Maintaining Gut Integrity Research Articles

P0023 Methionine Restriction Promotes Intestinal Mucosal Repair by Regulating Selenbp1 and Modulating Macrophage Polarization

Abstract Background Intestinal epithelial homeostasis is critical for maintaining gut integrity and function. Methionine is an essential amino acid involved in various cellular processes, and its dietary regulation may impact intestinal injury and repair mechanisms. Selenbp1, an oxidase of the methionine metabolite methanethiol, plays an important role in this process. This study investigates the role of methionine intake and Selenbp1 in colonic injury and epithelial repair. Methods Animal models with radiation-induced intestinal injury were used to assess the effects of methionine restriction and supplementation. Intestinal epithelial-specific knockout of Selenbp1 and control mice were used for in vivo experiments. Colonic organoids, macrophage co-culture assays, and biochemical assays, including qPCR, immunoblotting, and flow cytometry, were employed to study epithelial proliferation, SUMOylation of Satb2, and macrophage polarization. Clinical samples from patients with Crohn's disease were also analyzed for macrophage markers, as well as Satb2 and SUMO2/3 expression levels. Results Methionine restriction alleviated radiation-induced colonic injury in mice, as evidenced by improved histological scores and reduced inflammatory markers. In contrast, high methionine levels decreased Selenbp1 expression in the colon. Intestinal epithelial-specific Selenbp1 knockout exacerbated radiation-induced colonic mucosal injury, with significantly lower organoid survival rates and budding efficiency post-irradiation. However, this detrimental effect of Selenbp1 knockout was reversed upon methionine restriction, demonstrating the potential of dietary modulation. Furthermore, methionine supplementation led to a reduction in the SUMOylation of Satb2, a key regulator of intestinal epithelial homeostasis. The lower the level of Satb2 SUMOylation, the higher the clinical pathological features of Crohn's disease, such as disease activity. In co-culture assays, methionine supplementation enhanced M1 polarization of macrophages, further indicating a role of methionine in modulating immune responses. In clinical Crohn's disease (CD) specimens, we also found that a higher proportion of M1 macrophages correlated with lower expression levels of Selenbp1. Conclusion Methionine restriction promotes intestinal mucosal repair by regulating Selenbp1 and macrophage polarization, suggesting its potential as a therapeutic strategy for colonic repair.

Exploring the Therapeutic Potential of Bottle Gourd-Bael-Triphala Churna in Cancer Treatment

This study aims to investigate the anticancer activity of the herbal formulation using a hepatocellular carcinoma (HepG2) cell as an in vitro model system. Bael leaves (Aegle marmelos) In the same study, bael may be related to antioxidant and anti-inflammatory effects that protect cells. It is an ancient Ayurvedic formulation of three fruits (Amalaki, Bibhitaki, and Haritaki), known to promote detoxification and maintain gut integrity. Bottle gourd (Lagenaria siceraria) is hydrating, which could enhance the defenses of the body due to its nutrient profile. Each of these ingredients is believed to have synergistic benefits for cancer prevention and fighting ability, infectious disease immunity, and maintenance of overall health. In this context, this combination could represent a complementary option of therapy to standard cancer treatments and should be tested in preclinical in vitro and in vivo experiments and subsequently by clinical trials for the evaluation of efficacy and safety in oropharyngeal cancer

Potential probiotic Lactiplantibacillus plantarum strains alleviate TNF-α by regulating ADAM17 protein and ameliorate gut integrity through tight junction protein expression in in vitro model

