Intestinal Bacterial Translocation Research Articles

Sclareol protected against intestinal barrier dysfunction ameliorating Crohn's disease-like colitis via Nrf2/NF-B/MLCK signalling

BackgroundInflammation-induced intestinal barrier dysfunction is not only a pathological feature of Crohn's disease (CD) but also an important therapeutic target. Sclareol (SCL) is a nontoxic natural plant compound with anti-inflammatory effect, but its role in CD has not been established. MethodsIn vivo studies of mice with TNBS-induced colitis were carried out to evaluate the effects of SCL on CD-like colitis and intestinal barrier function. In vitro, a TNF-α-induced colonic organoid model was established to test the direct effect of SCL on inflammation-induced intestinal barrier injure and inflammatory response. The Nrf2/NF-κB/MLCK signalling was analysed to explore the mechanism of SCL. ResultsIn vivo, SCL largely alleviated the colitis in TNBS mice, as evidenced by improvements in the weight loss, colitis symptoms, endoscopic score, macroscopic histological score, and histological inflammation score. Moreover, SCL significantly improved intestinal barrier dysfunction, manifested as reduced intestinal permeability and decreased intestinal bacterial translocation in TNBS mice. Importantly, SCL antagonised the intestinal mucosal inflammation while protecting tight junctions in TNBS mice. In vitro, SCL largely depressed pro-inflammatory cytokines levels and improved intestinal epithelial permeability in a TNF-α-induced colonic organoid model. In the context of CD, the protective effects of SCL against inflammation and intestinal barrier damage are at least partially results from the Nrf2 signalling activation and the NF-κB/MLCK signalling inhibition. ConclusionsSCL improved intestinal barrier dysfunction and alleviated CD-like colitis, possibly through modulation of Nrf2/NF-κB/MLCK signalling. In view of SCL's safety profile, there is hope that it will be useful in the clinic.

Obesity and polycystic ovary syndrome influence on intestinal permeability at fasting, and modify the effect of diverse macronutrients on the gut barrier

Women with the extremely prevalent polycystic ovary syndromegather multiple cardiovascular risk factors and chronic subclinical inflammation. Interactions between diet, adiposity, and gut microbiota modulate intestinal permeabilityand bacterial product translocation, and may contribute to the chronic inflammation process associated with the polycystic ovary syndrome. In the present study, we aimed to address the effects of obesity, functional hyperandrogenism, and diverse oral macronutrients on intestinal permeabilityby measuring circulating markers of gut barrier dysfunction and endotoxemia. Participants included 17 non-hyperandrogenic control women, 17 women with polycystic ovary syndrome, and 19 men that were submitted to glucose, lipid, and protein oral loads. Lipopolysaccharide-binding protein, plasma soluble CD14, succinate, zonulin family peptide, and glucagon-like peptide-2 were determined at fasting and after oral challenges. Macronutrient challenges induced diverse changes on circulating intestinal permeabilitybiomarkers in the acute postprancial period, with lipids and proteins showing the most unfavorable and favorable effects, respectively. Particularly, lipopolysaccharide-binding protein, zonulin family peptide, and glucagon-like peptide-2 responses were deregulated by the presence of obesity after glucose and lipid challenges. Obese subjects showed higher fasting intestinal permeabilitybiomarkers levels than non-obese individuals, except for plasma soluble CD14. The polycystic ovary syndromeexacerbated the effect of obesity further increasing fasting glucagon-like peptide-2, lipopolysaccharide-binding protein, and succinate concentrations. We observed specific interactions of the polycystic ovary syndromewith obesity in the postprandial response of succinate, zonulin family peptide, and glucagon-like peptide-2. In summary, obesity and polycystic ovary syndromemodify the effect of diverse macronutrients on the gut barrier, and alsoinfluence intestinal permeabilityat fasting,contributing to the morbidity of functional hyperandrogenism by inducing endotoxemia and subclinical chronic inflammation.

Ameliorative Effects of Larazotide Acetate on Intestinal Permeability and Bacterial Translocation in Acute Pancreatitis Model in Rats.

