(Epi)catechin damage effects on the development of mouse intestinal epithelial structure through the PERK-eIF2α-ATF4-CHOP pathway.

As powerful bioactive compounds found in a variety of plant-based foods, (epi)catechins have been identified to be associated with an abundant array of health benefits. While their adverse impacts have also been gaining increasing attention, their intestinal impact is still unclear. In this study, intestinal organoids were used as an in vitro model to analyze the effects of four (epi)catechins on the development of the intestinal epithelial structure. Morphological characteristics, oxidative stress, and endoplasmic reticulum (ER) stress assays with (epi)catechins treatment showed that (epi)catechins promoted intestinal epithelial apoptosis and stress response. These effects had dose-dependent and structural differences (EGCG > EGC > ECG > EC). Furthermore, GSK2606414, a protein kinase RNA (PKR)-like ER kinase (PERK) pathway inhibitor, confirmed that the PERK-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4)-C/EBP-homologous protein (CHOP) pathway is closely related to the damage. In addition, the results for the intestinal inflammatory mouse model further verified that (epi)catechins significantly delayed intestinal repair. Taken together, these findings revealed that overdosage of (epi)catechins has damage potential on the intestinal epithelium and may increase the risk of intestinal damage.

Statin Therapy Induces Gut Leakage and Neuromuscular Disjunction in Patients With Chronic Heart Failure.

ABSTRACT: Statins are commonly used to limit the risk of cardiovascular diseases, including ischemic heart attack and stroke. However, treatment often leads to myopathy and muscle weakness. Therefore, a better understanding of underlying pathomechanism is needed to improve the clinical outcomes. Here, we assessed the physical performance, including handgrip strength (HGS), gait speed (GS), and short physical performance battery, in 172 patients diagnosed with chronic heart failure (CHF) treated with (n = 50) or without (n = 122) statin and 59 controls. The plasma biomarkers, including sarcopenia marker C-terminal agrin fragment-22 (CAF22), intestinal barrier integrity marker zonulin, and C-reactive protein (CRP), were measured and correlated with the physical performance of patients. The HGS, short physical performance battery scores, and GS were significantly compromised in patients with CHF versus controls. Irrespective of etiology, significant elevation of plasma CAF22, zonulin, and CRP was observed in patients with CHF. There were strong inverse correlations of CAF22 with HGS (r 2 = 0.34, P < 0.0001), short physical performance battery scores (r 2 = 0.08, P = 0.0001), and GS (r 2 = 0.143, P < 0.0001). Strikingly, CAF22 and zonulin were positively correlated with each other (r 2 = 0.10, P = 0.0002) and with the level of CRP in patients with CHF. Further investigations revealed a significant induction of CAF22, zonulin, and CRP in patients with CHF taking statin versus nonstatin group. Consistently, HGS and GS were significantly lower in the statin versus nonstatin CHF patients' group. Collectively, statin therapy adversely affects the neuromuscular junction and intestinal barrier, which potentially induces systemic inflammation and physical disability in patients with CHF. Further prospective confirmation of the findings is required in a well-controlled study.

A polysaccharide from Rosa roxburghii Tratt fruit attenuates high-fat diet-induced intestinal barrier dysfunction and inflammation in mice by modulating the gut microbiota.

Obesity-induced colonic inflammation-stimulated colitis is one of the main causes of colorectal cancer. Dietary polysaccharides are considered an effective agent for relieving obesity-induced inflammatory diseases such as diabetes and colitis. In this work, the protective effects of a polysaccharide (RTFP) extracted from Rosa roxburghii Tratt fruit on barrier dysfunction and inflammation were investigated using obesity-induced colitis model mice. RTFP treatment repaired intestinal barrier dysfunction by increasing the expression of tight junction proteins (ZO-1, claudin-1, and occludin) and reducing the levels of inflammatory cytokines, intestinal permeability, and colonic oxidative stress in mice fed a high-fat diet. Most significantly, RTFP decreased gut inflammation and ameliorated the metabolic dysbiosis of intestinal microflora by decreasing the Firmicutes/Bacteroidetes ratio, reducing the levels of serum D-lactic acid and lipopolysaccharides, and inhibiting the TLR4/NF-κB signaling pathway. Furthermore, RTFP significantly increased the abundance of beneficial bacteria (Ruminococcaceae, Muribaculaceae, Akkermansiaceae, etc.) but decreased the abundance of pathogenic bacteria. These findings indicate that RTFP can be used as a natural anti-inflammatory agent to reduce chronic obesity-induced colitis.