BackgroundLactiplantibacillus species are extensively studied for their ability to regulate host immune responses and functional therapeutic potentials. Nevertheless, there is a lack of understanding on the mechanisms of interactions with the hosts during immunoregulatory activities.MethodsTwo Lactiplantibacillus plantarum strains MKMB01 and MKMB02 were tested for probiotic potential following Indian Council of Medical Research (ICMR) guidelines. Human colorectal adenocarcinoma cells such as HT-29, caco-2, and human monocytic cell THP-1 were also used to study the potential of MKMB01 and MKMB02 in regulating the host immune response when challenged with enteric pathogen Salmonella enterica typhimurium. Cells were pre-treated with MKMB01 and MKMB02 for 4 h and then stimulated with Salmonella. qRT-PCR and ELISA were used to analyze the genes and protein expression. Confocal microscopy and field emission scanning electron microscopy (FESEM) were used to visualize the effects. An Agilent Seahorse XF analyzer was used to determine real-time mitochondrial functioning.ResultsBoth probiotic strains could defend against Salmonella by maintaining gut integrity via expressing tight junction proteins (TJPs), MUC-2, and toll-like receptors (TLRs) negative regulators such as single Ig IL-1-related receptor (SIGIRR), toll-interacting protein (Tollip), interleukin-1 receptor-associated kinase (IRAK)-M, A20, and anti-inflammatory transforming growth factor-β and interleukin-10. Both strains also downregulated the expression of pro-inflammatory cytokines/chemokines interleukin-1β, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor-alpha (TNF-α), interleukin 6, and nitric oxide (NO). Moreover, TNF-α sheddase protein, a disintegrin and metalloproteinase domain 17 (ADAM17), and its regulator iRhom2 were downregulated by both strains. Moreover, the bacteria also ameliorated Salmonella-induced mitochondrial dysfunction by restoring bioenergetic profiles, such as non-mitochondrial respiration, spare respiratory capacity (SRC), basal respiration, adenosine triphosphate (ATP) production, and maximal respiration.ConclusionsMKMB01 and MKMB02 can reduce pathogen-induced gut-associated disorders and therefore should be further explored for their probiotic potential.

Targeting the osteoclastogenic cytokine IL-9 as a novel immunotherapeutic strategy in mitigating inflammatory bone loss in post-menopausal osteoporosis.

Recent discoveries have established the pivotal role of IL-9-secreting immune cells in a wide spectrum of inflammatory and autoimmune diseases. However, little is known about how IL-9 contributes to the etiology of inflammatory bone loss in PMO. We observed that IL-9 has a pathological impact on inflammatory bone loss in ovariectomized (Ovx) mice. Our in vivo temporal kinetics analysis revealed that estrogen deprivation enhanced the production of IL-9 from Th cells (majorly Th9 and Th17). Both our ex vivo and in vivo studies corroborated these findings in Ovx mice, as estrogen diminishes the potential of Th9 cells to produce IL-9. Mechanistically, Th9 cells in an IL-9-dependent manner enhance osteoclastogenesis and thus could establish themselves as a novel osteoclastogenic Th cell subset. Therapeutically neutralizing/blocking IL-9 improves bone health by inhibiting the differentiation and function of osteoclasts, Th9, and Th17 cells along with maintaining gut integrity in Ovx mice. Post-menopausal osteoporotic patients have increased IL-9-secreting Th9 cells, which may suggest a potential role for IL-9 in the development of osteoporosis. Collectively, our study identifies IL-9-secreting Th9 cells as a driver of bone loss with attendant modulation of gut-immune-bone axis, which implies IL-9-targeted immunotherapies as a potential strategy for the management and treatment of inflammatory bone loss observed in PMO.

Insights into the Mechanisms of Action of Akkermansia muciniphila in the Treatment of Non-Communicable Diseases.

This comprehensive review delineates the extensive roles of Akkermansia muciniphila in various health domains, spanning from metabolic and inflammatory diseases to neurodegenerative disorders. A. muciniphila, known for its ability to reside in the mucous layer of the intestine, plays a pivotal role in maintaining gut integrity and interacting with host metabolic processes. Its influence extends to modulating immune responses and potentially easing symptoms across several non-communicable diseases, including obesity, diabetes, inflammatory bowel disease, and cancer. Recent studies highlight its capacity to interact with the gut-brain axis, suggesting a possible impact on neuropsychiatric conditions. Despite the promising therapeutic potential of A. muciniphila highlighted in animal and preliminary human studies, challenges remain in its practical application due to stability and cultivation issues. However, the development of pasteurized forms and synthetic mediums offers new avenues for its use in clinical settings, as recognized by regulatory bodies like the European Food Safety Authority. This narrative review serves as a crucial resource for understanding the broad implications of A. muciniphila across different health conditions and its potential integration into therapeutic strategies.