Intestinal barrier dysfunction in acute pancreatitis (AP) may progress to systemic inflammatory response syndrome (SIRS) and multi-organ failures by causing bacterial translocation. Larazotide acetate (LA) is a molecule that acts as a tight junction (TJ) regulator by blocking zonulin (Zo) receptors in the intestine. In our study, we aimed to investigate the effects of LA on intestinal barrier dysfunction and bacterial translocation in the AP model in rats. Thirty-two male Sprague-Dawley rats were divided into 4 groups; control, larazotide (LAR), AP, and AP + LAR. The AP model was created by administering 250 mg/100 g bm L-Arginine intraperitoneally 2 times with an hour interval. AP + LAR group received prophylactic 0.01 mg/mL LA orally for 7 days before the first dose of L-Arginine. For intestinal permeability analysis, fluorescein isothiocyanate-dextran (FITC-Dextran) was applied to rats by gavage. The positivity of any of the liver, small intestine mesentery, and spleen cultures were defined as bacterial translocation. Histopathologically damage and zonulin immunoreactivity in the intestine were investigated. Compared to the control group, the intestinal damage scores, anti-Zo-1 immunoreactivity H-Score, serum FITC-Dextran levels and bacterial translocation frequency (100% versus 0%) in the AP group were significantly higher (all p < 0.01). Intestinal damage scores, anti-Zo-1 immunoreactivity H-score, serum FITC-Dextran levels, and bacterial translocation frequency (50% versus 100%) were significantly lower in the AP + LAR group compared to the AP group (all p < 0.01). Our findings show that LA reduces the increased intestinal permeability and intestinal damage by its effect on Zo in the AP model in rats, and decreases the frequency of bacterial translocation as a result of these positive effects.

Comparison of Integrase Strand Transfer Inhibitors (INSTIs) and Protease-Boosted Inhibitors (PIs) on the Reduction in Chronic Immune Activation in a Virally Suppressed, Mainly Male Population Living with HIV (PLWH).

Background and Objectives: The success of combined antiretroviral therapy (cART) has led to a dramatic improvement in the life expectancy of people living with HIV (PLWH). However, there has been an observed increase in cardiometabolic, bone, renal, hepatic, and neurocognitive manifestations, as well as neoplasms, known as serious non-AIDS events/SNAEs, compared to the general population of corresponding age. This increase is linked to a harmful phenomenon called inflammaging/immunosenescence, which is driven by chronic immune activation and intestinal bacterial translocation. In this study, we examined immunological and metabolic parameters in individuals receiving current cART. Materials and Methods: The study was conducted at Laiko General Hospital in Athens, Greece. Plasma concentrations of sCD14, IL-6, SuPAR, I-FABP, and LBP were measured in virally suppressed PLWH under cART with at least 350 CD4 lymphocytes/μL. We compared these levels between PLWH receiving integrase strand transfer inhibitors (INSTIs) and protease inhibitors (PIs) and attempted to correlate them with chronic immune activation and metabolic parameters. Results: Data from 28 PLWH were analyzed, with a mean age of 52 and 93% being males. Among the two comparison groups, IL-6 levels were higher in the PIs group (5.65 vs. 7.11 pg/mL, p = 0.03). No statistically significant differences were found in the other measured parameters. A greater proportion of PLWH under INSTIs had normal-range LBP (33% vs. 0%, p = 0.04). When using inverse probability of treatment weighting, no statistically significant differences in the measured parameters were found between the two groups (sCD14 p = 0.511, IL-6 p = 0.383, SuPAR p = 0.793, I-FABP p = 0.868, and LBP p = 0.663). Glucose levels were found to increase after viral suppression in the entire sample (92 mg/dL vs. 98 mg/dL, p = 0.009). Total (191 mg/dL vs. 222 mg/dL, p = 0.005) and LDL cholesterol (104 mg/dL vs. 140 mg/dL, p = 0.002) levels were higher in the PIs group. No significant differences were observed in liver and renal function tests. Conclusions: Further investigation is warranted for PLWH on cART-containing INSTI regimens to explore potential reductions in chronic immune activation and intestinal bacterial translocation.

Liver cirrhosis and complications from the perspective of dysbiosis.