The Zonulin-transgenic mouse displays behavioral alterations ameliorated via depletion of the gut microbiota.

The gut-brain axis hypothesis suggests that interactions in the intestinal milieu are critically involved in regulating brain function. Several studies point to a gut-microbiota-brain connection linking an impaired intestinal barrier and altered gut microbiota composition to neurological disorders involving neuroinflammation. Increased gut permeability allows luminal antigens to cross the gut epithelium, and via the blood stream and an impaired blood-brain barrier (BBB) enters the brain impacting its function. Pre-haptoglobin 2 (pHP2), the precursor protein to mature HP2, is the first characterized member of the zonulin family of structurally related proteins. pHP 2 has been identified in humans as the thus far only endogenous regulator of epithelial and endothelial tight junctions (TJs). We have leveraged the Zonulin-transgenic mouse (Ztm) that expresses a murine pHP2 (zonulin) to determine the role of increased gut permeability and its synergy with a dysbiotic intestinal microbiota on brain function and behavior. Here we show that Ztm mice display sex-dependent behavioral abnormalities accompanied by altered gene expression of BBB TJs and increased expression of brain inflammatory genes. Antibiotic depletion of the gut microbiota in Ztm mice downregulated brain inflammatory markers ameliorating some anxiety-like behavior. Overall, we show that zonulin-dependent alterations in gut permeability and dysbiosis of the gut microbiota are associated with an altered BBB integrity, neuroinflammation, and behavioral changes that are partially ameliorated by microbiota depletion. Our results suggest the Ztm model as a tool for the study of the cross-talk between the microbiome/gut and the brain in the context of neurobehavioral/neuroinflammatory disorders.

Dissection of Barrier Dysfunction in Organoid-Derived Human Intestinal Epithelia Induced by Giardia duodenalis.

BACKGROUND & AIMS: The protozoa Giardia duodenalis is a major cause of gastrointestinal illness worldwide, but underlying pathophysiological mechanisms remain obscure, partly due to the absence of adequate cellular models. We aimed at overcoming these limitations and recapitulating the authentic series of pathogenic events in the primary human duodenal tissue by using the human organoid system. METHODS: We established a compartmentalized cellular transwell system with electrophysiological and barrier properties akin to duodenal mucosa and dissected the events leading to G. duodenalis-induced barrier breakdown by functional analysis of transcriptional, electrophysiological, and tight junction components. RESULTS: Organoid-derived cell layers of different donors showed a time- and parasite load-dependent leak flux indicated by collapse of the epithelial barrier upon G. duodenalis infection. Gene set enrichment analysis suggested major expression changes, including gene sets contributing to ion transport and tight junction structure. Solute carrier family 12 member 2 and cystic fibrosis transmembrane conductance regulator-dependent chloride secretion was reduced early after infection, while changes in the tight junction composition, localization, and structural organization occurred later as revealed by immunofluorescence analysis and freeze fracture electron microscopy. Functionally, barrier loss was linked to the adenosine 3',5'-cyclic monophosphate (cAMP)/protein kinase A-cAMP response element-binding protein signaling pathway. CONCLUSIONS: Data suggest a previously unknown sequence of events culminating in intestinal barrier dysfunction upon G. duodenalis infection during which alterations of cellular ion transport were followed by breakdown of the tight junctional complex and loss of epithelial integrity, events involving a cAMP/protein kinase A-cAMP response element-binding protein mechanism. These findings and the newly established organoid-derived model to study G. duodenalis infection may help to explore new options for intervening with disease and infection, in particular relevant for chronic cases of giardiasis.