Efficacy of pre, pro, and synbiotic on clinical endpoint of acute pancreatitis: a systematic review and meta-analysis

Background: Acute pancreatitis (AP) commonly presents as gastrointestinal disease and can become a life-threatening condition. The pathophysiological process involves impairment in the gut barrier and bacterial translocation, mediating the infection of necrotic pancreatic tissue. Therefore, a strategy to maintain gut integrity is rational. The Probiotics in Pancreatitis Trial (PROPATRIA) found that probiotics had a harmful effect on severe AP. However, additional research revealed neither favorable nor unfavorable effects. This study aimed to analyze the efficacy of these medications on clinical endpoints in patients with AP. Methods: We performed a systematic search up to April 14, 2023. The study population in this review were patients with AP. The intervention consisted of prebiotic group, probiotic group, and synbiotic group. The effectiveness of each group in treating LoH was the main result, while infection complications were the secondary result. The analysis was conducted using a random effect model, and publication bias was found using a funnel plot. Results: 16 studies were used in this review and meta-analysis. A total of 1,044 acute pancreatitis patients and 779 patients were included for primary and secondary outcomes, respectively. The use of either pre-, pro-, and synbiotics reduces the LoH significantly (-3.32 days, p = 0.001). Subgroup analysis of the interventions revealed that probiotics (-3.02 days, p =0.02) and prebiotics (-3.9 days, p =0.02) reduce the LoH, but not for synbiotics (-4.37 days, p =0.18). As for secondary outcomes, the use of pre-, pro-, and synbiotics reduce the risk of infection in acute pancreatitis patients with odds ratio (OR) of 0.32 (p = 0.006). Conclusion: Additional medication of prebiotics, probiotics, and synbiotics as an adjunctive to standard therapy showed clinical benefits in AP patients. Therefore, its usage on acute pancreatitis patients could provide clinical benefit, albeit further studies are warranted.

Pathophysiology and Therapeutic Management of Bone Loss in Patients with Critical Illness.

Patients with critical illnesses are at higher risk of comorbidities, which can include bone mineral density loss, bone turnover marker increase, and fragility fractures. Patients admitted to intensive care units (ICUs) have a higher risk of bone fractures. Since hypermetabolism is a characteristic of ICU patients, such patients are often rapidly affected by systemic deterioration, which often results in systemic wasting disease. Major risk factors for ICU-related bone loss include physical restraint, inflammation, neuroendocrine stress, malnutrition, and medications. A medical history of critical illness should be acknowledged as a risk factor for impaired bone metabolism. Bone loss associated with ICU admission should be recognized as a key component of post-intensive care syndrome, and further research that focuses on treatment protocols and prevention strategies is required. Studies aimed at maintaining gut integrity have emphasized protein administration and nutrition, while research is ongoing to evaluate the therapeutic benefits of anti-resorptive agents and physical therapy. This review examines both current and innovative clinical strategies that are used for identifying risk factors of bone loss. It provides an overview of perioperative outcomes and discusses the emerging novel treatment modalities. Furthermore, the review presents future directions in the treatment of ICU-related bone loss.

Kinetics of severe dengue virus infection and development of gut pathology in mice.

