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PubMed abstracts for UC ALP/cholesterol/gut-liver-lipid digest 005

Saved 24 records from NCBI E-utilities on 2026-06-18. DOI fields corrected using PubmedData/ArticleIdList only.

PMID 37692785 — Association of serum lipids with inflammatory bowel disease: a systematic review and meta-analysis.

Serum lipid levels seem to be abnormal in Inflammatory bowel disease (IBD). However, the specific manifestation of abnormal serum lipid levels in IBD are heterogeneous among studies and have not been sufficiently determined yet. PubMed, EMBASE, and Cochrane Library databases were searched. Serum lipid levels were compared between IBD patients and Health individuals, Crohn’s (CD) and ulcerative colitis (UC), active and inactive, mild and non-mild patients, respectively. Meta-analyses were performed by using a random-effect model. Weight mean difference (WMD) with 95% confidence intervals (CIs) were calculated. Overall, 53 studies were included. Compared with healthy controls, IBD patients had significantly lower TC (WMD = -0.506, 95%CI = -0.674 to -0.338, p < 0.001), HDL-c (WMD = -0.122, 95%CI = -0.205 to -0.039, p = 0.004), and LDL-c (WMD = -0.371, 95%CI = -0.547 to -0.194, p < 0.001) levels. CD groups had a significantly lower TC (WMD = -0.349, 95%CI = -0.528 to -0.170, p < 0.0001) level as compared to UC groups. Active IBD and non-mild UC groups had significantly lower TC (WMD = -0.454, 95%CI = -0.722 to -0.187, p = 0.001) (WMD =0.462, 95%CI = 0.176 to 0.748, p = 0.002) and LDL-c (WMD = -0.225, 95%CI = -0.445 to -0.005, p = 0.045) (WMD =0.346, 95%CI = 0.084-0.609, p = 0.010) levels as compared to inactive IBD and mild UC groups, respectively. The overall level of serum lipids in IBD patients is lower than that of healthy individuals and is negatively associated with disease severity. https://www.crd.york.ac.uk/prospero/, identifier: CRD42022383885.

PMID 34722721 — Targeting the Intestinal Barrier to Prevent Gut-Derived Inflammation and Disease: A Role for Intestinal Alkaline Phosphatase.

Intestinal alkaline phosphatase (IAP) as a tissue-specific isozyme of alkaline phosphatases is predominantly produced by enterocytes in the proximal small intestine. In recent years, an increasing number of pathologies have been identified to be associated with an IAP deficiency, making it very worthwhile to review the various roles, biological functions, and potential therapeutic aspects of IAP. IAP primarily originates and acts in the intestinal tract but affects other organs through specific biological axes related to its fundamental roles such as promoting gut barrier function, dephosphorylation/detoxification of lipopolysaccharides (LPS), and regulation of gut microbiota. Numerous studies reporting on the different roles and the potential therapeutic value of IAP across species have been published during the last decade. While IAP deficiency is linked to varying degrees of physiological dysfunctions across multiple organ systems, the supplementation of IAP has been proven to be beneficial in several translational and clinical studies. The increasing evidence of the salutary functions of IAP underlines the significance of the naturally occurring brush border enzyme.

PMID 41227212 — Gut-Liver Axis, Microbiota, Bile Acids, and Immune Response in Pathogenesis of Primary Sclerosing Cholangitis: An Overview.

Primary sclerosing cholangitis (PSC) is a chronic, immune-mediated cholestatic liver disease characterized by progressive bile duct inflammation and fibrosis. Its strong association with inflammatory bowel disease (IBD) highlights the possible role of the gut-liver axis in disease pathogenesis. Here, we review the mechanisms that may contribute to the disruption of the gut-liver axis, leading to liver injury and the development of PSC. In particular, disruption of the intestinal barrier allows microbial products to enter the portal circulation, stimulating hepatic immune cells and triggering biliary inflammation. Concurrently, gut-primed lymphocytes expressing mucosal homing receptors migrate aberrantly to the liver, where they may contribute to biliary epithelial cell injury. Dysbiosis, characterized by reduced microbial diversity and the expansion of bile-tolerant and pro-inflammatory taxa, amplifies this immune activation and disturbs gut-liver homeostasis. Moreover, bile acids act as signaling molecules, regulating metabolism and immune responses through receptors such as FXR and TGR5. Dysregulation of these pathways may promote cholestasis, inflammation, and fibrosis. By understanding these interactions, we may identify novel therapeutic targets for PSC.