Modulation of Gut Barrier Functions in Ulcerative Colitis by Hyaluronic Acid System.

The active stages of intestinal inflammation and the pathogenesis of ulcerative colitis are associated with superficial mucosal damage and intermittent wounding that leads to epithelial barrier defects and increased permeability. The standard therapeutic interventions for colitis have focused mainly on maintaining the remission levels of the disease. Nonetheless, such treatment strategies (using anti-inflammatory, immunomodulatory agents) do not address colitis' root cause, especially the mucosal damage and dysregulated intestinal barrier functions. Restoration of barrier functionality by mucosal healing or physical barrier protecting strategies shall be considered as an initial event in the disease suppression and progression. Herein, a biphasic hyaluronan (HA) enema suspension, naïve-HA systems that protect the dysregulated gut epithelium by decreasing the inflammation, permeability, and helping in maintaining the epithelial barrier integrity in the dextran sodium sulfate-induced colitis mice model is reported. Furthermore, HA-based system modulates intestinal epithelial junctional proteins and regulatory signaling pathways, resulting in attenuation of inflammation and mucosal protection. The results suggest that HA-based system can be delivered as an enema to act as a barrier protecting system for managing distal colonic inflammatory diseases, including colitis.

Mucosal Integrity Testing Can Detect Differences in the Rectums of Patients with Inflammatory Bowel Disease Compared to Controls: A Pilot Study.

BACKGROUND: While the pathogenesis of inflammatory bowel disease (IBD) is incompletely understood, disruption of epithelial integrity is suspected to play a prominent role in disease initiation and progression. Currently, there is no convenient way to measure this in vivo. AIMS: Our aim is to determine whether a mucosal integrity (MI) testing device that has been used to measure MI in the esophagus can also be used to measure barrier function in the colon during colonoscopy. METHODS: Mucosal integrity testing was measured in patients with IBD (n = 17) and controls (n = 7) during colonoscopy. During the procedure, an MI catheter was passed down the working channel of the colonoscope and placed along the mucosal wall to measure MI in the rectum, left, transverse, and right colon. In patients with IBD, MI measurements and biopsies were taken in areas which appeared inflamed when present. We then determined if there was a significant difference in MI between patients with IBD and controls. RESULTS: MI was significantly higher in the rectum of patients with IBD (CD and UC combined) versus control colons [767 (618-991) vs. 531 (418-604) ohms, P < 0.01]. There were no significant differences in MI among patients with IBD versus controls in the right, transverse, or left colon. Within the IBD group, there were no significant differences in MI between inflamed versus non-inflamed rectums. There was no correlation between quality of life scores or endoscopic severity with MI, though this study was likely underpowered to detect these differences. CONCLUSION: Rectal MI is significantly higher in patients with IBD versus controls. Future studies are needed to determine how this information can be used clinically.

Gastrointestinal tissue as a "new" target of pollution exposure.

Airborne pollution has become a leading cause of global death in industrialized cities and the exposure to environmental pollutants has been demonstrated to have adverse effects on human health. Among the pollutants, particulate matter (PM) is one of the most toxic and although its exposure has been more commonly correlated with respiratory diseases, gastrointestinal (GI) complications have also been reported as a consequence to PM exposure. Due to its composition, PM is able to exert on intestinal mucosa both direct damaging effects, (by reaching it either via direct ingestion of contaminated food and water or indirect inhalation and consequent macrophagic mucociliary clearance) and indirect ones via generation of systemic inflammation. The relationship between respiratory and GI conditions is well described by the lung-gut axis and more recently, has become even clearer during coronavirus disease 2019 (COVID-19) pandemic, when respiratory symptoms were associated with gastrointestinal conditions. This review aims at pointing out the mechanisms and the models used to evaluate PM induced GI tract damage.