Dengue virus, an arbovirus, causes an estimated 100 million symptomatic infections annually and is an increasing threat as the mosquito range expands with climate change. Dengue epidemics are a substantial strain on local economies and health infrastructure, and an understanding of what drives severe disease may enable treatments to help reduce hospitalizations. Factors exacerbating dengue disease are debated, but gut-related symptoms are much more frequent in severe than mild cases. Using mouse models of dengue infection, we have shown that inflammation and damage are earlier and more severe in the gut than in other tissues. Additionally, we observed impairment of the gut mucus layer and propose that breakdown of the barrier function exacerbates inflammation and promotes severe dengue disease. This idea is supported by recent data from human patients showing elevated bacteria-derived molecules in dengue patient serum. Therapies aiming to maintain gut integrity may help to abrogate severe dengue disease.

Prolonged experimental CD4+ T-cell depletion does not cause disease progression in SIV-infected African green monkeys

CD4+ T-cell depletion is a hallmark of HIV infection, leading to impairment of cellular immunity and opportunistic infections, but its contribution to SIV/HIV-associated gut dysfunction is unknown. Chronically SIV-infected African Green Monkeys (AGMs) partially recover mucosal CD4+ T-cells, maintain gut integrity and do not progress to AIDS. Here we assess the impact of prolonged, antibody-mediated CD4 + T-cell depletion on gut integrity and natural history of SIV infection in AGMs. All circulating CD4+ T-cells and >90% of mucosal CD4+ T-cells are depleted. Plasma viral loads and cell-associated viral RNA in tissues are lower in CD4+-cell-depleted animals. CD4+-cell-depleted AGMs maintain gut integrity, control immune activation and do not progress to AIDS. We thus conclude that CD4+ T-cell depletion is not a determinant of SIV-related gut dysfunction, when gastrointestinal tract epithelial damage and inflammation are absent, suggesting that disease progression and resistance to AIDS are independent of CD4+ T-cell restoration in SIVagm-infected AGMs.

Increased arginine, lysine, and methionine levels can improve the performance, gut integrity and immune status of turkeys but the effect is interactive and depends on challenge conditions

Arginine (Arg), lysine (Lys), and methionine (Met) can be used to support the health status of turkeys. The present study investigated selected performance, gut integrity, and immunological parameters in turkeys reared in optimal or challenge conditions. The experiment lasted for 28 days, and it had a completely randomized 2 × 3 factorial design with two levels of dietary Arg, Lys and Met (high or low) and challenge with Clostridium perfringens (C. perfringens), Escherichia coli lipopolysaccharide (LPS) or no challenge (placebo). Increased dietary levels of Arg, Lys and Met had a beneficial effect on turkey performance and immunological parameters, and it improved selected indicators responsible for maintaining gut integrity in different challenge conditions. Under optimal conditions (with no challenge), high ArgLysMet diets did not compromise bird performance and they improved selected performance parameters in challenged birds. The immune system of turkeys was not excessively stimulated by high ArgLysMet diets, which did not disrupt the redox balance and had no negative effect on gut integrity. High ArgLysMet diets increased the expression levels of selected genes encoding nutrient transporters and tight junction proteins. However, the influence exerted by different dietary inclusion levels of Arg, Lys and Met on gut integrity was largely determined by the stressor (C. perfringens vs. LPS). Further studies are required to investigate the role of Arg, Lys and Met levels in the diet on the immune response, gut function and performance of turkeys in different challenge conditions.

Saccharomyces Boulardii Ameliorates Non-alcoholic Steatohepatitis in Mice Induced by a Methionine-Choline-Deficient Diet Through Gut-Liver Axis.