PMID 40504416 — The 2024 diagnostic criteria for primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is an idiopathic chronic cholestatic disease with a poor prognosis. As there were no specific biomarkers for diagnosing PSC, we developed diagnostic criteria in 2016 based on cholangiography and elevated biliary enzymes. Novel findings and knowledge have subsequently accumulated, and we now propose the 2024 diagnostic criteria, to overcome several limitations of the 2016 diagnostic criteria. The Intractable Hepato-Biliary Diseases Study Group in Japan of the Committee of Research on Measures for Intractable Diseases established a working group consisting of experts in PSC comprising gastroenterologists, endoscopists, hepatologists, liver-transplant surgeons, pediatric hepatologists, pathologists, and radiologists. This working group proposed the 2024 diagnostic criteria after several discussions and public hearings. There are additional diagnostic targets; small duct PSC, pediatric PSC, and PSC recurrence following liver transplantation differ from the 2016 diagnostic criteria, which were for diagnosing large duct PSC in adults. The 2024 diagnostic criteria facilitate the use of magnetic resonance cholangiography in addition to endoscopic retrograde cholangiography in imaging, and incorporate gamma-glutamyl transferase for evaluating cholestasis to diagnose pediatric patients. Furthermore, PSC recurrence following liver transplantation can be diagnosed based on a liver biopsy and characteristic biliary findings. We hope that the 2024 diagnostic criteria will help not only hepatologists treating adults but also general physicians, pediatric hepatologists, and liver-transplant surgeons who manage patients with various forms of PSC.

PMID 42072281 — Inflammatory, Nutritional, and Atherogenic Profiles Associated with Histologic Activity in Inflammatory Bowel Disease.

Background/Objectives: Histologic remission has emerged as a key treatment target in inflammatory bowel disease (IBD), but routine assessment requires repeated endoscopy and biopsies. Blood-based indices reflecting inflammation, nutritional status and atherogenic risk are inexpensive and widely available, yet their integrated contribution to histologic activity remains unclear. This study addresses this gap by simultaneously analyzing a broad panel of 44 variables-including nutritional status indicators, CBC-derived inflammation indices, and atherogenic lipid indices-in IBD patients. Methods: In this retrospective study, 100 patients with IBD (50 Crohn’s disease [CD], 50 ulcerative colitis [UC]) without additional comorbidities and with concomitant histologic assessment were analyzed. Histologic activity was coded as active vs. remission. At the time of biopsy, the complete blood count, biochemistry and lipid profile were used to calculate immuno-nutritional indices (CONUT score, prognostic nutritional index), inflammatory indices (neutrophil-to-platelet ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio [LMR], systemic immune-inflammation index, systemic immune-inflammation index, systemic inflammation response index [SIRI], aggregate index of systemic inflammation, C-reactive protein to albumin ratio) and atherogenic indices (atherogenic index of plasma [AIP], triglyceride-to-HDL cholesterol ratio). Variable selection was performed separately for CD and UC using least absolute shrinkage and selection operator (LASSO) regression and sparse partial least squares discriminant analysis (sPLS-DA). Independently associated predictors were then entered into multivariable logistic regression models, and their discriminative performance was evaluated using ROC analysis with bootstrap-derived 95% confidence intervals. Results: LASSO analysis identified a broadly similar systemic profile associated with histologic activity in CD and UC, dominated by the CONUT score, SIRI, AIP, LMR and red blood cell parameters, whereas demographic features and most routine biochemical markers were shrunk towards zero. Cross-validated AUCs for the LASSO models were 0.93 in CD and 0.87 in UC. sPLS-DA confirmed this pattern: CONUT, SIRI and AIP consistently showed the highest variable importance in projection scores and loadings on the first latent component. In multivariable regression, the CONUT score, SIRI and AIP remained independent predictors of histologic activity in CD, while hematocrit, CONUT score, SIRI and AIP were independently associated with histologic activity in UC. In ROC analysis, AUCs for CONUT, SIRI and AIP were 0.81, 0.89 and 0.87 in UC, and 0.72, 0.82 and 0.83 in CD, respectively. Conclusions: Histologic activity in IBD is characterized by a coupled systemic profile in which immuno-nutritional compromise (captured by CONUT) forms the core signal, supplemented by systemic inflammation (SIRI) and atherogenic dyslipidemia (AIP). These readily available blood-based indices may help to approximate histologic disease activity in clinical practice. However, considering that comorbid diseases may affect these indices, the strict exclusion criteria applied in this study may limit the generalizability of the findings among patients with IBD. Consequently, further validation in larger prospective cohorts is warranted.

PMID 42065513 — Intestinal alkaline phosphatase and gut health: insights into homeostasis, barrier protection, and immune signaling.

Intestinal alkaline phosphatase (IAP) is a brush border enzyme critical for maintaining gut homeostasis by detoxifying bacterial endotoxins, regulating nutrient metabolism, and modulating immune responses. IAP activity is modulated by dietary components such as carbohydrates, fats, probiotics, and vitamins, and has a dose-dependent effect. It strengthens intestinal barrier function by upregulating tight junction proteins and mitigating inflammation via lipopolysaccharide (LPS) detoxification and immunomodulatory pathways. Emerging evidence highlights its pleiotropic roles in intestinal barrier protection, microbiota regulation, and inflammation modulation, positioning IAP as a potential therapeutic target for gastrointestinal and systemic disorders, including inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), and metabolic syndrome. This review synthesizes current knowledge on IAP’s biological functions, focusing on its interactions with dietary components, gut microbiota, and critical signaling pathways. It explores innovative delivery systems such as liposomes, hydrogels, and exosomes to enhance IAP stability and bioavailability, alongside artificial intelligence (AI)-driven personalized nutrition strategies to optimize IAP activity. Future research should focus on bridging molecular mechanisms with clinical applications to harness IAP’s full potential in promoting gut health and preventing disease.