Procyanidin A1 and its digestive products prevent acrylamide-induced intestinal barrier dysfunction via the MAPK-mediated MLCK pathway.

Procyanidins can alleviate small-intestine damage induced by acrylamide (ACR). However, little is known about whether procyanidins, after gastrointestinal digestion, can prevent ACR-induced intestinal barrier damage and the possible mechanism. Here, Caco-2 cells were differentiated into an intestinal epithelial cell monolayer membrane, which was stimulated with or without ACR in the presence or absence of procyanidin A1 (A1) and its digestive products (D-A1). Our findings show that both A1 and D-A1 significantly increased the transepithelial electrical resistance (TEER) value; decreased FITC-dextran 4 kDa (FITC-4 kDa) permeability, apoptosis and lactic dehydrogenase (LDH) release; and enhanced the expression of claudin-1, occludin and zonula occludens-1 (ZO-1) in ACR-induced Caco-2 cell monolayer membrane. In addition, A1 and D-A1 suppressed ACR-induced phosphorylation of mitogen-activated protein kinase (MAPK). Finally, A1 and D-A1 inhibited the myosin light chain kinase (MLCK) signaling pathway, thereby maintaining normal intestinal barrier functions, similar to the MLCK inhibitor in ACR-induced Caco-2 cell monolayer membrane. These findings indicate that A1 can alleviate ACR-induced intestinal barrier dysfunction via inhibiting the MAPK/MLCK signaling pathway, and it still has excellent inhibitory effects after digestion.

Association Between Peripheral Blood Monocyte Count and Mucosal Healing in Japanese Patients With Ulcerative Colitis.

INTRODUCTION: Monocytes play an important role in innate immunity. Some epidemiological evidence indicates an association between peripheral blood monocytes and ulcerative colitis (UC). The association between peripheral blood monocytes and mucosal healing (MH), however, remains unclear. We evaluated this issue in patients with UC. METHODS: Study subjects consisted of 272 Japanese patients with UC. Monocyte counts were taken in the morning after overnight fasting. Monocyte count was divided into tertiles based on the distribution of values among all study subjects. Information on clinical remission was obtained from medical records. MH was assessed using the Mayo endoscopic subscore. RESULTS: The mean monocyte count was 360.1 ± 155.3/mm3. Rates of clinical remission, MH, and complete MH were 61.0%, 66.2%, and 27.9%, respectively. High monocyte count was significantly inversely associated with clinical remission, MH, and complete MH (adjusted odds ratio [OR] 0.45 [95% confidence interval [CI]: 0.23-0.89], OR 0.45 [95% CI: 0.23-0.89], and OR 0.48 [95% CI: 0.23-0.97], respectively). Patients were also classified according to C-reactive protein (CRP) levels; in the low CRP group (<0.1 mg/dL), high monocyte count was independently inversely associated with complete MH but not with clinical remission or MH (OR 0.33 [95% CI: 0.10-0.92], P for trend = 0.027). In the high CRP group, there was no association between monocyte count and clinical outcomes. DISCUSSION: Our findings suggest that peripheral blood monocyte count can be used as a serum supplemental marker for MH in UC patients with low CRP levels.

The mechanism of intestinal flora dysregulation mediated by intestinal bacterial biofilm to induce constipation.

