulation of A. muciniphila induced by SVP. SVP also induced a noteworthy elevation of A. muciniphila level in vitro, supporting the observation in vivo. Therefore, we speculate that A. muciniphila MucT may be a potential therapeutic strategy for SVP-induced hepatotoxicity. In addition, the increased A. muciniphila induced by SVP may differ from A. muciniphila MucT, but further evidence is needed. These findings provide new insights into the relationships between A. muciniphila and SVP-induced hepatotoxicity, highlighting the potential for different A. muciniphila strains to have distinct or even opposing effects on SVP-induced hepatotoxicity.

Influence of the gut microbiome on appetite-regulating neuropeptides in the hypothalamus: Insight from conventional, antibiotic-treated, and germ-free mouse models of anorexia nervosa.

Recent research highlights the profound impact of the gut microbiome on neuropsychiatric disorders, shedding light on its potential role in shaping human behavior. In this study, we investigate the role of the gut microbiome in appetite regulation using activity-based anorexia (ABA) mouse model of anorexia nervosa (AN) - a severe eating disorder with significant health consequences. ABA was induced in conventional, antibiotic-treated, and germ-free mice. Our results show the clear influence of the gut microbiome on the expression of four orexigenic (neuropeptide Y, agouti-related peptide, melanin-concentrating hormone, and orexin) and four anorexigenic peptides (cocaine- and amphetamine-regulated transcript, corticotropin-releasing hormone, thyrotropin-releasing hormone, and pro-opiomelanocortin) in the hypothalamus. Additionally, we assessed alterations in gut barrier permeability. While variations were noted in germ-free mice based on feeding and activity, they were not directly attributable to the gut microbiome. This research emphasizes that the gut microbiome is a pivotal factor in AN's appetite regulation beyond just dietary habits or physical activity.

Protective effects of metformin in the pro-inflammatory cytokine induced intestinal organoids injury model.

Pathogenesis of inflammatory bowel disease (IBD) accompanies disrupted intestinal tight junctions. However, many approaches of therapeutics for IBD are focused only on anti-inflammatory effects and most cellular experiments are based on two-dimensional cell lines which have insufficient circumstances of intestine. Thus, here, we used three-dimensional structure intestinal organoids to investigate effects of metformin in the in vitro IBD condition. In this study, we focused on both tight junctions and the levels of inflammatory cytokines. Metformin enhances the intestinal barrier in injured intestine via upregulation of AMP-activated protein kinase, dysfunction of which contributes to the pathogenesis of intestinal diseases. We aim to investigate the effects of metformin on cytokine-induced injured intestinal organoids. Tumor necrosis factor-alpha (TNF-α) was used to induce intestinal injury in an organoid model, and the effects of metformin were assessed. Cell viability and levels of inflammatory cytokines were quantified in addition to tight junction markers. Furthermore, 4 kDa FITC-dextran was used to assess intestinal permeability. The upregulation of inflammatory cytokine levels was alleviated by metformin, which also restored the intestinal epithelium permeability in TNF-α-treated injury organoids. We confirmed that claudin-2 and claudin-7, representative tight junction markers, were also protected by metformin treatment. This study confirms the protective effects of metformin, which could be used as a therapeutic strategy for inflammatory intestinal diseases.

Human-derived bacterial strains mitigate colitis via modulating gut microbiota and repairing intestinal barrier function in mice.