PMID 40202676 — The current findings on the gut-liver axis and the molecular basis of NAFLD/NASH associated with gut microbiome dysbiosis.

Recent research has highlighted the complex relationship between gut microbiota, metabolic pathways, and nonalcoholic fatty liver disease (NAFLD) progression. Gut dysbiosis, commonly observed in NAFLD patients, impairs intestinal permeability, leading to the translocation of bacterial products like lipopolysaccharides, short-chain fatty acids, and ethanol to the liver. These microbiome-associated mechanisms contribute to intestinal and hepatic inflammation, potentially advancing NAFLD to NASH. Dietary habits, particularly those rich in saturated fats and fructose, can modify the microbiome composition, leading to dysbiosis and fatty liver development. Metabolomic approaches have identified unique profiles in NASH patients, with specific metabolites like ethanol linked to disease progression. While bariatric surgery has shown promise in preventing NAFLD progression, the role of gut microbiome and metabolites in this improvement remains to be proven. Understanding these microbiome-related pathways may provide new diagnostic and therapeutic targets for NAFLD and NASH. A comprehensive review of current literature was conducted using multiple medical research databases, including PubMed, Scopus, Web of Science, Embase, Cochrane Library, ClinicalTrials.gov, ScienceDirect, Medline, ProQuest, and Google Scholar. The review focused on studies that examine the relationship between gut microbiota composition, metabolic pathways, and NAFLD progression. Key areas of interest included microbial dysbiosis, endotoxin production, and the influence of diet on gut microbiota. The analysis revealed that gut dysbiosis contributes to NAFLD through several mechanisms, diet significantly influences gut microbiota composition, which in turn affects liver function through the gut-liver axis. High-fat diets can lead to dysbiosis, altering microbial metabolic activities and promoting liver inflammation. Specifically, gut microbiota-mediated generation of saturated fatty acids, such as palmitic acid, can activate liver macrophages and increase TNF-α expression, contributing to NASH development. Different dietary components, including cholesterol, fiber, fat, and carbohydrates, can modulate the gut microbiome and influence NAFLD progression. This gut-liver axis plays a crucial role in maintaining immune homeostasis, with the liver responding to gut-derived bacteria by activating innate and adaptive immune responses. Microbial metabolites, such as bile acids, tryptophan catabolites, and branched-chain amino acids, regulate adipose tissue and intestinal homeostasis, contributing to NASH pathogenesis. Additionally, the microbiome of NASH patients shows an elevated capacity for alcohol production, suggesting similarities between alcoholic steatohepatitis and NASH. These findings indicate that targeting the gut microbiota may be a promising approach for NASH treatment and prevention. Recent research highlights the potential of targeting gut microbiota for managing nonalcoholic fatty liver disease (NAFLD). The gut-liver axis plays a crucial role in NAFLD pathophysiology, with dysbiosis contributing to disease progression. Various therapeutic approaches aimed at modulating gut microbiota have shown promise, including probiotics, prebiotics, synbiotics, fecal microbiota transplantation, and dietary interventions. Probiotics have demonstrated efficacy in human randomized controlled trials, while other interventions require further investigation in clinical settings. These microbiota-targeted therapies may improve NAFLD outcomes through multiple mechanisms, such as reducing inflammation and enhancing metabolic function. Although lifestyle modifications remain the primary recommendation for NAFLD management, microbiota-focused interventions offer a promising alternative for patients struggling to achieve weight loss targets.

PMID 41396480 — Oxysterol-mediated modulation of intestinal inflammation: insights into sex differences and GPR183 signaling.

Oxysterols, oxidized derivatives of cholesterol, play complex roles in inflammatory processes, but their specific functions in inflammatory bowel diseases remain incompletely understood. This study investigates the roles of key oxysterols - 7α,25-dihydroxycholesterol, 25-hydroxycholesterol, 25-hydroxycholesterol-3-sulfate, and 4β-hydroxycholesterol - and potential sex differences in intestinal inflammation. We used complementary approaches including dextran sulfate sodium-induced colitis, and ex vivo studies with colon explants, organoids, and immune cells to examine oxysterol properties. Principal component analysis was employed to analyze variance between disease and sex. In vivo administration of 7α,25-dihydroxycholesterol and NIBR189, an antagonist of its receptor GPR183, was performed to assess effects on inflammatory markers and immune cell trafficking. We observed sex-specific differences in both basal and colitis-induced oxysterol profiles, with female mice showing greater resistance to dextran sulfate sodium-induced inflammation and distinct patterns of oxysterol metabolism. Principal component analysis highlighted a separation of samples by both treatment and sex, with dextran sulfate sodium treatment accounting for approximately 55% of variance and sex differences explaining 25%. In vitro, 25-hydroxycholesterol-3-sulfate and 7α,25-dihydroxycholesterol decreased inflammatory cytokine expression in colon explants from female mice and reduced cytokine production in THP-1-derived macrophages in a dose-dependent manner. GPR183 antagonists decreased cell activation, suggesting constitutive receptor activity. In vivo 7α,25-dihydroxycholesterol administration showed modest effects on inflammatory markers but significantly decreased immune cell counts in lymph nodes, consistent with altered immune cell trafficking. Our findings reveal sex-specific regulation of inflammatory processes by oxysterols and highlight the therapeutic potential of targeting these pathways in inflammatory bowel diseases.