The gut-liver axis refers to the intimate relationship and rigorous interaction between the gut and the liver. The intestinal barrier's integrity is critical for maintaining liver homeostasis. The liver operates as a second firewall in this interaction, limiting the movement of potentially dangerous compounds from the gut and, as a result, contributing in barrier management. An increasing amount of evidence shows that increased intestinal permeability and subsequent bacterial translocation play a role in liver damage development. The major pathogenic causes in cirrhotic individuals include poor intestinal permeability, nutrition, and intestinal flora dysbiosis. Portal hypertension promotes intestinal permeability and bacterial translocation in advanced liver disease, increasing liver damage. Bacterial dysbiosis is closely related to the development of cirrhosis and its related complications. This article describes the potential mechanisms of dysbiosis in liver cirrhosis and related complications, such as spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis, hepatic encephalopathy, and hepatocellular carcinoma, using dysbiosis of the intestinal flora as an entry point.

Hypoxia exacerbates intestinal injury and inflammatory response mediated by myeloperoxidase during Salmonella Typhimurium infection in mice

BackgroundHigh-altitude exposure can cause oxidative stress damage in the intestine, which leads to increased intestinal permeability and bacterial translocation, resulting in local and systemic inflammation. Control of infection is critically dependent on the host’s ability to kill pathogens with reactive oxygen species (ROS). Myeloperoxidase (MPO) targets ROS in pathogens. This study aimed to investigate the effects of hypoxia on the colonic mucosal barrier and myeloperoxidase (MPO)-mediated innate immune response in the colon.Methods and ResultsGenetically engineered mice were exposed to a hypobaric oxygen chamber for 3 days and an inflammation model was established using Salmonella Typhimurium infection. We found that hypoxic exposure caused the development of exacerbated bacterial colitis and enhanced bacterial dissemination in MPO-deficient mice. Infection and disease severity were associated with significantly increased Ly6G+ neutrophil and F4/80+ macrophage counts in infected tissues, which is consistent with elevated proinflammatory cytokines and chemoattractant molecules. Hypoxia restrained antioxidant ability and MPO deficiency aggravated the respiratory burst in the colon.ConclusionHypoxia can damage the colonic mucosa. MPO mediates the innate immune response and regulates the mucosal and systemic inflammatory responses to Salmonella infection during hypoxia.

The Role of Intestinal Barrier Function in Overweight Patients with IBS with Diarrhea Undergoing a Long-Term Low Fermentable Oligo-, Di-, and Monosaccharide and Polyol Diet

Overweight and obesity have been suggested as significant factors in irritable bowel syndrome (IBS) development. However, the relationship between overweight/obesity and IBS is unclear. It is known that a modified intestinal barrier, especially the permeability of the small intestine (s-IP), can play a significant role in the pathogenesis of both obesity and IBS. Moreover, dietary interventions are essential for treating both pathologies. We evaluated the gastrointestinal (GI) symptoms and the urinary and circulating markers of GI barrier function and integrity, the markers of intestinal dysbiosis and bacterial translocation, in 40 IBS patients with predominant diarrhea (IBS-D) (32 females and 8 males; mean age = 43.5 ± 1.4 years), categorized using their Body Mass Index levels as normal (NW) and overweight (OW). Evaluations were performed before and after 12 weeks of a Low FODMAP Diet (LFD). At the baseline, OW patients showed a significantly higher s-IP than NW. After an LFD, a significant improvement of s-IP in OW patients occurred, along with a significant decrease in markers of epithelial integrity and bacterial translocation. Our findings highlight the close relationship between overweight and the intestinal barrier and support their involvement in IBS-D pathophysiology. Furthermore, the positive role of an LFD in managing overweight IBS-D was highlighted.

Unveiling the interplay between NSAID-induced dysbiosis and autoimmune liver disease in children: insights into the hidden gateway to autism spectrum disorders. Evidence from ex vivo, in vivo, and clinical studies.