BACKGROUND: Unbalanced gut microbiota is considered as a pivotal etiological factor in colitis. Nevertheless, the precise influence of the endogenous gut microbiota composition on the therapeutic efficacy of probiotics in colitis remains largely unexplored. RESULTS: In this study, we isolated bacteria from fecal samples of a healthy donor and a patient with ulcerative colitis in remission. Subsequently, we identified three bacterial strains that exhibited a notable ability to ameliorate dextran sulfate sodium (DSS)-induced colitis, as evidenced by increased colon length, reduced disease activity index, and improved histological score. Further analysis revealed that each of Pediococcus acidilactici CGMCC NO.17,943, Enterococcus faecium CGMCC NO.17,944 and Escherichia coli CGMCC NO.17,945 significantly attenuated inflammatory responses and restored gut barrier dysfunction in mice. Mechanistically, bacterial 16S rRNA gene sequencing indicated that these three strains partially restored the overall structure of the gut microbiota disrupted by DSS. Specially, they promoted the growth of Faecalibaculum and Lactobacillus murinus, which were positively correlated with gut barrier function, while suppressing Odoribacter, Rikenella, Oscillibacter and Parasutterella, which were related to inflammation. Additionally, these strains modulated the composition of short chain fatty acids (SCFAs) in the cecal content, leading to an increase in acetate and a decrease in butyrate. Furthermore, the expression of metabolites related receptors, such as receptor G Protein-coupled receptor (GPR) 43, were also affected. Notably, the depletion of endogenous gut microbiota using broad-spectrum antibiotics completely abrogated these protective effects. CONCLUSIONS: Our findings suggest that selected human-derived bacterial strains alleviate experimental colitis and intestinal barrier dysfunction through mediating resident gut microbiota and their metabolites in mice. This study provides valuable insights into the potential therapeutic application of probiotics in the treatment of colitis.

Attenuated replication and damaging effects of SARS-CoV-2 Omicron variants in an intestinal epithelial barrier model.

Many COVID-19 patients suffer from gastrointestinal symptoms and impaired intestinal barrier function is thought to play a key role in Long COVID. Despite its importance, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on intestinal epithelia is poorly understood. To address this, we established an intestinal barrier model integrating epithelial Caco-2 cells, mucus-secreting HT29 cells and Raji cells. This gut epithelial model allows efficient differentiation of Caco-2 cells into microfold-like cells, faithfully mimics intestinal barrier function, and is highly permissive to SARS-CoV-2 infection. Early strains of SARS-CoV-2 and the Delta variant replicated with high efficiency, severely disrupted barrier function, and depleted tight junction proteins, such as claudin-1, occludin, and ZO-1. In comparison, Omicron subvariants also depleted ZO-1 from tight junctions but had fewer damaging effects on mucosal integrity and barrier function. Remdesivir, the fusion inhibitor EK1 and the transmembrane serine protease 2 inhibitor Camostat inhibited SARS-CoV-2 replication and thus epithelial barrier damage, while the Cathepsin inhibitor E64d was ineffective. Our results support that SARS-CoV-2 disrupts intestinal barrier function but further suggest that circulating Omicron variants are less damaging than earlier viral strains.

Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia and CRC development.

The role of fiber in modulating plant protein-induced metabolic responses.

The rising consumption of plant protein foods and the emergence of meat alternatives have prompted interest in the health benefits of such products, which contain fiber in addition to protein. This review investigates the effect of fiber on plant-based protein metabolism and evaluates its contribution to gut-derived health impacts. Plant proteins, which often come with added fiber, can have varying health outcomes. Factors such as processing and the presence of fiber and starch influence the digestibility of plant proteins, potentially leading to increased proteolytic fermentation in the gut and the production of harmful metabolites. However, fermentable fiber can counteract this effect by serving as a primary substrate for gut microbes, decreasing proteolytic activity. The increased amount of fiber, rather than the protein source itself, plays a significant role in the observed health benefits of plant-based diets in human studies. Differences between extrinsic and intrinsic fiber in the food matrix further impact protein fermentation and digestibility. Thus, in novel protein products without naturally occurring fiber, the health impact may differ from conventional plant protein sources. The influence of various fibers on plant-based protein metabolism throughout the gastrointestinal tract is not fully understood, necessitating further research.

Ultra-processed foods, allergy outcomes and underlying mechanisms in children: An EAACI task force report.