To explore mechanism of intestinal flora dysregulation promoting constipation, 60 specific pathogen-free (SPF) mice were used as research objects and were treated with constipation population fecal fluid gavage and distilled water gavage. Then, relationship between intestinal dysregulation and constipation in mice with biofilm-mediated intestinal flora was investigated in vitro. The results showed that recombinant serotonin transporter (SERT) messenger ribonucleic acid (mRNA) level of the constipation population fecal fluid gavage group and the relative expression level of SERT mRNA were 1.61 ± 0.08 and 1.49 ± 0.06, which were higher markedly than those of distilled water group (P < 0.05). The level of 5-hydroxytryptamine (5-HT) in colonic tissue of the constipation population fecal fluid gavage group was 145.36 ± 14.12 ng/mL, and the expression level of 5-HT on the surface of epithelial cells of biofilm-positive colonic tissue was 20.11 ± 2.03, which were significantly lower than those of the distilled water group, with statistical significance (P < 0.05). Besides, the microbial sequencing of fecal flora indicated that The Akk and bacteroidetes ofconstipation population fecal fluid gavage group were higher hugely than those of distilled water group (P < 0.05).In conclusion, after the occurrence of constipation, the diversity of intestinal microflora decreased, and the probiotics reduced. Iintestinal microflora dysregulation would lead to increase of SERT expression level in defecation function and intestinal motility in mice, and the decrease of 5-HT, thereby changing the intestinal movement resulting in mucosal protective barrier damage,thereby causing changes in intestinal movement and the destruction of the intestinal mucosal protective barrier, which eventually resulted in constipation. The occurrence of constipation could be improved by regulating balance of intestinal flora, increasing the diversity of flora, and reducing the genus of opportunistic pathogens.

Gold nanoparticles alleviates the lipopolysaccharide-induced intestinal epithelial barrier dysfunction.

Nanotechnology is used in the immune response manipulation to treat various human diseases. In the present study, we explored the effects of Au nanoparticles (AuNPs) on the lipopolysaccharide (LPS)-induced epithelial barrier dysfunction and inflammatory response of colonic epithelial NCM460 cells. According to the results of cell counting kit-8 and flow cytometry analysis, the viability of NCM460 cells was inhibited, and the apoptosis was increased after LPS treatment, and AuNPs reversed these changes in a dose-dependent way. The permeability was evaluated by detecting the flux of fluorescein isothiocyanate-dextran and transepithelial electrical resistance. LPS enhanced the permeability and promoted barrier dysfunction of NCM460 cells. Enzyme-linked immunosorbent sorbent assay results revealed that the concentrations of pro-inflammatory factors and nitric oxide were elevated by LPS treatment and decreased by the AuNPs. LPS aggravated the inflammatory response, which was rescued by the AuNPs. Moreover, LPS promoted the activation of the nuclear factor kappa-B and extracellular signal-regulated kinase/c-Jun NH-terminal kinase signaling pathways, which were inhibited by AuNPs.

Corrective Effect of Verbascoside on Histomorphological Differences and Oxidative Stress in Colon Mucosa of Rats in Which Colon Ischemia-Reperfusion Injury was Induced.

BACKGROUND: This study aims to show the corrective effect of verbascoside on histomorphological and biochemical differences in the colon mucosa of rats in which colon ischemia-reperfusion (I/R) injury was induced. METHODS: Fifty Sprague Dawley male rats were divided into 5 groups, of control, sham, ischemia (I), I/R, and I/R+verbascoside. Ischemia and reperfusion were applied to the suitable groups for 30 minutes and 120 minutes respectively, and 10 mg/kg verbascoside was administered intraperitoneally. Histomorphological assessment was done in the colon tissues obtained, and the goblet cells were assessed using the Alcian blue method. Proliferating cell nuclear antigen (PCNA), TUNEL, and hypoxia-induced factor 1 (HIF-1α) assays were used to assess oxidative stress with the immunohistochemical method. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), and total thiol (TT) levels were checked, for a biochemical analysis of oxidative stress. RESULTS: Compared with the I/R group, histomorphological differences were seen to be corrected in colon epithelium in the I/ R+verbascoside group. The goblet cell number increased and cell proliferation was increased, as seen with the PCNA assay; and apoptosis was decreased, as seen with the TUNEL assay. HIF-1α expression also decreased in the drug group. In the drug group, SOD, GSH-Px, TAS, and TT levels increased, but TOS, OSI, and MDA levels decreased. CONCLUSION: It was seen that verbascoside had a corrective effect on histomorphological and biochemical differences caused by I/R injury.

Psychological and Gastrointestinal Symptoms of Patients with Irritable Bowel Syndrome Undergoing a Low-FODMAP Diet: The Role of the Intestinal Barrier.

