Interplay of gut microbiota,glucagon-like peptide receptor agonists,and nutrition:New frontiers in metabolic dysfunction-associated steatotic liver disease therapy

The gut-liver axis plays a crucial role in the development and progression of metabolic dysfunction-associated steatotic liver disease(MASLD).Key metabolites,including lipopolysaccharides,short-chain fatty acids(SCFAs),bile acids,and beneficial gut bacteria such as Bifidobacterium and Lactobacillus,are pivotal in this process.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)show promise in managing MASLD by promoting weight loss,enhancing insulin secretion,and improving liver health.They restore gut-liver axis functionality,and their effects are amplified through dietary modifications and gut microbiometargeted therapies.Emerging research highlights the interplay between GLP-1 RAs and gut microbiota,indicating that the gut microbiome significantly influences therapeutic outcomes.Metabolites produced by gut bacteria,can stimulate glucagon-like peptide-1(GLP-1)secretion,further improving metabolic health.Integrating dietary interventions with GLP-1 RA treatment may enhance liver health by modulating the gut microbiota-SCFAs-GLP-1 pathway.Future research is needed to understand personalized effects,with prebiotics and probiotics offering treatment avenues for MASLD.

From fatty liver to fibrosis:A tale of “second hit”

Although much is known about how fat accumulates in the liver,much remains unknown about how this causes sustained hepatocellular injury.The consequences of injury are recognized as nonalcoholic steatohepatitis(NASH) and progressive fibrosis.The accumulation of fat within the hepatocytes sensitizes the liver to injury from a variety of causes and the regenerative capacity of a fatty liver is impaired.An additional stressor is sometimes referred to as a "second hit" in a paradigm that identifies the accumulation of fat as the "first hit".Possible candidates for the second hit include increased oxidative stress,lipid peroxidation and release of toxic products such as malondialdehyde and 4-hydroxynonenal,decreased antioxidants,adipocytokines,transforming growth factor(TGF)-β,Fas ligand,mitochondrial dysfunction,fatty acid oxidation by CYPs(CYP 2E1,4A10 and 4A14),and peroxisomes,excess iron,small intestinal bacterial overgrowth,and the generation of gut-derived toxins such as lipopolysaccharide and ethanol.Oxidative stress is one of the most popular proposed mechanisms of hepatocellular injury.Previous studies have specifically observed increased plasma and tissue levels of oxidative stress markers and lipid peroxidation products,with reduced hepatic and plasma levels of antioxidants.There is also some indirect evidence of the benefit of antioxidants such as vitamin E,S-adenosylmethionine,betaine,phlebotomy to remove iron,and N-acetylcysteine in NASH.However,a causal relationship or a pathogenic link between NASH and oxidative stress has not been established so far.A number of sources of increased reactive oxygen species production have been established in NASH that include proinflammatory cytokines such as tumor necrosis factor(TNF)-α,iron overload,overburdened and dysfunctional mitochondria,CYPs,and peroxisomes.Briefly,the pathogenesis of NASH is multifactorial and excess intracellular fatty acids,oxidant stress,ATP depletion,and mitochondrial dysfunction are important causes of hepatocellular injury in the steatotic liver.

Fructose as a key player in the development of fatty liver disease

We aimed to investigate whether increased consumption of fructose is linked to the increased prevalence of fatty liver.The prevalence of nonalcoholic steatohepatitis(NASH) is 3% and 20% in nonobese and obese subjects,respectively.Obesity is a low-grade chronic inflam-m-atory condition and obesity-related cytokines such as interleukin-6,adiponectin,leptin,and tumor necrosis factor-α may play important roles in the developm-ent of nonalcoholic fatty liver disease(NAFLD).Additionally,the prevalence of NASH associated with both cirrhosis and hepatocellular carcinom-a was reported to be high am-ong patients with type 2 diabetes with or without obesity.Our research group previously showed that consumption of fructose is associated with adverse alterations of plasma lipid profiles and metabolic changes in m-ice,the Am-erican Lifestyle-Induced Obesity Syndrom-e m-odel,which included consum-ption of a high-fructose corn syrup in amounts relevant to that consum-ed by som-e Am-ericans.The observation reinforces the concerns about the role of fructose in the obesity epidem-ic.Increased availability of fructose(e.g.,high-fructose corn syrup) increases not only abnorm-al glucose flux but also fructose m-etabolism-in the hepatocyte.Thus,the anatomic position of the liver places it in a strategic buffering position for absorbed carbohydrates and am-ino acids.Fructose was previously accepted as a beneficial dietary com-ponent because it does not stim-ulate insulin secretion.However,since insulin signaling plays an important role in central m-echanism-s of NAFLD,this property of fructose m-ay be undesirable.Fructose has a selective hepatic m-etabolism,and provokes a hepatic stress response involving activation of c-Jun N-term-inal kinases and subsequent reduced hepatic insulin signaling.As high fat diet alone produces obesity,insulin resistance,and som-e degree of fatty liver with m-inim-al inflam-m-ation and no fibrosis,the fast food diet which includes fructose and fats produces a gene expression signature of increased hepatic fibrosis,inflam-m-ation,endoplasm-ic reticulumstress and lipoapoptosis.Hepatic de novo lipogenesis(fatty acid and triglyceride synthesis) is increased in patients with NAFLD.Stable-isotope studies showed that increased de novo lipogenesis(DNL) in patients with NAFLD contributed to fat accum-ulation in the liver and the developm-ent of NAFLD.Specifically,DNL was responsible for 26% of accum-ulated hepatic triglycerides and 15%-23% of secreted very low-density lipoprotein triglycerides in patients with NAFLD com-pared to an estim-ated less than 5% DNL in healthy subjects and 10% DNL in obese people with hyperinsulinem-ia.In conclusion,understanding the underlying causes of NAFLD form-s the basis for rational preventive and treatm-ent strategies of this m-ajor form-of chronic liver disease.