BACKGROUND: Consumption of ultra-processed foods [UPFs] may be associated with negative health outcomes. Limited data exist regarding the potential role of UPFs in the occurrence of allergic diseases. The underlying mechanisms underpinning any such associations are also poorly elucidated. METHODS: We performed a systematic review and narrative evidence synthesis of the available literature to assess associations between UPF consumption and pediatric allergy outcomes (n = 26 papers), including data on the association seen with the gut microbiome (n = 16 papers) or immune system (n = 3 papers) structure and function following PRISMA guidelines. RESULTS: Dietary exposure to fructose, carbonated soft drinks, and sugar intake was associated with an increased risk of asthma, allergic rhinitis, and food allergies in children. Commercial baby food intake was associated with childhood food allergy. Childhood intake of fructose, fruit juices, sugar-sweetened beverages, high carbohydrate UPFs, monosodium glutamate, UPFs, and advanced glycated end-products (AGEs) was associated with the occurrence of allergic diseases. Exposure to UPFs and common ingredients in UPFs seem to be associated with increased occurrence of allergic diseases such as asthma, wheezing, food allergies, atopic dermatitis, and allergic rhinitis, in many, but not all studies. CONCLUSION: More preclinical and clinical studies are required to better define the link between UPF consumption and the risk of allergies and asthma. These observational studies ideally require supporting data with clearly defined UPF consumption, validated dietary measures, and mechanistic assessments to definitively link UPFs with the risk of allergies and asthma.

The Leaky Gut and Human Diseases: "Can't Fill the Cup if You Don't Plug the Holes First".

BACKGROUND: The gut barrier is a sophisticated and dynamic system that forms the frontline defense between the external environment and the body's internal milieu and includes various structural and functional components engaged not only in digestion and nutrient absorption but also in immune regulation and overall health maintenance. SUMMARY: When one or more components of the intestinal barrier lose their structure and escape their function, this may result in a leaky gut. Mounting evidence emphasizes the crucial role of the gut microbiome in preserving the integrity of the gut barrier and provides insights into the pathophysiological implications of conditions related to leaky gut in humans. Assessment of intestinal permeability has evolved from invasive techniques to noninvasive biomarkers, but challenges remain in achieving consensus about the best testing methods and their accuracy. Research on the modulation of gut permeability is just starting, and although no medical guidelines for the treatment of leaky gut syndrome are available, several treatment strategies are under investigation with promising results. KEY MESSAGES: This review discusses the composition of the intestinal barrier, the pathophysiology of the leaky gut and its implications on human health, the measurement of intestinal permeability, and the therapeutic strategies to restore gut barrier integrity.

Vitamin D3 supplementation shapes the composition of gut microbiota and improves some obesity parameters induced by high-fat diet in mice.

PURPOSE: Individuals with vitamin D (VD) insufficiency have a greater tendency to develop obesity and have increased systemic inflammation. Gut microbiota are involved in the regulation of host inflammation and energy metabolism, which plays a role in the pathogenesis of obesity. Thus, we aimed to evaluate the effects of different doses of VD3 on body weight, serum lipids, inflammatory factors, and intestinal barrier function in obese mice and to explore the regulatory effect of VD3 on gut microbiota in obese mice. METHODS: Male C57BL/6 J mice received a normal chow diet (NCD, 10% fat) or high-fat diet (HFD, 60% fat) to induce obesity within 10 weeks. Then, HFD mice were supplemented with 5650, 8475, or 11,300 IU VD3/kg diet for 8 weeks. Finally, 16 s rRNA analysis was performed to analyze gut microbiota composition in cecal contents. In addition, body weight, serum lipids, inflammatory factors, and intestinal barrier function were analyzed. RESULTS: VD3 supplementation reduced body weight and the levels of TG, TC, HDL-C, TNF-α, IL-1ß and LPS, and increased ZO-1 in HFD-fed mice. Moreover, it increased α-diversity, reduced F/B ratio and altered microbiota composition by increasing relative abundance of Bacteroidetes, Proteobacteria, Desulfovibrio, Dehalobacterium, Odoribacter, and Parabacteroides and reducing relative abundance of Firmicutes and Ruminococcus. There were significant differences between HFD and NCD groups in several metabolic pathways, including endotoxin biosynthesis, tricarboxylic acid cycle, lipid synthesis and metabolism, and glycolysis. CONCLUSIONS: Low, medium, and high doses of VD3 inhibited weight gain, reduced levels of blood lipids and inflammatory factors, and improved endotoxemia and gut barrier function in obese mice. It also increased the α-diversity of gut microbiota in obese mice and reduced the relative abundance of some intestinal pathogenic bacteria, increased the relative abundance of some beneficial bacteria, and corrected the intestinal flora disorder of obese mice, with the low- and high-dose groups showing better effects than the medium-dose group.