A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (LFD) improves both gastrointestinal (GI) symptoms and the psychological profile of patients with irritable bowel syndrome with diarrhea (IBS-D). The effects of 12 weeks of LFD on GI symptom and psychological profiles in relation to inflammation and the involvement of the intestinal barrier were studied in twenty IBS-D patients. The IBS Severity Scoring System, the Symptom Checklist-90-Revised, the Italian version of the 36-Item Short-Form Health Survey, the IBS-Quality of Life (QoL) questionnaire, and the Psychophysiological questionnaire were administered. The GI barrier function was assessed by sugar absorption test, the serum and fecal zonulin levels, and the serum levels of intestinal fatty-acid binding protein and diamine oxidase. Interleukins (ILs) and lipopolysaccharide (LPS) serum levels were evaluated along with dysbiosis. At the end of LFD, GI symptoms, psychological state (mainly anxiety, somatization, psychoticism, and interpersonal sensitivity), and QoL significantly improved in these patients. Simultaneously, an improvement in small intestinal permeability and intestinal mucosal integrity occurred, while IL-6, Il-10, LPS, and fermentative dysbiosis significantly decreased. The LFD can modify the immune-inflammatory features and enhance intestinal permeability and mucosal integrity, thus determining a concurrent improvement in the clinical and psychological conditions.

Short intense psychological stress induced by skydiving does not impair intestinal barrier function.

BACKGROUND AND AIM: Psychological stress has been shown to increase intestinal permeability and is associated with the development of gastrointestinal disorders. This study aimed to investigate skydiving as an alternative model to analyse the effect of acute psychological stress on intestinal barrier function. MATERIALS AND METHODS: Twenty healthy subjects participated in a tandem skydive followed by a negative control visit, of which 19 (9 females and 10 males, 25.9 ± 3.7 years) were included in the study. Intestinal permeability was assessed by a multi-sugar urinary recovery test. Sucrose recovery and lactulose/rhamnose ratio in 0-5h urine indicated gastroduodenal and small intestinal permeability, respectively, and sucralose/erythritol ratio in 5-24h urine indicated colonic permeability. Blood samples were taken to assess markers associated with barrier function. This study has been registered at ClinicalTrials.gov (NCT03644979) on August 23, 2018. RESULTS: Skydiving resulted in a significant increase in salivary cortisol levels directly after skydiving compared to the control visit. Cortisol levels were still increased two hours after landing, while cortisol levels before skydiving were not significantly different from the baseline at the control visit. Skydiving did not induce a significant increase in gastroduodenal, small intestinal or colonic permeability. There was also no significant increase in plasma intestinal and liver fatty acid-binding proteins, suggesting no damage to the enterocytes. DISCUSSION: These results show that the acute intense psychological stress induced by skydiving does not affect intestinal permeability in healthy subjects. Future models aiming to investigate the effect of stress on human intestinal barrier function should consider a more sustained exposure to the psychological stressor.

Pathophysiological Roles of Neuro-Immune Interactions between Enteric Neurons and Mucosal Mast Cells in the Gut of Food Allergy Mice.

Recently, the involvement of the nervous system in the pathology of allergic diseases has attracted increasing interest. However, the precise pathophysiological role of enteric neurons in food allergies has not been elucidated. We report the presence of functional high-affinity IgE receptors (FcεRIs) in enteric neurons. FcεRI immunoreactivities were observed in approximately 70% of cholinergic myenteric neurons from choline acetyltransferase-eGFP mice. Furthermore, stimulation by IgE-antigen elevated intracellular Ca2+ concentration in isolated myenteric neurons from normal mice, suggesting that FcεRIs are capable of activating myenteric neurons. Additionally, the morphological investigation revealed that the majority of mucosal mast cells were in close proximity to enteric nerve fibers in the colonic mucosa of food allergy mice. Next, using a newly developed coculture system of isolated myenteric neurons and mucosal-type bone-marrow-derived mast cells (mBMMCs) with a calcium imaging system, we demonstrated that the stimulation of isolated myenteric neurons by veratridine caused the activation of mBMMCs, which was suppressed by the adenosine A3 receptor antagonist MRE 3008F20. Moreover, the expression of the adenosine A3 receptor gene was detected in mBMMCs. Therefore, in conclusion, it is suggested that, through interaction with mucosal mast cells, IgE-antigen-activated myenteric neurons play a pathological role in further exacerbating the pathology of food allergy.