Autism spectrum disorders (ASD) represent a diverse group of neuropsychiatric conditions, and recent evidence has suggested a connection between ASD and microbial dysbiosis. Immune and gastrointestinal dysfunction are associated with dysbiosis, and there are indications that modulating the microbiota could improve ASD-related behaviors. Additionally, recent findings highlighted the significant impact of microbiota on the development of autoimmune liver diseases, and the occurrence of autoimmune liver disease in children with ASD is noteworthy. In the present study, we conducted both an in vivo study and a clinical study to explore the relationship between indomethacin-induced dysbiosis, autoimmune hepatitis (AIH), and the development of ASD. Our results revealed that indomethacin administration induced intestinal dysbiosis and bacterial translocation, confirmed by microbiological analysis showing positive bacterial translocation in blood cultures. Furthermore, indomethacin administration led to disturbed intestinal permeability, evidenced by the activation of the NLRP3 inflammasomes pathway and elevation of downstream biomarkers (TLR4, IL18, caspase 1). The histological analysis supported these findings, showing widened intestinal tight junctions, decreased mucosal thickness, inflammatory cell infiltrates, and collagen deposition. Additionally, the disturbance of intestinal permeability was associated with immune activation in liver tissue and the development of AIH, as indicated by altered liver function, elevated ASMA and ANA in serum, and histological markers of autoimmune hepatitis. These results indicate that NSAID-induced intestinal dysbiosis and AIH are robust triggers for ASD existence. These findings were further confirmed by conducting a clinical study that involved children with ASD, autoimmune hepatitis (AIH), and a history of NSAID intake. Children exposed to NSAIDs in early life and complicated by dysbiosis and AIH exhibited elevated serum levels of NLRP3, IL18, liver enzymes, ASMA, ANA, JAK1, and IL6. Further, the correlation analysis demonstrated a positive relationship between the measured parameters and the severity of ASD. Our findings suggest a potential link between NSAIDs, dysbiosis-induced AIH, and the development of ASD. The identified markers hold promise as indicators for early diagnosis and prognosis of ASD. This research highlights the importance of maintaining healthy gut microbiota and supports the necessity for further investigation into the role of dysbiosis and AIH in the etiology of ASD.

Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: implications for disease-related biomarker discovery.

There is growing evidence of the significance of gastrointestinal complaints in the impairment of the intestinal mucosal barrier function and inflammation in fibromyalgia (FM) and in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, data on intestinal permeability and gut barrier dysfunction in FM and ME/CFS are still limited with conflicting results. This study aimed to assess circulating biomarkers potentially related to intestinal barrier dysfunction and bacterial translocation and their association with self-reported symptoms in these conditions. A pilot multicenter, cross-sectional cohort study with consecutive enrolment of 22 patients with FM, 30 with ME/CFS and 26 matched healthy controls. Plasma levels of anti-beta-lactoglobulin antibodies (IgG anti-β-LGB), zonulin-1 (ZO-1), lipopolysaccharides (LPS), soluble CD14 (sCD14) and interleukin-1-beta (IL-1β) were assayed using ELISA. Demographic and clinical characteristics of the participants were recorded using validated self-reported outcome measures. The diagnostic accuracy of each biomarker was assessed using the receiver operating characteristic (ROC) curve analysis. FM patients had significantly higher levels of anti-β-LGB, ZO-1, LPS, and sCD14 than healthy controls (all P < 0.0001). In ME/CFS patients, levels of anti-β-LGB, ZO-1, LPS, and sCD14 were significantly higher than controls, but lower than in FM (all P < 0.01), while there was no significant difference in IL-1β level. In the FM and ME/CFS cohorts, both anti-β-LGB and ZO-1 correlated significantly with LPS and sCD14 (P < 0.001 for both). In the FM group, both anti-β-LGB and ZO-1 were correlated significantly with physical and mental health components on the SF-36 scale (P < 0.05); whereas IL-1β negatively correlated with the COMPASS-31 score (P < 0.05). In the ME/CFS cohort, ZO-1 was positively correlated with the COMPASS-31 score (P < 0.05). The ROC curve analysis indicated a strong ability of anti-β-LGB, ZO-1, LPS and sCD14 to predictively distinguish between FM and ME/CFS from healthy controls (P < 0.0001). Biomarkers of intestinal barrier function and inflammation were associated with autonomic dysfunction assessed by COMPASS-31 scores in FM and ME/CFS respectively. Anti-β-LGB antibodies, ZO-1, LPS, and sCD14 may be putative predictors of intestinal barrier dysfunction in these cohorts. Further studies are needed to assess whether these findings are causal and can therefore be applied in clinical practice.

The Role of Short-Chain Fatty Acids in Acute Pancreatitis

Acute pancreatitis (AP) is a digestive emergency and can develop into a systematic illness. The role of the gut in the progression and deterioration of AP has drawn much attention from researchers, and areas of interest include dysbiosis of the intestinal flora, weakened intestinal barrier function, and bacterial and endotoxin translocation. Short-chain fatty acids (SCFAs), as one of the metabolites of gut microbiota, have been proven to be depleted in AP patients. SCFAs help restore gut homeostasis by rebuilding gut flora, stabilizing the intestinal epithelial barrier, and regulating inflammation. SCFAs can also suppress systematic inflammatory responses, improve the injured pancreas, and prevent and protect other organ dysfunctions. Based on multiple beneficial effects, increasing SCFAs is an essential idea of gut protective treatment in AP. Specific strategies include the direct use of butyrate or indirect supplementation through fiber, pre/pro/synbiotics, or fecal microbiota transplantation as a promising adjective therapy to enteral nutrition.