Baicalin ameliorates the gut barrier function and intestinal microbiota of broiler chickens.

The deoxynivalenol (DON)-contaminated feeds can impair chicken gut barrier function, disturb the balance of the intestinal microbiota, decrease chicken growth performance and cause major economic loss. With the aim of investigating the ameliorating effects of baicalin on broiler intestinal barrier damage and gut microbiota dysbiosis induced by DON, a total of 150 Arbor Acres broilers are used in the present study. The morphological damage to the duodenum, jejunum, and ileum caused by DON is reversed by treatment with different doses of baicalin, and the expression of tight junction proteins (ZO-1, claudin-1, and occludin) is also significantly increased in the baicalin-treated groups. Moreover, the disturbance of the intestinal microbiota caused by DON-contaminated feed is altered by baicalin treatment. In particular, compared with those in the DON group, the relative abundances of Lactobacillus, Lachnoclostridium, Ruminiclostridium and other beneficial microbes in the baicalin-treated groups are significantly greater. However, the percentage of unclassified_f__Lachnospiraceae in the baicalin-treated groups is significantly decreased in the DON group. Overall, the current results demonstrate that different doses of baicalin can improve broiler intestinal barrier function and the ameliorating effects on broiler intestinal barrier damage may be related to modulations of the intestinal microbiota.

Macrophages and Gut Barrier Function: Guardians of Gastrointestinal Health in Post-Inflammatory and Post-Infection Responses.

The gut barrier is essential for protection against pathogens and maintaining homeostasis. Macrophages are key players in the immune system, are indispensable for intestinal health, and contribute to immune defense and repair mechanisms. Understanding the multifaceted roles of macrophages can provide critical insights into maintaining and restoring gastrointestinal (GI) health. This review explores the essential role of macrophages in maintaining the gut barrier function and their contribution to post-inflammatory and post-infectious responses in the gut. Macrophages significantly contribute to gut barrier integrity through epithelial repair, immune modulation, and interactions with gut microbiota. They demonstrate active plasticity by switching phenotypes to resolve inflammation, facilitate tissue repair, and regulate microbial populations following an infection or inflammation. In addition, tissue-resident (M2) and infiltration (M1) macrophages convert to each other in gut problems such as IBS and IBD via major signaling pathways mediated by NF-κB, JAK/STAT, PI3K/AKT, MAPK, Toll-like receptors, and specific microRNAs such as miR-155, miR-29, miR-146a, and miR-199, which may be good targets for new therapeutic approaches. Future research should focus on elucidating the detailed molecular mechanisms and developing personalized therapeutic approaches to fully harness the potential of macrophages to maintain and restore intestinal permeability and gut health.

Upregulation of Insulin-like Growth Factor-I in Response to Chemotherapy in Children with Acute Lymphoblastic Leukemia.