Pathophysiology of insulin resistance and steatosis in patients with chronic viral hepatitis

Chronic hepatitis due to any cause leads to cirrhosis and end-stage liver disease.A growing body of literature has also shown that fatty liver due to overweight or obesity is a leading cause of cirrhosis.Due to the obesity epidemic,fatty liver is now a significant problem in clinical practice.Steatosis has an impact on the acceleration of liver damage in patients with chronic hepatitis due to other causes.An association between hepatitis C virus (HCV) infection,steatosis and the onset of insulin resistance has been reported.Insulin resistance is one of the leading factors for severe fibrosis in chronic HCV infections.Moreover,hyperinsulinemia has a deleterious effect on the management of chronic HCV.Response to therapy is increased by decreasing insulin resistance by weight loss or the use of thiazolidenediones or metformin.The underlying mechanisms of this complex interaction are not fully understood.A direct cytopathic effect of HCV has been suggested.The genomic structure of HCV (suggesting that some viral sequences are involved in the intracellular accumulation of triglycerides),lipid metabolism,the molecular links between the HCV core protein and lipid droplets (the core protein of HCV and its transcriptional regulatory function which induce a triglyceride accumulation in hepatocytes) and increased neolipogenesis and inhibited fatty acid degradation in mitochondria have been investigated.

Understanding mechanisms of the pathogenesis of nonalcoholic fatty liver disease

A central issue in the understanding of the pathogenesis of nonalcoholic fatty liver disease is the problem of the underlying mechanisms which are not fully understood.In the setting of excessive central adiposity,insulin resistance is the major underlying cause of fat accumulation in hepatocytes.Because of the difficulties with human trials,several animal models have been developed for this purpose mainly characterized as follows:genetically disturbed or murine fatty liver,methionine-choline deficient diet fed or murine steatohepatitis,and high-fat or sucrose diet fed models.Although these animal models have provided useful information,none of them accurately reflect genetic,metabolic and biochemical characteristics of the human disease.

Mallory-Denk Bodies in chronic hepatitis

Mallory-Denk Bodies(MDB) are important as investigators,suggesting MDB as an indicator of the histologic severity of chronic hepatitis,causes of which include hepatitis C,primary biliary cirrhosis(PBC),and nonalcoholic fatty liver disease(NAFLD).Matteoni et al scored MDB in patients with NAFLD as none,rare and many,and reported that MDB plays a prominent role in this classification scheme in an earlier classification system.In this study,we evaluated 258 patients with chronic hepatitis due to metabolic,autoimmune and viral etiologies.Liver biopsy samples were evaluated with hematoxylin and eosin,periodic acid-Schiff-diastase,Gordon and Sweet's reticulin,Masson's trichrome,and iron stains.Both staging and grading were performed.Additionally,MDB were evaluated and discussed for each disease.We examined patients with nonalcoholic steatohepatitis(NASH;50 patients),alcoholic hepatitis(10 patients),PBC(50 patients),Wilson disease(WD;20 patients),hepatitis B(50 patients),hepatitis C(50 pati-ents) and hepatocellular carcinoma(HCC;30 patients).Frequency of MDB was as follows;NASH:10 patients with mild in 60% and moderate in 40% and observed in every stage of the disease and frequently seen in zone 3.PBC:11 patients with mild in 10%,moderate in 70%,and cirrhosis in 20%,and frequently seen in zone 1.WD:16 patients with moderate and severe in 60% and cirrhosis in 40% and frequently seen in zone 1.Hep B:3 patients with mild in 66% and severe in 34%.Hep C:7 patients with mild in 40% and moderate in 60% and observed in every stage.HCC:3 patients with hep B in 2 patients.We found that there is no relationship between MDB and any form of chronic hepatitis regarding histologic severity such as alcoholic steatohepatitis and NAFLD and variable zone distribution by etiology.