Non-alcoholic steatohepatitis (NASH) is affecting people worldwide. Changes in the intestinal microbiome are crucial to NASH. A previous study showed that eradicating intestinal fungi ameliorates NASH; however, the role of intestinal fungi in the development of NASH remains unclear. Saccharomyces boulardii (SB), a dietary supplement yeast, has been reported to restore the integrity of the intestine. Here, we tested the effect of SB in the treatment of NASH. For this study, we fed eight-week-old C57/BL6 male mice either a methionine-choline deficient (MCD) diet or a normal chow diet (NCD) for eight weeks. Half of the MCD diet-fed mice were gavaged with SB (5 mg/day) once daily. The remainder of the NCD–fed mice were gavaged with normal saline as a control. The MCD diet-fed mice on SB supplement showed better liver function, less hepatic steatosis, and decreased inflammation. Both hepatic inflammatory gene expression and fibrogenic gene expression were suppressed in mice with SB gavage. Intestinal damage caused by the MCD diet was tampered with, intestine inflammation decreased, and gut permeability improved in mice that had been given the SB supplement. Deep sequencing of the fecal microbiome showed a potentially increased beneficial gut microbiota and increased microbiota diversity in the SB-supplemented mice. The SB supplement maintains gut integrity, increases microbial diversity, and increases the number of potentially beneficial gut microbiota. Thus, the SB supplement attenuates gut leakage and exerts a protective effect against NASH. Our results provide new insight into the prevention of NASH.

Lactobacillus acidophilus Supplementation Restores Gut Epithelial Integrities and Barrier Functions in Non-specific Diarrhea

Objectives: The study was aimed to evaluate the roles of Lactobacillus acidophilus supplementation in maintaining intestinal epithelial integrities, tight junction proteins, and adhesion molecules in non-specific diarrhea.
 Methods: In this study, we used the pre-weaned BL/6 pups (3 weeks of age, same litters) as a model animal. We supplied the non-sterilized and poor-quality water to experimental pups (n=7) to develop non-specific diarrheic symptoms. Then diarrheic pups were supplemented with Lactobacillus acidophilus (LA) for three consecutive weeks. The control group (n=5) was supplied with sterilized water and no LA. The sampling and analysis were performed on day 0, day 7, day 14, and day 21. The expressions of pro-inflammatory cytokines (IL-6, TNF-a) and tight junction proteins (TJPs) of gut mucosa were determined using qRT-PCR. And the serum cytokines level was screened through sandwich ELISA.
 Results: The intestinal cytoskeletal integrity becomes disrupted and characterized by lower ZO-1, Occludin, Claudin-1, Claudin-5, and JAM mRNA expressions upon real-time qRT-PCR. However, Claudin-4 was found to be not affected and illustrated with a higher expression like control pups. Interestingly, supplementing Lactobacillus acidophilus was found to maintain gut integrity and effectively reduce diarrheic symptoms. Like the control pups, the Lactobacillus acidophilus supplemented pups exhibited a higher expression of gut epithelial TJPs and adhesion molecules. Moreover, the diseased pups produced significantly increased IL-6, and TNF-α production in blood serum, compared to control BL/6 pups. 
 Conclusion: We concluded that L. acidophilus supplementation might orchestrate the equilibrium of gut health and immunity against non-specific diarrhea.

Tanshinone IIA and Neural Stem Cell Combination Therapy Decreases Gut Inflammation and Maintains Gut Integrity in a Translational Pig Ischemic Stroke Model