Effect of high-refined carbohydrate diet on intestinal integrity

ObjectivesOne of the leading causes of obesity is the consumption of excess nutrients. Obesity is characterized by adipose tissue expansion, chronic low-grade inflammation, and metabolic alterations. Although consumption of a high-fat diet has been demonstrated to be a diet-induced obesity model associated with gut disorders, the same effect is not well explored in a mild-obesity model induced by high-refined carbohydrate (HC) diet intake. The intestinal tract barrier comprises mucus, epithelial cells, tight junctions, immune cells, and gut microbiota. This system is susceptible to dysfunction by excess dietary components that could increase intestinal permeability and bacterial translocation. The aim of this study was to evaluate whether an HC diet and the alterations resulting from its intake are linked to small intestine changes. MethodsMale BALB/c mice were fed a chow or an HC diet for 8 wk. ResultsAlthough differences in body weight gain were not observed between the groups, mice fed the HC diet showed increased adiposity associated with metabolic alterations. The interferon-γ expression and myeloperoxidase levels were increased in the small intestine in mice fed an HC diet. However, the intestinal villi length, the expression of tight junctions (zonula occludens-1 and claudin-4) and tumor necrosis factor-α cytokine, and the percentage of intraepithelial lymphocytes did not differ in the jejunum or ileum between the groups. We did not observe differences in intestinal permeability and bacterial translocation. ConclusionMetabolic alterations caused by consumption of an HC diet lead to a mild obesity state that does not necessarily involve significant changes in intestinal integrity.

Bile acid dysmetabolism in inflammatory bowel diseases

Aim: To summarize the state-of-the-art data on the molecular mechanisms of bile acid (BA) synthesis and absorption, their impaired absorption and receptor-dependent signaling, as well as on the effects of the gut microbiota on BA metabolism in inflammatory bowel diseases (IBD).&#x0D; Key messages: BA malabsorption is one of the relevant mechanisms in the development of diarrhea in IBD. It may occur due to various disorders of the ileum, such as terminal ileitis, ileocolitis or ileocecal resection in Crohn's disease and ileoanal reservoir in ulcerative colitis. Molecular mechanisms of BA malabsorption in IBD are related to a defect in the BA uptake by the apical sodium dependent bile acid transporter (ASBT), as well as to a decrease in the expression of pregnane X receptor (PXR) and farnesoid X receptor (FXR), whose activation by glucocorticoids results in an increase in the BA reabsorption in the ileum and a decrease in hologenic diarrhea. The metabolic profile of luminal BA in IBD is characterized by an increased content of conjugated and 3-OH-sulfated BA and reduced levels of secondary BA. The decrease in the relative abundance of the Lachnospiraceae and Oscillospiraceae spp. in IBD patients leads to a decrease in the efficiency of microbial biotransformation of BA. Changes in the BA metabolic profile in IBD affect the gut microbiota, and impaired interaction with the FXR, PXR, G protein-coupled bile acid receptor (GPBAR1), retinoid-related orphan receptors (RORs) and vitamin D receptor (VDR) results in a pro-inflammatory response and increased intestinal permeability, bacterial translocation, and IBD progression. BA metabolism in IBD-associated primary sclerosing cholangitis (PSC-IBD) is characterized by a significant decrease in the luminal BA pool, and the microbiota composition is remarkable for an increase in the relative abundance of Fusobacterium and Ruminococcus spp., and a decrease in Veillonella, Dorea, Blautia, Lachnospira and Roseburia.&#x0D; Conclusion: Disordered synergistic interplay of BA with intestinal microbiota results in disruption of the ligand-receptor interaction and BA metabolic transformation, which contributes to the activation of the immune system, formation of a vicious circle of chronic inflammation and IBD progression. Further studies into mutual influence of the gut microbiota, BA metabolism and receptor signaling may promote the development of new methods for the diagnosis and treatment of IBD.