PMID 40555888 — The gut microbiota-bile acid axis: a crucial regulator of immune function and metabolic health.

The gut microbiota and bile acid metabolism are intricately linked, playing a crucial role in immune regulation, metabolic processes, and overall health. The gut microbiome, consisting of diverse bacterial genera such as Bacteroides, Clostridium, Lactobacillus, Bifidobacterium, and Eubacterium, facilitates the conversion of primary bile acids into secondary bile acids through enzymatic modifications. Bile acids, synthesized in the liver and modified by gut microbiota, act as signaling molecules that regulate immune responses via bile acid receptors, including the farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1), pregnane X receptor (PXR), vitamin D receptor (VDR), and sphingosine-1-phosphate receptor 2 (S1PR2). Dysbiosis-an imbalance in gut microbial composition-disrupts bile acid metabolism, leading to impaired activation of bile acid receptors and contributing to various diseases. These include inflammatory bowel disease, metabolic disorders such as obesity and type 2 diabetes, autoimmune diseases like multiple sclerosis, and liver conditions such as cholestasis and non-alcoholic fatty liver disease. Dysfunctional bile acid receptor signaling further promotes chronic inflammation, metabolic dysregulation, and disturbances in gut-liver-immune homeostasis. Emerging therapeutic strategies targeting bile acid receptors, restoring microbiota balance, and implementing dietary interventions offer promising avenues for disease prevention and management. This review explores the pivotal role of gut microbiota in modulating immune responses through bile acid receptors and highlights their therapeutic potential in improving treatment outcomes.

PMID 36927343 — Anthocyanins-gut microbiota-health axis: A review.

Anthocyanins are a subclass of flavonoids responsible for color in some fruits and vegetables with potent antioxidative capacity. During digestion, a larger proportion of dietary anthocyanins remains unabsorbed and reach the large intestine where they interact with the gut microbiota. Anthocyanins can modulate gut microbial populations to improve diversity and the proportion of beneficial populations, leading to alterations in short chain fatty acid and bile acid production. Some anthocyanins can be degraded into colonic metabolites, such as phenolic acids, which accumulate in the body and regulate a range of biological activities. Here we provide an overview of the effects of dietary anthocyanin consumption on gut microbial interactions, metabolism, and composition. Progression of chronic diseases has been strongly associated with imbalances in gut microbial populations. We therefore focus on the role of the gut microbiota as the ‘mediator’ that facilitates the therapeutic potential of anthocyanins against various chronic diseases, including obesity, type II diabetes, cardiovascular disease, neurodegenerative disease, inflammatory bowel disease, cancer, fatty liver disease, chronic kidney disease and osteoarthritis.

PMID 38663798 — Nitazoxanide protects against experimental ulcerative colitis through improving intestinal barrier and inhibiting inflammation.

Ulcerative colitis is a chronic disease with colonic mucosa injury. Nitazoxanide is an antiprotozoal drug in clinic. Nitazoxanide and its metabolite tizoxanide have been demonstrated to activate AMPK and inhibit inflammation, therefore, the aim of the present study is to investigate the effect of nitazoxanide on dextran sulfate sodium (DSS)-induced colitis and the underlying mechanism. Oral administration of nitazoxanide ameliorated the symptoms of mice with DSS-induced colitis, as evidenced by improving the increased disease activity index (DAI), the decreased body weight, and the shortened colon length. Oral administration of nitazoxanide ameliorated DSS-induced intestinal barrier dysfunction and reduced IL-6 and IL-17 expression in colon tissues. Mechanistically, nitazoxanide and its metabolite tizoxanide treatment activated AMPK and inhibited JAK2/STAT3 signals. Nitazoxanide and tizoxanide treatment increased caudal type homeobox 2 (CDX2) expression, increased alkaline phosphatase (ALP) activity and promoted tight junctions in Caco-2 cells. Nitazoxanide and tizoxanide treatment restored the decreased zonula occludens-1(ZO-1) and occludin protein levels induced by LPS or IL-6 in Caco-2 cells. On the other hand, nitazoxanide and tizoxanide regulated macrophage bias toward M2 polarization, as evidenced by the increased arginase-1expression in bone marrow-derived macrophages (BMDM). Nitazoxanide and tizoxanide reduced the increased IL-6, iNOS and CCL2 pro-inflammatory gene expressions and inhibited JAK2/STAT3 activation in BMDM induced by LPS. In conclusion, nitazoxanide protects against DSS-induced ulcerative colitis in mice through improving intestinal barrier and inhibiting inflammation and the underlying mechanism involves AMPK activation and JAK2/STAT3 inhibition.