ObjectivesImpaired gut homeostasis has been found in stroke, leading to leaky gut syndrome, increased levels of gut, brain, and systemic inflammation that further exacerbating brain damage. Tanshinone IIA (Tan IIA) and induced pluripotent stem cell derived neural stem cells (iNSCs) have been shown to decrease inflammation in the brain post-stroke resulting in reduced lesion volume and improved recovery response in rodent models. However, no group has evaluated the effect of Tan IIA and iNSCs brain treatments on intestinal changes. We evaluate the effects of Tan IIA and iNSCs delivered to the brain post-stroke on gut homeostasis in an ischemic stroke pig model.MethodsYucatan pigs (n = 12) underwent middle cerebral artery occlusion surgery and received either PBS (CON) or Tan IIA loaded PLGA nanoparticle (Tan IIA-NPs) and iNSCs treatment (TRT). PBS or Tan IIA-NPs were administered intracisternally at 1 hour post-stroke and PBS or iNSCs were transplanted into the perilesional region at 5 days post-stroke. Changes in fecal total SCFAs level were analyzed up to 12 weeks (wk) post-treatment (PT) and jejunum scrapings were collected at 12 wk PT for analysis.ResultsTRT had higher levels of total SCFAs than CON throughout the study period. Protein levels of jejunal TNF-α, TNFR1, and phosphorylation of Ikbα at 12 wk PT were lower in TRT compared to CON, suggesting that the treatment in brain decreased gut inflammation. The expression of jejunal Occludin, Claudin1, and ZO-1 was higher in TRT compared to CON. Moreover, protein levels of TNF-α and phosphorylation of Ikbα were negatively correlated with fecal total SCFAs levels at early stages of treatment (1–4 wk PT). Interestingly, total SCFA level at early treatment stages (up to 4 wk PT) was inversely related to hemorrhage volume measured by magnetic resonance imaging 1 day post-stroke, indicating a potential link between stroke severity and gut homeostasis.ConclusionsThe findings of the study indicate that local post-stroke brain treatment with Tan IIA and iNSCs decreases inflammation and membrane permeability through dynamic interplay with SCFAs in the gut. This study suggests further research on inflammation and SCFAs as key regulatory components and potential therapeutic targets that can modulate the gut brain axis to enhance stroke recovery in patients.Funding SourcesThis work was supported by the National Institutes of Health.

HIV Infection and Spread between Th17 Cells.

HIV mainly targets CD4+ T cells, from which Th17 cells represent a major cell type, permissive, and are capable of supporting intracellular replication at mucosal sites. Th17 cells possess well-described dual roles, while being central to maintaining gut integrity, these may induce inflammation and contribute to autoimmune disorders; however, Th17 cells’ antiviral function in HIV infection is not completely understood. Th17 cells are star players to HIV-1 pathogenesis and a potential target to prevent or decrease HIV transmission. HIV-1 can be spread among permissive cells via direct cell-to-cell and/or cell-free infection. The debate on which mode of transmission is more efficient is still ongoing without a concrete conclusion yet. Most assessments of virus transmission analyzing either cell-to-cell or cell-free modes use in vitro systems; however, the actual interactions and conditions in vivo are not fully understood. The fact that infected breast milk, semen, and vaginal secretions contain a mix of both cell-free viral particles and infected cells presents an argument for the probability of HIV taking advantage of both modes of transmission to spread. Here, we review important insights and recent findings about the role of Th17 cells during HIV pathogenesis in mucosal surfaces, and the mechanisms of HIV-1 infection spread among T cells in tissues.

Exploring the long-term risk factors associated with intestinal failure-associated liver disease in pediatric and adult patients: The role of lipid injectable emulsions in the development of liver disease.

Despite parenteral nutrition (PN) being life sustaining, one of the risk factors associated with its long-term use is intestinal failure-associated liver disease (IFALD), which increases the risk for morbidity and mortality. This review examines some of the risk factors associated with IFALD. A literature review using the databases PubMed, EMBASE, and CINAHL between 2010 and 2020 was performed using search terms, including long-term total PN and liver failure, serum plant sterols and liver failure, and complications and PN. Articles in English using both human and animal participants were included. The pathophysiology associated with PN and liver disease is multifactorial and influenced by the remaining small-bowel length, presence of the ileal cecal valve, lack of enteral stimulation, type of lipid injectable emulsion (ILE), plant sterol content, and excessive calories. The type of ILE plays a major role because of the phytosterol (PS) content, affecting the microbiome composition and inhibiting key gut signals. The PS content is highest in soy oil (SO)-based ILE, which increases inflammation and impairs biliary flow. Serum PS correlates with liver biomarker abnormalities and is highest in SO-based ILE use compared with mixed-oil emulsions. Selection of a low-PS content ILE is recommended to reduce the risk of biliary cholestasis. Stimulation of the gut, if possible, is recommended to maintain gut integrity and reduce bacterial overgrowth. Fish oil (FO) shows promise in IFALD reversal however, large randomized controlled trials are needed to further establish support for the use of FO in adults.