Bryostatin-1 attenuates intestinal ischemia/reperfusion-induced intestinal barrier dysfunction, inflammation, and oxidative stress via activation of Nrf2/HO-1 signaling.

Bryostatin-1 (Bryo-1) exerts antioxidative stress effects in multiple diseases, and we confirmed that it improves intestinal barrier dysfunction in experimental colitis. Nevertheless, there are few reports on its action on intestinal ischemia/reperfusion (I/R). In this study, we mainly explored the effect of Bryo-1 on intestinal I/R injury and determined the mechanism. C57BL/6J mice underwent temporary superior mesenteric artery (SMA) obturation to induce I/R, on the contrary, Caco-2 cells suffered to oxygen and glucose deprivation/reperfusion (OGD/R) to establish the in vitro model. RAW264.7 cells were stimulated with LPS to induce macrophage inflammation. The drug gradient experiment was used to demonstrate in vivo and in vitro models. Bryo-1 ameliorated the intestinal I/R-induced injury of multiple organs and epithelial cells. It also alleviated intestinal I/R-induced barrier disruption of intestines according to the histology, intestinal permeability, intestinal bacterial translocation rates, and tight junction protein expression results. Bryo-1 significantly inhibited oxidative stress damages and inflammation, which may contribute to the restoration of intestinal barrier function. Further, Bryo-1 significantly activated Nrf2/HO-1 signaling in vivo. However, the deletion of Nrf2 in Caco-2 and RAW264.7 cells attenuated the protective functions of Bryo-1 and significantly abolished the anti-inflammatory effect of Bryo-1 on LPS-induced macrophage inflammation. Bryo-1 protects intestines against I/R-induced injury. It is associated with intestinal barrier protection, as well as inhibition of inflammation and oxidative stress partly through Nrf2/HO-1 signaling.

Jinhong decoction protects sepsis-associated acute lung injury by reducing intestinal bacterial translocation and improving gut microbial homeostasis.

Background: Currently no specific treatments are available for sepsis and the associated syndromes including acute lung injury (ALI). Jinhong Decoction (JHD) is a traditional Chinese prescription, and it has been applied clinically as an efficient and safe treatment for sepsis, but the underlying mechanism remains unknown. The aim of the study was to explore the potential mechanisms of JHD ameliorating sepsis and concurrent ALI. Methods: The cecum ligation puncture (CLP)- induced murine sepsis model was established for determining the efficacy of JHD protecting CLP and ALI. The role of gut microbiota involved in the efficacy of JHD was evaluated by 16S rRNA sequencing and fecal microbiota transplantation (FMT). Translocation of intestinal Escherichia coli (E. coli) to lungs after CLP was verified by qPCR and in vivo-imaging. Intestinal permeability was analyzed by detecting FITC-dextran leakness. Junction proteins were evaluated by Western blotting and immunofluorescence. Results: JHD treatment remarkably increased survival rate of septic mice and alleviated sepsis-associated lung inflammation and injury. FMT suggested that the protective role for JHD was mediated through the regulation of gut microbiota. We further revealed that JHD administration partially restored the diversity and configuration of microbiome that was distorted by CLP operation. Of interest, the intestinal bacteria, E. coli particularly, was found to translocate into the lungs upon CLP via disrupting the intestinal mucosal barrier, leading to the inflammatory response and tissue damage in lungs. JHD impeded the migration and hence lung accumulation of intestinal E. coli, and thereby prevented severe ALI associated with sepsis. This effect is causatively related with the ability of JHD to restore intestinal barrier by up-regulating tight junctions. Conclusion: Our study unveils a mechanism whereby the migration of gut bacteria leads to sepsis-associated ALI, and we demonstrate the potential of JHD as an effective strategy to block this bacterial migration for treating sepsis and the associated immunopathology in the distal organs.

Multifaceted involvements of Paneth cells in various diseases within intestine and systemically.

