Multinational evaluation of clinical decision-making in the treatment and management of mild-to-moderate ulcerative colitis.

OBJECTIVES: To understand current thinking and clinical decision-making in the treatment and management of patients with mild-to-moderate ulcerative colitis (UC). METHODS: This multinational, survey-based study was conducted in 2021. Two meetings were held, involving 11 IBD specialists, that used a series of questions and discussion to identify all factors possibly related to the management of UC. The importance of identified factors was assessed using an online questionnaire covering three scenarios - active disease, remission and patient empowerment. Each factor was scored on a scale of 0 (very-unimportant) to 100 (very-important) within each scenario, by a separate group of healthcare professionals working in IBD. RESULTS: A total of 157 individual factors were identified by the 11 IBD specialists and scored in the three scenarios by 56 respondents (52; 93% specialist gastroenterologists) from Europe and North America (25; 45%), South America (19; 34%) and the Middle East, Asia and Australia (12; 21%). For all scenarios, factors related to educating patients regarding UC and its treatment and understanding of patient goals ranked highest, ahead of clinical considerations regarding disease activity and treatment history. Setting realistic short-term treatment targets was a key consideration. 5-ASA optimisation and use of faecal calprotectin monitoring were core strategies across the three scenarios tested. Support for patients during longer-term management of their disease, starting from initial flare, was an important recurring theme. CONCLUSION: The current management approach for mild-to-moderate UC was found to be guided primarily by the patient's perspectives and goals, alongside assessment of their medical and disease history.

The Underestimated and Overlooked Burden of Diarrhea and Constipation in Cancer Patients.

PURPOSE OF REVIEW: This review aims to summarize and discuss the diverse causes of two major gastrointestinal dysfunction symptoms, diarrhea and constipation, in cancer patients. We also discuss short- and long-term clinical, economic, and humanistic consequences, including the impact on cancer treatment regimens and patient quality of life, highlighting the limitations of the literature. RECENT FINDINGS: Diarrhea and constipation as a result of cancer and its treatment can risk the success of anti-cancer therapies by requiring treatment delay or withdrawal, and imposes a substantial humanistic burden in patients with cancer. Despite its importance and frequency, gastrointestinal side effects may be overlooked due to the focus on cancer treatment, and the impact on patients may be underestimated. Additionally, the burden reported may not fully reflect current cancer management, particularly the true impact of economic consequences. A full understanding of the burden of diarrhea and constipation in patients with cancer is required, including broad evaluation of clinical considerations, the patient experience, and an updated assessment of economic burden. This would improve caregivers' appreciation of the impact of gastrointestinal dysfunction and aid the prioritization of future research efforts.

Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans.

OBJECTIVE: Alcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD. DESIGN: An unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models. RESULTS: Cirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis. CONCLUSION: Cirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.

Liver-Microbiome Axis in Health and Disease.

The intestinal and hepatobiliary tract exhibits host-specific commensal colonization. The resident microbiota has emerged as a key player in intestinal and hepatic diseases. Alcoholic and nonalcoholic fatty liver diseases (ALD/NAFLD), primary sclerosing cholangitis (PSC), liver cirrhosis, and some of their clinical complications, such as hepatic encephalopathy (HE), have been linked to a microbial signature, as also observed for severe liver inflammation in alcoholic hepatitis. In turn, the liver impacts, and communicates with, the microbiota through hepatic mediators, such as bile acids or inflammatory signals. Therefore, a liver-microbiome bidirectional crosstalk appears to be critical in health and various liver diseases and could be therapeutically targeted, such as by fecal microbiota transplantation.

Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-κB-inducible immune pathways.

Erythropoietin (EPO) is the principal cytokine regulating erythropoiesis through its receptor, EPOR. Interestingly, EPORs are also found on immune cells with incompletely understood functions. Here, we show that EPO inhibits the induction of proinflammatory genes including tumor necrosis factor (TNF)-α and inducible nitric oxide (NO) synthase in activated macrophages, which is mechanistically attributable to blockage of nuclear factor (NF)-κB p65 activation by EPO. Accordingly, in systemic Salmonella infection, treatment of mice with EPO results in reduced survival and impaired pathogen clearance because of diminished formation of anti-microbial effector molecules such as TNF-α and NO. However, neutralization of endogenous EPO or genetic ablation of Epor promotes Salmonella elimination. In contrast, in chemically induced colitis, EPO-EPOR interaction decreases the production of NF-κB-inducible immune mediators, thus limiting tissue damage and ameliorating disease severity. These immune-modulatory effects of EPO may be of therapeutic relevance in infectious and inflammatory diseases.