Targeting the gut to treat multiple sclerosis.

The gut-brain axis (GBA) refers to the complex interactions between the gut microbiota and the nervous, immune, and endocrine systems, together linking brain and gut functions. Perturbations of the GBA have been reported in people with multiple sclerosis (pwMS), suggesting a possible role in disease pathogenesis and making it a potential therapeutic target. While research in the area is still in its infancy, a number of studies revealed that pwMS are more likely to exhibit altered microbiota, altered levels of short chain fatty acids and secondary bile products, and increased intestinal permeability. However, specific microbes and metabolites identified across studies and cohorts vary greatly. Small clinical and preclinical trials in pwMS and mouse models, in which microbial composition was manipulated through the use of antibiotics, fecal microbiota transplantation, and probiotic supplements, have provided promising outcomes in preventing CNS inflammation. However, results are not always consistent, and large-scale randomized controlled trials are lacking. Herein, we give an overview of how the GBA could contribute to MS pathogenesis, examine the different approaches tested to modulate the GBA, and discuss how they may impact neuroinflammation and demyelination in the CNS.

LncRNA Bmp1 promotes the healing of intestinal mucosal lesions via the miR-128-3p/PHF6/PI3K/AKT pathway.

Intestinal mucosal injuries are directly or indirectly related to many common acute and chronic diseases. Long non-coding RNAs (lncRNAs) are expressed in many diseases, including intestinal mucosal injury. However, the relationship between lncRNAs and intestinal mucosal injury has not been determined. Here, we investigated the functions and mechanisms of action of lncRNA Bmp1 on damaged intestinal mucosa. We found that Bmp1 was increased in damaged intestinal mucosal tissue and Bmp1 overexpression was able to alleviate intestinal mucosal injury. Bmp1 overexpression was found to influence cell proliferation, colony formation, and migration in IEC-6 or HIEC-6 cells. Moreover, miR-128-3p was downregulated after Bmp1 overexpression, and upregulation of miR-128-3p reversed the effects of Bmp1 overexpression in IEC-6 cells. Phf6 was observed to be a target of miR-128-3p. Furthermore, PHF6 overexpression affected IEC-6 cells by activating PI3K/AKT signaling which was mediated by the miR-128-3p/PHF6 axis. In conclusion, Bmp1 was found to promote the expression of PHF6 through the sponge miR-128-3p, activating the PI3K/AKT signaling pathway to promote cell migration and proliferation.

Gut-brain communication and obesity: understanding functions of the vagus nerve.

Given the crucial role of the gastrointestinal tract and associated organs in handling nutrient assimilation and metabolism, it has long been known that its communication with the brain is important for the control of ingestive behavior and body weight regulation. It is also clear that gut-brain communication is bidirectional and utilizes both rapid neural and slower humoral mechanisms and pathways. However, progress in understanding these mechanisms and leveraging them for the treatment of obesity and metabolic disease has been hindered by the enormous dimension of the gut mucosa, the complexity of the signaling systems, and lack of specific tools. With the ascent of modern neurobiological technology, our understanding of the role of vagal afferents in gut-brain communication has begun to change. The first function-specific populations of vagal afferents providing nutritional feedback as well as feed-forward signals have been identified with genetics-guided methodology, and it is hoped that extension of the methodology to other neural communication pathways will follow soon. Currently, efficient clinical leveraging of gut-brain communication to treat obesity and metabolic disease is limited to a few gut hormones, but a more complete understanding of function-specific and projection-specific neuronal populations should make it possible to develop selective and more effective neuromodulation approaches.