Serving as the guardians of small intestine, Paneth cells (PCs) play an important role in intestinal homeostasis maintenance. Although PCs uniquely exist in intestine under homeostasis, the dysfunction of PCs is involved in various diseases not only in intestine but also in extraintestinal organs, suggesting the systemic importance of PCs. The mechanisms under the participation of PCs in these diseases are multiple as well. The involvements of PCs are mostly characterized by limiting intestinal bacterial translocation in necrotizing enterocolitis, liver disease, acute pancreatitis and graft-vs-host disease. Risk genes in PCs render intestine susceptible to Crohn's disease. In intestinal infection, different pathogens induce varied responses in PCs, and toll-like receptor ligands on bacterial surface trigger the degranulation of PCs. The increased level of bile acid dramatically impairs PCs in obesity. PCs can inhibit virus entry and promote intestinal regeneration to alleviate COVID-19. On the contrary, abundant IL-17A in PCs aggravates multi-organ injury in ischemia/reperfusion. The pro-angiogenic effect of PCs aggravates the severity of portal hypertension. Therapeutic strategies targeting PCs mainly include PC protection, PC-derived inflammatory cytokine elimination, and substituting AMP treatment. In this review, we discuss the influence and importance of Paneth cells in both intestinal and extraintestinal diseases as reported so far, as well as the potential therapeutic strategies targeting PCs.

Small Intestinal Bacterial Overgrowth and Non-Alcoholic Fatty Liver Disease: What Do We Know in 2023?

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with the pathological accumulation of lipids inside hepatocytes. Untreated NAFL can progress to non-alcoholic hepatitis (NASH), followed by fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The common denominator of the above-mentioned metabolic disorders seems to be insulin resistance, which occurs in NAFLD patients. Obesity is the greatest risk factor for lipid accumulation inside hepatocytes, but a part of the NAFLD patient population has a normal body weight according to the BMI index. Obese people with or without NAFLD have a higher incidence of small intestinal bacterial overgrowth (SIBO), and those suffering from NAFLD show increased intestinal permeability, including a more frequent presence of bacterial overgrowth in the small intestine (SIBO). The health consequences of SIBO are primarily malabsorption disorders (vitamin B12, iron, choline, fats, carbohydrates and proteins) and bile salt deconjugation. Undetected and untreated SIBO may lead to nutrient and/or energy malnutrition, thus directly impairing liver function (e.g., folic acid and choline deficiency). However, whether SIBO contributes to liver dysfunction, decreased intestinal barrier integrity, increased inflammation, endotoxemia and bacterial translocation is not yet clear. In this review, we focus on gut-liver axis and discuss critical points, novel insights and the role of nutrition, lifestyle, pre- and probiotics, medication and supplements in the therapy and prevention of both SIBO and NAFLD.

Expression profile of microRNAs related with viral infectivity, inflammatory response, and immune activation in people living with HIV

To evaluate the serum expression of microRNAs (miRNAs) with ability to modulate the human immunodeficiency (HIV) replication or inflammatory status in people living with HIV (PLWH). Forty healthy controls and two groups of PLWH were evaluated: (a) Group 1 (n = 30), patients with detectable viral load at inclusion, analyzed before receiving antiretroviral therapy (ART) and 12 months after initiating it; (b) Group 2 (n = 55), PLWH with prolonged undetectable viral load. Intestinal barrier disruption (I-FABP) and bacterial translocation (16S rDNA) markers, inflammatory markers such as interleukin (IL)-6 and sCD163, immune activation and expression of specific miRNAs were evaluated. Serum concentrations of I-FABP, 16S rDNA, IL-6, sCD163 and activated T lymphocytes were increased in PLWH. Serum miR-34a was overexpressed at inclusion and remained elevated after ART. The expression of the remaining miRNAs that modulate HIV infectivity (miR-7, mir-29a, miR-150, and miR-223) was similar in PLWH and controls. Related to miRNAs implicated in inflammation (miR-21, miR-155, and miR-210), significant overexpression were observed in miR-21 and miR-210 levels in untreated PLWH, but levels were restored in those patients treated for a long period. A sustained overexpression of miR-34a was detected even after prolonged HIV controlled replication. miR-21 and miR-210 can be considered new markers of inflammation with high sensitivity to its modifications.

Outcomes of beta blocker use in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors.