Montmorencytart cherry supplementation improved markers of glucose homeostasis but has modest effects on indicators of gut health in mice fed a Western diet

The gut microbiota plays an important role in the pathophysiology of obesity and type 2 diabetes. Emerging evidence suggests that anthocyanin-rich foods such as US Montmorency tart cherry (TC) can promote health by influencing the gut microbiota and maintaining gut integrity. This study investigated the effects of TC supplementation on the gut microbiota, markers of gut health, and metabolic parameters in mice fed a western diet (WD). Seventy-two C57BL/6 male mice were assigned to dietary treatments in a 2 × 3 factorial design with diet (control, WD) and TC (0, 5, 10% wt/wt) as factors. After 12 weeks of dietary treatment, tissues were collected to evaluate metabolic parameters and markers of gut health including cecal content microbiota and fecal short chain fatty acids (SCFAs). TC supplementation significantly increased the bacterial phylum, Actinobacteria, cecal weight, and fecal SCFAs and reduced the Proteobacteria and Deferribacteres phyla. However, gut histological parameters and expression of genes related to gut integrity were unaffected by TC. Body weight, serum cholesterol, triglyceride, leptin, plasminogen activator inhibitor-1 and resistin were increased with WD and TC had no effect on these parameters. Fasting blood glucose and the surrogate marker of insulin resistance, homeostatic model assessment of insulin resistance (HOMA-IR), was significantly increased by WD which was improved by TC particularly the 5% dose. In conclusion, TC supplementation, particularly the 5% dose, improved markers of glucose homeostasis but has modest effects on gut microbial population and SCFAs production. The mechanism by which TC improved markers of glucose homeostasis needs to be further investigated.

Gut Microbiota as an Emerging Therapeutic Avenue for the Treatment of Nonalcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of death related to liver diseases worldwide. Despite this, there is no specific treatment approved for the disease till now, which could be due to the poor understanding of the pathophysiology of this disease. In the past few decades, several scientists have speculated the root cause of NAFLD to be dysbalance in the gut microbiome resulting in a susceptibility to the inflammatory cascade in the liver. Herein, we hypothesize to fabricate a novel formulation containing prebiotic with probiotics which thereby would help in maintaining the gut homeostasis, and be used for the treatment of NAFLD. The proposed novel formulation would contain a Bifidobacterium sp. with Faecalibacterium prausnitzii in the presence of a dietary fibre having hepatoprotective activity. These two strains of probiotics would help in increasing the concentration of butyrate in the gut which in turn would inhibit intestinal inflammation and maintain gut integrity. The dietary fibre would serve a dual mechanism; firstly, it would act as a prebiotic helping in the proliferation of administered probiotics, and secondly, it would protect the liver via its own hepatoprotective action. This combinatorial approach would pave a new therapeutic avenue for the treatment of NAFLD.

S1430 Early Enteral Nutrition Reduces In-Hospital Mortality of Critically Ill COVID-19 Patients