PMID 38565010 — Maternal PFOS exposure in mice induces hepatic lipid accumulation and inflammation in adult female offspring: Involvement of microbiome-gut-liver axis and autophagy.

Perfluorooctane sulfonates (PFOS) are the persistent organic pollutants. In the present study, 0, 0.3, or 3-mg/kg PFOS were administered to pregnant mice from GD 11 to GD 18. The histopathology of liver and intestine, serum and hepatic lipid levels, lipid metabolism related genes, and gut microbiota were examined in adult female offspring. The results suggested that maternal PFOS exposure increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and induced F4/80+ macrophage infiltration in adult female offspring, in addition to the elevation of TNF-α and IL-1β mRNA levels in low-dose and high-dose groups, respectively. Furthermore, maternal exposure to PFOS increased serum triglyceride (TG) and hepatic total cholesterol (TC) levels, which was associated with the alteration of the process of fatty acid transport and β-oxidation, TG synthesis and transport, cholesterol synthesis and excretion in the liver. The AMPK/mTOR/autophagy signaling was also inhibited in the liver of adult female offspring. Moreover, changes in gut microbiota were also related to lipid metabolism, especially for the Desulfovibrio, Ligilactobacillus, Enterorhabdus, HT002 and Peptococcaceae_unclassified. Additionally, maternal exposure to PFOS decreased mRNA expressions of the tight junction protein and AB+ goblet cells in the colon, while increasing the overproduction of lipopolysaccharides (LPS) and F4/80+ macrophage infiltration. Collectively, maternal PFOS exposure induced liver lipid accumulation and inflammation, which strongly correlated with the disruption of the gut-liver axis and autophagy in adult female offspring, highlighting the persistent adverse effects in offspring exposed to PFOS.

PMID 38769683 — Novel approaches in IBD therapy: targeting the gut microbiota-bile acid axis.

Inflammatory bowel disease (IBD) is a chronic and recurrent condition affecting the gastrointestinal tract. Disturbed gut microbiota and abnormal bile acid (BA) metabolism are notable in IBD, suggesting a bidirectional relationship. Specifically, the diversity of the gut microbiota influences BA composition, whereas altered BA profiles can disrupt the microbiota. IBD patients often exhibit increased primary bile acid and reduced secondary bile acid concentrations due to a diminished bacteria population essential for BA metabolism. This imbalance activates BA receptors, undermining intestinal integrity and immune function. Consequently, targeting the microbiota-BA axis may rectify these disturbances, offering symptomatic relief in IBD. Here, the interplay between gut microbiota and bile acids (BAs) is reviewed, with a particular focus on the role of gut microbiota in mediating bile acid biotransformation, and contributions of the gut microbiota-BA axis to IBD pathology to unveil potential novel therapeutic avenues for IBD.

PMID 37027337 — Assessment of Nonalcoholic Fatty Liver Disease Symptoms and Gut-Liver Axis Status in Zebrafish after Exposure to Polystyrene Microplastics and Oxytetracycline, Alone and in Combination.

Environmental pollution may give rise to the incidence and progression of nonalcoholic fatty liver disease (NAFLD), the most common cause for chronic severe liver lesions. Although knowledge of NAFLD pathogenesis is particularly important for the development of effective prevention, the relationship between NAFLD occurrence and exposure to emerging pollutants, such as microplastics (MPs) and antibiotic residues, awaits assessment. This study aimed to evaluate the toxicity of MPs and antibiotic residues related to NAFLD occurrence using the zebrafish model species. Taking common polystyrene MPs and oxytetracycline (OTC) as representatives, typical NAFLD symptoms, including lipid accumulation, liver inflammation, and hepatic oxidative stress, were screened after 28-d exposure to environmentally realistic concentrations of MPs (0.69mg/L) and antibiotic residue (3.00μg/L). The impacts of MPs and OTC on gut health, the gut-liver axis, and hepatic lipid metabolism were also investigated to reveal potential affecting mechanisms underpinning the NAFLD symptoms observed. Compared with the control fish, zebrafish exposed to MPs and OTC exhibited significantly higher levels of lipid accumulation, triglycerides, and cholesterol contents, as well as inflammation, in conjunction with oxidative stress in their livers. In addition, a markedly smaller proportion of Proteobacteria and higher ratios of Firmicutes/Bacteroidetes were detected by microbiome analysis of gut contents in treated samples. After the exposures, the zebrafish also experienced intestinal oxidative injury and yielded significantly fewer numbers of goblet cells. Markedly higher levels of the intestinal bacteria-sourced endotoxin lipopolysaccharide (LPS) were also detected in serum. Animals treated with MPs and OTC exhibited higher expression levels of LPS binding receptor (LBP) and downstream inflammation-related genes while also exhibiting lower activity and gene expression of lipase. Furthermore, MP-OTC coexposure generally exerted more severe effects compared with single MP or OTC exposure. Our results suggested that exposure to MPs and OTC may disrupt the gut-liver axis and be associated with NAFLD occurrence. https://doi.org/10.1289/EHP11600.