Dimethyl fumarate ameliorates hepatic inflammation in alcohol related liver disease.

BACKGROUND & AIMS: Alcohol-related liver disease (ALD) comprises different liver disorders which impose a health care issue. ALD and particularly alcoholic steatohepatitis, an acute inflammatory condition, cause a substantial morbidity and mortality as effective treatment options remain elusive. Inflammation in ALD is fuelled by macrophages (Kupffer cells [KCs]) which are activated by intestinal pathogen associated molecular patterns, eg lipopolysaccharide (LPS), disseminated beyond a defective intestinal barrier. We hypothesized that the immunomodulator dimethyl-fumarate (DMF), which is approved for the treatment of human inflammatory conditions such as multiple sclerosis or psoriasis, ameliorates the course of experimental ALD. METHODS: Dimethyl-fumarate or vehicle was orally administered to wild-type mice receiving a Lieber-DeCarli diet containing 5% ethanol for 15 days. Liver injury, steatosis and inflammation were evaluated by histology, biochemical- and immunoassays. Moreover, we investigated a direct immunosuppressive effect of DMF on KCs and explored a potential impact on ethanol-induced intestinal barrier disruption. RESULTS: Dimethyl-fumarate protected against ethanol-induced hepatic injury, steatosis and inflammation in mice. Specifically, we observed reduced hepatic triglyceride and ALT accumulation, reduced hepatic expression of inflammatory cytokines (Tnf-α, Il-1ß, Cxcl1) and reduced abundance of neutrophils and macrophages in ethanol-fed and DMF-treated mice when compared to vehicle. DMF protected against ethanol-induced barrier disruption and abrogated systemic LPS concentration. In addition, DMF abolished LPS-induced cytokine responses of KCs. CONCLUSIONS: Dimethyl-fumarate counteracts ethanol-induced barrier dysfunction, suppresses inflammatory responses of KCs and ameliorates hepatic inflammation and steatosis, hallmarks of experimental ALD. Our data indicates that DMF treatment might be beneficial in human ALD and respective clinical trials are eagerly awaited.

Nuclear orphan receptor NR2F6 as a safeguard against experimental murine colitis.

OBJECTIVE: Nuclear receptors are known to regulate both immune and barrier functions in the GI tract. The nuclear orphan receptor NR2F6 has been shown to suppress the expression of proinflammatory cytokines in T lymphocytes. NR2F6 gene expression is reduced in patients with IBS or UC, but its functional role and tissue dependency in healthy and inflamed gut have not yet been investigated. DESIGN: Intestinal inflammation was induced in wild-type, Nr2f6-deficient, Rag1-deficient or bone marrow-reconstituted mice by administration of chemical (dextran sodium sulfate (DSS)) and immunogenic (T cell transfer) triggers. Disease phenotypes were investigated by survival, body weight, colon length and analysis of immune cell infiltrates. Additionally, histology, intestinal permeability, tight junction proteins, bacterial fluorescence in situ hybridisation, apoptosis, cell proliferation and mucus production were investigated. RESULTS: Nr2f6-deficient mice were highly susceptible to DSS-induced colitis characterised by enhanced weight loss, increased colonic tissue destruction and immune cell infiltration together with enhanced intestinal permeability and reduced Muc2 expression. T cell transfer colitis and bone marrow reconstitution experiments demonstrated that disease susceptibility was not dependent on the expression of Nr2f6 in the immune compartment but on the protective role of NR2F6 in the intestinal epithelium. Mechanistically, we show that NR2F6 binds to a consensus sequence at -2 kb of the Muc2 promoter and transactivates Muc2 expression. Loss of NR2F6 alters intestinal permeability and results in spontaneous late-onset colitis in Nr2f6-deficient mice. CONCLUSION: We have for the first time identified a fundamental and non-redundant role of NR2F6 in protecting gut barrier homeostasis.