Introduction: Early enteral nutrition (EEN) is a therapeutic strategy that is used in critical illness to reduce morbidity and mortality. There is no data on the role of nutrition therapy for intubated critically ill COVID-19 patients. The aim of our study was to assess if early enteral nutrition reduced morbidity and mortality during the first wave of the COVID-19 pandemic. Methods: A retrospective chart review of COVID-19 patients >18 years who were mechanically ventilated for >48 hours at Montefiore Medical Center from March 2020 to November 2020 (n = 669) was performed. Using a landmark analysis approach, patients were divided into (1) an EEN group, defined as having enteral feeding initiated before 48 hours of mechanical ventilation; (2) delayed or no enteral nutrition ( >48 hours of mechanical ventilation). Patients who died or were extubated prior to the landmark time were excluded. Cumulative incidence curves stratified by EEN status were estimated for the primary endpoint of in-hospital death, accounting for the competing risk of discharge. Secondary analysis examined time to extubation. Cox PH models were estimated to examine the association between EEN and the hazard of death while adjusting for an a priori set of COVID-related predictors. Two-sided p-values ≤ 0.05 were considered statistically significant. All analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary NC, USA). Results: There were 515 patients in the EEN group and 154 patients in the delayed enteral nutrition group. EEN was associated with a lower hazard of in-hospital death (adjusted HR = 0.79, 95% CI: 0.63-1.0; P = 0.05). Older age, male gender, and CKD were significantly associated with a higher hazard of death. The cumulative incidence of mortality was lower in the EEN group, with an estimated incidence of 40% and 53% at 10 and 20 days compared to 47% and 60% with delayed EN. Time to extubation and hospital discharge were not associated with EEN. Conclusion: EEN helps treat critically ill patients to maintain gut integrity, modulate stress and the systemic immune response and attenuate disease severity. The lower risk of in-hospital death in the EEN group supports this therapeutic modality in critically ill intubated COVID-19 patients. Further analysis to assess barriers for EEN including prone positioning, fluid restriction, and use of vasopressors is an area of future research.Figure 1.: De Novo Patients and Patients With Prior Diagnoses of EG and/or EoD Have Significant Reductions in Symptoms Compared With Patients Given Placebo.Table 1.: Cause-specific Cox PH model for the time to death from landmark time of 48 hours post intubation.

Gut Microbiota in Metabolic-associated Fatty Liver Disease and in Other Chronic Metabolic Diseases.

The gut microbiome plays a key role in the health-disease balance in the human body. Although its composition is unique for each person and tends to remain stable throughout lifetime, it has been shown that certain bacterial patterns may be determining factors in the onset of certain chronic metabolic diseases, such as type 2 diabetes mellitus (T2DM), obesity, metabolic-associated fatty liver disease (MAFLD), and metabolic syndrome. The gut-liver axis embodies the close relationship between the gut and the liver; disturbance of the normal gut microbiota, also known as dysbiosis, may lead to a cascade of mechanisms that modify the epithelial properties and facilitate bacterial translocation. Regulation of gut microbiota is fundamental to maintaining gut integrity, as well as the bile acids composition. In the present review, we summarize the current knowledge regarding the microbiota, bile acids composition and their association with MAFLD, obesity, T2DM and metabolic syndrome.

Enhanced alcoholic liver disease in mice with intestine-specific farnesoid X receptor deficiency

AbstractAlcoholic fatty liver disease (AFLD) is one of the major causes of liver morbidity and mortality worldwide. We have previously shown that whole-body, but not hepatocyte-specific, deficiency of farnesoid X receptor (FXR) in mice worsens AFLD, suggesting that extrahepatic FXR deficiency is critical for AFLD development. Intestinal FXR is critical in suppressing hepatic bile acid (BA) synthesis by inducing fibroblast growth factor 15 (FGF15) in mice and FGF19 in humans. We hypothesized that intestinal FXR is critical for reducing AFLD development in mice. To test this hypothesis, we compared the AFLD severity in wild type (WT) and intestine-specific Fxr knockout (FXRInt−/−) mice following treatment with control or ethanol-containing diet. We found that FXRInt−/− mice were more susceptible to ethanol-induced liver steatosis and inflammation, compared with WT mice. Ethanol treatment altered the expression of hepatic genes involved in lipid and BA homeostasis, and ethanol detoxification. Gut FXR deficiency increased intestinal permeability, likely due to reduced mucosal integrity, as revealed by decreased secretion of Mucin 2 protein and lower levels of E-cadherin protein. In summary, intestinal FXR may protect AFLD development by maintaining gut integrity.Intestinal farnesoid X receptor (FXR) deficiency in mice leads to more severe liver injury and inflammation with ethanol treatment, which is associated with increased intestinal leakage. These results suggest that intestinal FXR may be critical in maintaining gut integrity and the epithelial barrier to protect the liver from ethanol-induced injury.