In patients with cirrhosis, portal hypertension increases intestinal permeability, dysbiosis, and bacterial translocation, promoting an inflammatory state that can lead to the progression of liver disease and development of hepatocellular carcinoma (HCC). We aimed to investigate whether beta blockers (BBs), which can mediate portal hypertension, conferred survival benefits in patients treated with immune checkpoint inhibitors (ICIs). We conducted a retrospective, observational study of 578 patients with unresectable HCC treated with ICI from 2017 to 2019 at 13 institutions across three continents. BB use was defined as exposure to BBs at any time during ICI therapy. The primary objective was to assess the association of BB exposure with overall survival (OS). Secondary objectives were to evaluate the association of BB use with progression-free survival (PFS) and objective response rate (ORR) according to RECIST 1.1 criteria. In our study cohort, 203 (35%) patients used BBs at any point during ICI therapy. Of these, 51% were taking a nonselective BB. BB use was not significantly correlated with OS (hazard ratio [HR] 1.12, 95% CI 0.9-1.39, P = 0.298), PFS (HR 1.02, 95% CI 0.83-1.26, P = 0.844) or ORR (odds ratio [OR] 0.84, 95% CI 0.54-1.31, P = 0.451) in univariate or multivariate analyses. BB use was also not associated with incidence of adverse events (OR 1.38, 95% CI 0.96-1.97, P = 0.079). Specifically, nonselective BB use was not correlated with OS (HR 0.94, 95% CI 0.66-1.33, P = 0.721), PFS (HR 0.92, 0.66-1.29, P = 0.629), ORR (OR 1.20, 95% CI 0.58-2.49, P = 0.623), or rate of adverse events (OR 0.82, 95% CI 0.46-1.47, P = 0.510). In this real-world population of patients with unresectable HCC treated with immunotherapy, BB use was not associated with OS, PFS or ORR.

The Microbiota-Dependent Worsening Effects of Melatonin on Gut Inflammation

Dysbiosis and disturbances in gut homeostasis may result in dysregulated responses, which are common in inflammatory bowel diseases (IBD). These conditions may be refractory to the usual treatments and novel therapies are still necessary to reach a more successful regulation of intestinal immunity. The hormone melatonin (MLT) has been raised as a therapeutic alternative because of its known interactions with immune responses and gut microbiota. Hence, we evaluated the effects of MLT in experimental colitis that evolves with intestinal dysbiosis, inflammation and bacterial translocation. C57BL/6 mice were exposed to dextran sulfate sodium and treated with MLT. In acute colitis, the hormone led to increased clinical, systemic and intestinal inflammatory parameters. During remission, continued MLT administration delayed recovery, increased TNF, memory effector lymphocytes and diminished spleen regulatory cells. MLT treatment reduced Bacteroidetes and augmented Actinobacteria and Verrucomicrobia phyla in mice feces. Microbiota depletion resulted in a remarkable reversion of the colitis phenotype after MLT administration, including a counter-regulatory immune response, reduction in TNF and colon macrophages. There was a decrease in Actinobacteria, Firmicutes and, most strikingly, Verrucomicrobia phylum in recovering mice. Finally, these results pointed to a gut-microbiota-dependent effect of MLT in the potentiation of intestinal inflammation.

Elevation of HO-1 expression protects the intestinal mucosal barrier in severe acute pancreatitis via inhibition of the MLCK/p-MLC signaling pathway

In severe acute pancreatitis (SAP), intestinal mucosal barrier damage can cause intestinal bacterial translocation and induce or aggravate systemic infections. Heme oxygenase-1 (HO-1) is a validated antioxidant and cytoprotective agent. This research aimed to investigate the effect and mechanism of HO-1 on SAP-induced intestinal barrier damage in SAP rats. Healthy adult male Sprague-Dawley rats were randomly separated into the sham-operated group, SAP group, SAP + Hemin group, and SAP + Znpp group. The rat model of SAP was established by retrograde injection of sodium taurocholate (5%) into the biliopancreatic duct. Hemin (a potent HO-1 activator) and Znpp (a competitive inhibitor of HO-1) were injected intraperitoneally in the selected groups 24 h before SAP. Serum and intestinal tissue samples were collected for analysis after 24 h in each group. Hemin pretreatment significantly reduced systemic inflammation, intestinal oxidative stress, and intestinal epithelial apoptosis in SAP by increasing HO-1 expression. Meanwhile, pretreatment with Hemin abolished the inhibitory effect on the expression of the tight junction proteins and significantly inhibited the activation of the MLCK/P-MLC signaling pathway. Conversely, ZnPP completely reversed these effects. Our study indicates that upregulation of HO-1 expression attenuates the intestinal mucosal barrier damage in SAP. The protective effect of HO-1 on the intestine is attributed to MLCK/p-MLC signaling pathway inhibition.