PMID 37544446 — Effects of glyphosate exposure on gut-liver axis: Metabolomic and mechanistic analysis in grass carp (Ctenopharyngodon idellus).

Glyphosate, one of the most widely used herbicide worldwide, is potentially harmful to non-target aquatic organisms. However, the environmental health risks regarding impacts on metabolism homeostasis and underlying mechanisms remain unclear. Here we investigated bioaccumulation, metabolism disorders and mechanisms in grass carp after exposure to glyphosate. Higher accumulation of glyphosate and its major metabolite, aminomethylphosphonic acid, in the gut was detected. Intestinal inflammation, barrier damage and hepatic steatosis were caused by glyphosate exposure. Lipid metabolism disorder was confirmed by the decreased triglyceride, increased total cholesterol and lipoproteins in serum and decreased visceral fat. Metabolomics analysis found that glyphosate exposure significantly inhibited bile acids biosynthesis in liver with decreased total bile acids content, which was further supported by significant downregulations of cyp27a1, cyp8b1 and fxr. Moreover, the dysbiosis of gut microbiota contributed to the inflammation in liver and gut by increasing lipopolysaccharide, as well as to the declined bile acids circulation by reducing secondary bile acids. These results indicated that exposure to environmental levels of glyphosate generated higher bioaccumulation in gut, where evoked enterohepatic injury, intestinal microbiota dysbiosis and disturbed homeostasis of bile acids metabolism; then the functional dysregulation of the gut-liver axis possibly resulted in ultimate lipid metabolism disorder. These findings highlight the metabolism health risks of glyphosate exposure to fish in aquatic environment.

PMID 35456797 — Intestinal Alkaline Phosphatase: A Review of This Enzyme Role in the Intestinal Barrier Function.

Intestinal alkaline phosphatase (IALP) has recently assumed a special relevance, being the subject of study in the prevention and treatment of certain diseases related to leaky gut. This brush border enzyme (ecto-enzyme) plays an important role in the maintenance of intestinal microbial homeostasis and intestinal barrier function through its ability to dephosphorylate lipopolysaccharide (LPS). This review addresses how IALP and intestinal barrier dysfunction may be implicated in the pathophysiology of specific diseases such as inflammatory bowel disease, necrotizing enterocolitis, and metabolic syndrome. The use of IALP as a possible biomarker to assess intestinal barrier function and strategies to modulate IALP activity are also discussed.

PMID 35393656 — The human microbiome in disease and pathology.

This narrative review seeks to examine the relationships between bacterial microbiomes and infectious disease. This is achieved by detailing how different human host microbiomes develop and function, from the earliest infant acquisitions of maternal and environmental species through to the full development of microbiomes by adulthood. Communication between bacterial species or communities of species within and outside of the microbiome is a factor in both maintenance of homeostasis and management of threats from the external environment. Dysbiosis of this homeostasis is key to understanding the development of disease states. Several microbiomes and the microbiota within are used as prime examples of how changes in species composition, particularly at the phylum level, leads to such diverse conditions as inflammatory bowel disease (IBD), type 2 diabetes, psoriasis, Parkinson’s disease, reflux oesophagitis and others. The review examines spatial relationships between microbiomes to understand how dysbiosis in the gut microbiome in particular can influence diseases in distant host sites via routes such as the gut-lung, gut-skin and gut-brain axes. Microbiome interaction with host processes such as adaptive immunity is increasingly identified as critical to developing the capacity of the immune system to react to pathogens. Dysbiosis of essential bacteria involved in modification of host substrates such as bile acid components can result in development of Crohn’s disease, small intestine bacterial overgrowth, hepatic cancer and obesity. Interactions between microbiomes in distantly located sites are being increasingly being identified, resulting in a ‘whole of body’ effect by the combined host microbiome.

PMID 34944428 — Role of Intestinal Alkaline Phosphatase in Innate Immunity.

Intestinal alkaline phosphatase (IAP) is a multi-functional protein that has been demonstrated to primarily protect the gut. The role of IAP in maintaining intestinal homeostasis is underscored by the observation that IAP expression is defective in many gastrointestinal-related disorders such as inflammatory bowel disease IBD, necrotizing enterocolitis, and metabolic syndrome and that exogenous IAP supplementation improves the outcomes associated with these disorders. Additionally, studies using transgenic IAP-knock out (IAP-KO) mouse models further support the importance of the defensive role of IAP in the intestine. Supplementation of exogenous IAP and cellular overexpression of IAP have also been used in vitro to dissect out the downstream mechanisms of this protein in mammalian cell lines. Some of the innate immune functions of IAP include lipopolysaccharide (LPS) detoxification, protection of gut barrier integrity, regulation of gut microbial communities and its anti-inflammatory roles. A novel function of IAP recently identified is the induction of autophagy. Due to its critical role in the gut physiology and its excellent safety profile, IAP has been used in phase 2a clinical trials for treating conditions such as sepsis-associated acute kidney injury. Many excellent reviews discuss the role of IAP in physiology and pathophysiology and here we extend these to include recent updates on this important host defense protein and discuss its role in innate immunity via its effects on bacteria as well as on host cells. We will also discuss the relationship between IAP and autophagy and how these two pathways may act in concert to protect the gut.