Significant cohort of non-alcoholic fatty liver disease with portal vein thrombosis in transplant waiting list

AIM: To characterize non-alcoholic fatty liver disease(NAFLD) presentation with esophageal varices. METHODS: We carried out a retrospective cohort study on 258 patients with esophageal varices at a single tertiary referral center. These patients underwent diagnosis of several liver diseases, including: NAFLDassociated cirrhosis, hepatitis B, hepatitis C, Wilson disease, autoimune liver diseases, and others. RESULTS: Of the 258 patients, 39% of patients exhibited esophageal varices due to NAFLD-associated cirrhosis. Of the 38(14.7%) patients developed hepatocellular carcinoma during follow-up, 52% were due to hepatitis B, 26% due to hepatitis C and 13.2% due to NAFLD. Of the 258 patients, 50.0% with NAFLD, 33.3% with hepatitis B, 26.3% with hepatitis C, and 58.3% with other diseases were alive at the end of the 5-year period with a significant difference according to the Kaplan-Meier log Rank test(P = 0.040). Portal vein thrombosis was detected in 47.5% of patients with NAFLD, in 29% of patients with hepatitis B, in 17% of patients with hepatitis C, and in 62% of patients with other related diseases(P < 0.0001). CONCLUSION: Our study showed a proportionally greater elevation in liver transplant candidacy in patients with NAFLD and portal vein thrombosis. Older patients were more prone to developing cirrhosis, hepatocellular carcinoma and a high mortality rate. However, younger patients exhibited more portal vein thrombosis and gastric varices.

Ankaferd hemostat in the management of gastrointestinal hemorrhages

Gastrointestinal (GI) bleeding refers to any hemorrhage ascribed to the pathologies of the gastrointestinal tract,extending from the mouth to the anal canal.Despite the recent improvements in the endoscopic,hemostatic and adjuvant pharmacologic techniques,the reported mortality is still around 5%-10% for peptic ulcer bleeding and about 15%-20% for variceal hemorrhages.Although endoscopic management reduces the rates of re-bleeding,surgery,and mortality in active bleeding;early recurrence ratios still occur in around 20% of the cases even with effective initial hemostatic measures.In this quest for an alternative pro-hemostatic agent for the management of GI bleedings,Ankaferd blood stopper (ABS) offers a successful candidate,specifically for "difficult-to-manage" situations as evidenced by data presented in several studies.ABS is a standardized mixture of the plants Thymus vulgaris,Glycyrrhiza glabra,Vitis vinifera,Alpinia officinarum,and Urtica dioica.It is effective in both bleeding individuals with normal hemostatic parameters and in patients with deficient primary and/or secondary hemostasis.ABS also modulates the cellular apoptotic responses to hemorrhagic stress,as well as hemostatic hemodynamic activity.Through its effects on the endothelium,blood cells,angiogenesis,cellular proliferation,vascular dynamics,and wound healing,ABS is now becoming an effective alternative hemostatic medicine for gastrointestinal bleedings that are resistant to conventional anti-hemorrhagic measurements.The aim of this review is to outline current literature experience suggesting the place of ABS in the management of GI bleeding,and potential future controlled trials in this complicated field.

Telenutrition for the management of inflammatory bowel disease:Benefits,limits,and future perspectives

Patients with inflammatory bowel disease(IBD)require lifelong and personalized care by a multidisciplinary healthcare team.However,the traditional medical model is not ideal for patients who require continuous close monitoring and whose symptoms may dramatically worsen between regularly scheduled visits.Additionally,close dietary follow-up and monitoring of IBD in a traditional setting are challenging because of the disease complexity,high pressure on outpatient clinics with a small number of IBD specialist dietitians,and rising incidence.Given the significant burden of IBD,there is a need to develop effective dietary management strategies.The coronavirus disease 2019 pandemic caused an unprecedented shift from in-person care to delivering health care via technological remote devices.Traditional nutrition therapy and consultation can be provided by telenutrition through remote electronic communication applications that could greatly benefit patient care.Telenutrition might be useful,safe,and cost-effective compared with standard care.It is likely that virtual care for chronic diseases including IBD will continue in some form into the future.This review article summarizes the evidence about telenutrition applications in the management of IBD patients,and we gave an overview of the acceptance and impact of these interventions on health outcomes.