The treatment of childhood cancer is challenged by toxic side effects mainly due to chemotherapy-induced organ damage and infections, which are accompanied by severe systemic inflammation. Insulin-like growth factor I (IGF-I) is a key regulating factor in tissue repair. This study investigated associations between the circulating IGF-I levels and chemotherapy-related toxicity in pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we included 114 patients (age: 1-17 years) with newly diagnosed ALL treated according to The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2013 and 2018. The patients' plasma levels of IGF-I, and the primary binding protein, IGFBP-3, were measured weekly during the first six weeks of treatment, including the induction therapy. The patients' systemic inflammation was monitored by their C-reactive protein (CRP) and interleukin (IL)-6 levels and their intestinal epithelial damage by their plasma citrulline levels. IGF-I and IGFBP-3 were converted into sex-and age-adjusted standard deviation scores (SDS) using 1621 healthy children as reference. At ALL diagnosis, IGF-I levels were decreased (median (quartiles): -1.2 SDS (-1.9 to -0.5), p = 0.001), but increased significantly following the initiation of chemotherapy, peaking on day 8 (0.0 SDS (from -0.8 to 0.7), p < 0.001). This increase correlated with the levels of CRP (rho = 0.37, p < 0.001) and IL-6 (rho = 0.39, p = 0.03) on day 15, when these markers reached maximum levels. A larger IGF-I increase from day 1 to 15 correlated with a slower recovery rate of the intestinal damage marker citrulline from day 15 to 29 (rho = -0.28, p = 0.01). Likewise, IGFBP-3 was reduced at diagnosis, followed by an increase after treatment initiation, and was highly correlated with same-day IGF-I levels. This study demonstrates a chemotherapy-induced increase in IGF-I, with a response that appears to reflect the severity of tissue damage and systemic inflammation, preceding CRP and IL-6 increases. IGF-I may have potential as an early reactive biomarker for acute toxicity in patients with ALL.

Capsaicin Reduces Obesity by Reducing Chronic Low-Grade Inflammation.

Chronic low-grade inflammation (CLGI) is associated with obesity and is one of its pathogenetic mechanisms. Lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls, is the principal cause of CLGI. Studies have found that capsaicin significantly reduces the relative abundance of LPS-producing bacteria. In the present study, TRPV1-knockout (TRPV1-/-) C57BL/6J mice and the intestinal epithelial cell line Caco-2 (TRPV1-/-) were used as models to determine the effect of capsaicin on CLGI and elucidate the mechanism by which it mediates weight loss in vivo and in vitro. We found that the intragastric administration of capsaicin significantly blunted increases in body weight, food intake, blood lipid, and blood glucose in TRPV1-/- mice fed a high-fat diet, suggesting an anti-obesity effect of capsaicin. Capsaicin reduced LPS levels in the intestine by reducing the relative abundance of Proteobacteria such as Helicobacter, Desulfovibrio, and Sutterella. Toll-like receptor 4 (TLR4) levels decreased following decreases in LPS levels. Then, the local inflammation of the intestine was reduced by reducing the expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6 mediated by TLR4. Attenuating local intestinal inflammation led to the increased expression of tight junction proteins zonula occludens 1 (ZO-1) and occludin and the restoration of the intestinal barrier function. Capsaicin increased the expression of ZO-1 and occludin at the transcriptional and translational levels, thereby increasing trans-endothelial electrical resistance and restoring intestinal barrier function. The restoration of intestinal barrier function decreases intestinal permeability, which reduces the concentration of LPS entering the circulation, and reduced endotoxemia leads to decreased serum concentrations of inflammatory cytokines such as TNF-α and IL-6, thereby attenuating CLGI. This study sheds light on the anti-obesity effect of capsaicin and its mechanism by reducing CLGI, increasing our understanding of the anti-obesity effects of capsaicin. It has been confirmed that capsaicin can stimulate the expression of intestinal transmembrane protein ZO-1 and cytoplasmic protein occludin, increase the trans-epithelial electrical resistance value, and repair intestinal barrier function.