PMID 34445822 — [Correlation of serum lipid profile and disease activity in patients with inflammatory bowel disease].

To analyze the correlation between lipid profile and disease activity in patients with inflammatory bowel disease (IBD).A total of 307 Crohn’s disease (CD) patients, 232 ulcerative colitis (UC) patients and 165 healthy subjects from the same geographic region were included. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a)[Lp(a)] were retrieved from their medical records. Crohn disease activity index (CDAI) and Mayo scores were calculated as measurement of disease severity for CD and UC separately. Patients with CD and UC had lower TC, TG, HDL-C and LDL-C levels than those in control group (P<0.05). Additionally, CDAI was negatively associated with TC, HDL-C and LDL-C levels (r=-0.218, -0.210, -0.176, P<0.05), while TG level was not associated with CDAI. Mayo scores was not significantly associated with TC, HDL-C, LDL-C and TG. Patients with CD had higher Lp(a) levels than those in UC and control group (P<0.05). Furthermore, patients with active CD had higher Lp (a) levels than those with inactive disease (P<0.05).The Lp(a) levels in CD patients were positively associated with CDAI (r=0.151, P<0.05), while Lp(a) level in UC group was nor assocriated with Mayo score. Patients with IBD have dyslipidemia and lipid profile is associated with disease activity in CD patients.

PMID 34579027 — Bile Acid-Gut Microbiota Axis in Inflammatory Bowel Disease: From Bench to Bedside.

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract, with increasing prevalence, and its pathogenesis remains unclear. Accumulating evidence suggested that gut microbiota and bile acids play pivotal roles in intestinal homeostasis and inflammation. Patients with IBD exhibit decreased microbial diversity and abnormal microbial composition marked by the depletion of phylum Firmicutes (including bacteria involved in bile acid metabolism) and the enrichment of phylum Proteobacteria. Dysbiosis leads to blocked bile acid transformation. Thus, the concentration of primary and conjugated bile acids is elevated at the expense of secondary bile acids in IBD. In turn, bile acids could modulate the microbial community. Gut dysbiosis and disturbed bile acids impair the gut barrier and immunity. Several therapies, such as diets, probiotics, prebiotics, engineered bacteria, fecal microbiota transplantation and ursodeoxycholic acid, may alleviate IBD by restoring gut microbiota and bile acids. Thus, the bile acid-gut microbiota axis is closely connected with IBD pathogenesis. Regulation of this axis may be a novel option for treating IBD.

PMID 34132111 — Leptin-resistant Zucker rats with trinitrobenzene sulfonic acid colitis present a reduced inflammatory response but enhanced epithelial damage.

The role of leptin in the development of intestinal inflammation remains controversial, since proinflammatory and anti-inflammatory effects have been described. This study describes the effect of the absence of leptin signaling in intestinal inflammation. Experimental colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to lean and obese Zucker rats (n = 10). Effects on inflammation and mucosal barrier were studied. Bacterial translocation and LPS concentration were evaluated together with colonic permeability to 4-kDa FITC-dextran. Obese Zucker rats showed a lower intestinal myeloperoxidase and alkaline phosphatase activity, reduced alkaline phosphatase sensitivity to levamisole, and diminished colonic expression of Nos2, Tnf, and Il6, indicating attenuated intestinal inflammation, associated with attenuated STAT3, AKT, and ERK signaling in the colonic tissue. S100a8 and Cxcl1 mRNA levels were maintained, suggesting that in the absence of leptin signaling neutrophil activation rather than infiltration is hampered. Despite the lower inflammatory response, leptin resistance enhanced intestinal permeability, reflecting an increased epithelial damage. This was shown by augmented LPS presence in the portal vein of colitic obese Zucker rats, associated with induction of tissue nonspecific alkaline phosphatase, LPS-binding protein, and CD14 hepatic expression (involved in LPS handling). This was linked to decreased ZO-1 immunoreactivity in tight junctions and lower occludin expression. Our results indicate that obese Zucker rats present an attenuated inflammatory response to TNBS, but increased intestinal epithelial damage allowing the passage of bacterial antigens.NEW & NOTEWORTHY Obese Zucker rats, which are resistant to leptin, exhibit a diminished inflammatory response in the trinitrobenzenesulfonic acid (TNBS) model of colitis, suggesting leptin role is proinflammatory. At the same time, obese Zucker rats present a debilitated intestinal barrier function, with increased translocation of LPS. Zucker rats present a dual response in the TNBS model of rat colitis.

PMID 31750766 — Metabolic Syndrome in Inflammatory Bowel Disease: Association with Genetic Markers of Obesity and Inflammation.

Background: This study analyzed poorly understood relationship of two overlapping conditions: metabolic syndrome (MeS) and inflammatory bowel disease (IBD), both associated with inflammation in the visceral adipose tissue. Methods: Newly diagnosed 104 IBD patients, of which 50 Crohn’s disease (CD) and 54 ulcerative colitis (UC), and 45 non-IBD controls were examined for MeS-related obesity and lipid markers. Th-17 immune genes IL17A, IL17F, IL23A, and TLR9 mRNAs were measured in intestinal mucosa by qRT-PCR. Subjects were genotyped for obesity-associated FTO variant rs9939609 by polymerase chain reaction-amplification refractory mutation system. Results: CD was associated with MeS (P = 0.01), while both CD and UC were associated with central obesity (P = 10-5, P = 0.002, respectively) and low levels of high-density lipoprotein (HDL) cholesterol (P = 5 × 10-6, P = 6 × 10-6, respectively). IBD lipid profile was characterized by decreased total and HDL cholesterol, while low-density lipoprotein cholesterol was reduced only in CD. Negative correlations were found between total cholesterol and CD activity index (P = 0.005), waist circumference and IL17A as well as IL17F mRNA levels in inflamed CD colon (P = 0.003, P = 0.001, respectively). Carriers of FTO rs9939609 AA genotype showed increased risk of CD (OR 2.6, P = 0.01). Conclusions: MeS, central obesity, and dyslipidemia could be important for IBD pathogenesis. This could influence therapeutic approaches and prevention strategies in high-risk groups.

PMID 33167028 — Exposure to dibutyl phthalate impairs lipid metabolism and causes inflammation via disturbing microbiota-related gut-liver axis.

Dibutyl phthalate (DBP), a kind of typical environmental pollutant, is widely used as plasticizers, and its neurotoxicity and developmental toxicity have been found in recent years. However, whether oral DBP exposure will affect the homeostasis of gut microbiota and its adverse response in liver of mammalians remain unclear. In the present study, 10-week experimental cycles of vehicle or DBP (0.1 and 1 mg/kg) were given to 6-week-old C57BL/6J mice by oral gavage. Our results revealed that the body weight of mice was increased after exposure to both low and high doses of DBP. The serum levels of hepatic triglyceride and total cholesterol were significantly increased in response to both doses of DBP. In addition, some pivotal genes related to lipogenesis were also increased in liver at the mRNA level. Evaluation of gut microbiota by 16S rRNA sequencing technology showed that 0.1 mg/kg DBP exposure significantly affected gut microbiota at the phylum and genus levels. Moreover, DBP exposure decreased mucus secretion and caused inflammation in the gut, leading to the impairment of intestinal barrier function. Exposure to DBP inhibited the expression of peroxisome proliferator-activated receptor-γ and activated the expression of nuclear factor kappa B. In addition, DBP exposure increased the level of lipopolysaccharide in serum, and increased the expression of toll-like receptor 4 and the levels of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha, in the liver. These results indicated that exposure to DBP disturbed the homeostasis of gut microbiota, induced hepatic lipid metabolism disorder, and caused liver inflammation in mice via the related gut-liver axis signaling pathways.

PMID 18597099 — Lipid and phospholipid profile after bowel resection for Crohn’s disease.

Chronic inflammation, impaired intestinal adsorption, and bowel resection may have an impact on lipid metabolism before and after intestinal surgery for Crohn’s disease (CD). The aim of this prospective study was to define the impact of intestinal surgery for CD on plasma phospholipid fatty acid (FA) composition and of serum plasma lipoprotein concentrations and to investigate the role of CD recurrence on lipid parameters. Twenty-four consecutive patients who had intestinal surgery for CD since December 2004 to March 2006 were enrolled in this prospective study. The total amount of calorie intake and the quality of the aliments, systemic inflammatory activity, and plasma lipoproteins and phospholipid fatty acid composition were determined at operation and at follow-up. Statistical analysis was performed with pair-matched tests. The median follow-up was 6 (4-20) months. During the follow-up, no significant modification of body mass index was observed. An increase of high-density lipoprotein (HDL) cholesterol (p=0.02) without other modifications in the plasma phospholipid FA composition were evidenced after surgery. The comparison between colectomy and ileo-colonic or ileal resection groups did not show any significant difference in the lipoprotein concentration and phospholipid FA profile. The length of resected bowel did not show any significant correlation with any relevant difference in lipid, phospholipid profile, or in inflammatory parameters. Patients who experienced a recurrence of CD reported significantly higher levels of total (p<0.01), HDL (p=0.01), and low-density lipoprotein cholesterol (p=0.01) were observed in patients in remission than in those with recurrent active disease. Patients who are submitted to intestinal resection for CD improve their inflammatory status as well as their lipid metabolism, and CD recurrence, but not the extent of bowel resection, is the main predictor of alteration of serum lipid concentration.

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