NAD metabolism fuels human and mouse intestinal inflammation.

OBJECTIVE: Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway. NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism. DESIGN: We investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD. RESULTS: FK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1-/- mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10. CONCLUSION: Our data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.

Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease.

OBJECTIVE: Alcoholic liver disease (ALD) is a global health problem with limited therapeutic options. Intestinal barrier integrity and the microbiota modulate susceptibility to ALD. Akkermansia muciniphila, a Gram-negative intestinal commensal, promotes barrier function partly by enhancing mucus production. The aim of this study was to investigate microbial alterations in ALD and to define the impact of A. muciniphila administration on the course of ALD. DESIGN: The intestinal microbiota was analysed in an unbiased approach by 16S ribosomal DNA (rDNA) sequencing in a Lieber-DeCarli ALD mouse model, and faecal A. muciniphila abundance was determined in a cohort of patients with alcoholic steatohepatitis (ASH). The impact of A. muciniphila on the development of experimental acute and chronic ALD was determined in a preventive and therapeutic setting, and intestinal barrier integrity was analysed. RESULTS: Patients with ASH exhibited a decreased abundance of faecal A. muciniphila when compared with healthy controls that indirectly correlated with hepatic disease severity. Ethanol feeding of wild-type mice resulted in a prominent decline in A. muciniphila abundance. Ethanol-induced intestinal A. muciniphila depletion could be restored by oral A. muciniphila supplementation. Furthermore, A. muciniphila administration when performed in a preventive setting decreased hepatic injury, steatosis and neutrophil infiltration. A. muciniphila also protected against ethanol-induced gut leakiness, enhanced mucus thickness and tight-junction expression. In already established ALD, A. muciniphila used therapeutically ameliorated hepatic injury and neutrophil infiltration. CONCLUSION: Ethanol exposure diminishes intestinal A. muciniphila abundance in both mice and humans and can be recovered in experimental ALD by oral supplementation. A. muciniphila promotes intestinal barrier integrity and ameliorates experimental ALD. Our data suggest that patients with ALD might benefit from A. muciniphila supplementation.

Ethanol-mediated suppression of IL-37 licenses alcoholic liver disease.

BACKGROUND & AIMS: Chronic alcohol consumption and alcoholic liver disease (ALD) afflicts individuals with substantial morbidity and mortality with limited treatment options available. Hepatic inflammation, triggered by activated Kupffer cells, is a driving force in alcoholic liver disease. Interleukin 37 (IL-37) exerts anti-inflammatory effects in hepatic diseases, however, the impact of Interleukin 37 on alcoholic liver disease is unknown. In this study, we addressed the role of Interleukin 37 in alcoholic liver disease. METHODS: We utilized Interleukin 37 expressing transgenic mice and human recombinant Interleukin 37 in models of alcoholic liver disease. Interleukin 37 expression was measured in liver samples of 20 alcoholic steatohepatitis and 36 non-alcoholic fatty liver disease patients. RESULTS: Interleukin 37 transgenic mice are not protected against hepatic injury and inflammation in alcoholic liver disease. Ethanol suppressed Interleukin 37 expression in transgenic mice. Alcoholic steatohepatitis (ASH) patients similarly exhibited reduced Interleukin 37 expression when compared to non-alcoholic fatty liver disease (NAFLD) patients. Human recombinant Interleukin 37 ameliorated hepatic inflammation in a binge drinking model of alcoholic liver disease. CONCLUSION: We provide evidence for an exogenous noxae that suppresses Interleukin 37 expression which limits its anti-inflammatory effects in alcoholic liver disease.

Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

UNLABELLED: Both alcoholic liver disease (ALD) and nonalcoholic fatty liver disease are characterized by massive lipid accumulation in the liver accompanied by inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma in a substantial subgroup of patients. At several stages in these diseases, mediators of the immune system, such as cytokines or inflammasomes, are crucially involved. In ALD, chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharides through Toll-like receptors, e.g., Toll-like receptor 4. This sensitization enhances the production of various proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha, thereby contributing to hepatocyte dysfunction, necrosis, and apoptosis and the generation of extracellular matrix proteins leading to fibrosis/cirrhosis. Indeed, neutralization of IL-1 by IL-1 receptor antagonist has recently been shown to potently prevent liver injury in murine models of ALD. As IL-1 is clearly linked to key clinical symptoms of acute alcoholic hepatitis such as fever, neutrophilia, and wasting, interfering with the IL-1 pathway might be an attractive treatment strategy in the future. An important role for IL-1-type cytokines and certain inflammasomes has also been demonstrated in murine models of nonalcoholic fatty liver disease. IL-1-type cytokines can regulate hepatic steatosis; the NLR family pyrin domain containing 3 inflammasome is critically involved in metabolic dysregulation. CONCLUSION: IL-1 cytokine family members and various inflammasomes mediate different aspects of both ALD and nonalcoholic fatty liver disease. (Hepatology 2016;64:955-965).

Weight loss induced by bariatric surgery restores adipose tissue PNPLA3 expression.

BACKGROUND & AIMS: Obesity and its related co-morbidities such as non-alcoholic fatty liver disease (NAFLD) are increasing dramatically worldwide. The genetic variation in Patatin-like phospholipase domain-containing protein 3 (PNPLA3), which is also called adiponutrin (ADPN), in residue 148 (I148M, rs738409) has been associated with NAFLD. However, the regulation and function of PNPLA3 in metabolic diseases remains unclear. Laparoscopic gastric banding (LAGB) of severely obese patients reduces body weight, liver and adipose tissue inflammation. In this study, we investigated whether weight loss induced by LAGB affected PNPLA3 expression in hepatic and adipose tissue. METHODS: Liver and subcutaneous adipose tissue samples were collected from 28 severely obese patients before and 6 months after LAGB. PNPLA3 expression was assessed by quantitative real-time PCR. To understand whether inflammatory stimuli regulated PNPLA3 expression, we studied the effect of tumour necrosis factor alpha (TNFα) and lipopolysaccharide (LPS) on PNPLA3 expression in human adipocytes and hepatocytes. RESULTS: PNPLA3 was strongly expressed in the liver and clearly detectable in subcutaneous adipose tissue of obese patients. Weight loss induced by LAGB of severely obese patients led to significantly increased adipose, but not hepatic, tissue expression of PNPLA3. Subcutaneous PNPLA3 expression negatively correlated with body-mass-index, fasting glucose and fasting insulin. TNFα potently suppressed PNPLA3 expression in adipocytes but not hepatocytes. CONCLUSIONS: Weight loss induced by LAGB restored adipose tissue PNPLA3 expression which is suppressed by TNFα. Further studies will be required to determine the functional impact of PNPLA3 and its related genetic variation on adipose tissue inflammation and NAFLD.

Adipocytokines: mediators linking adipose tissue, inflammation and immunity.

There has been much effort recently to define the role of adipocytokines, which are soluble mediators derived mainly from adipocytes (fat cells), in the interaction between adipose tissue, inflammation and immunity. The adipocytokines adiponectin and leptin have emerged as the most abundant adipocyte products, thereby redefining adipose tissue as a key component not only of the endocrine system, but also of the immune system. Indeed, as we discuss here, several adipocytokines have a central role in the regulation of insulin resistance, as well as many aspects of inflammation and immunity. Other adipocytokines, such as visfatin, have only recently been identified. Understanding this rapidly growing family of mainly adipocyte-derived mediators might be of importance in the development of new therapies for obesity-associated diseases.

Food, immunity, and the microbiome.

There is increasing evidence that ingested diet-borne components are involved in the pathogenesis of disorders such as inflammatory bowel diseases, atherosclerosis, and type 2 diabetes. Nutrients can have short- and long-term effects in shaping the composition of the microbiota. Western diets (enriched in fat, phosphatidylcholine, and L-carnitine) promote inflammation and atherosclerosis through specific fatty acids and degradation products such as trimethylamine N-oxide. Other dietary factors such as carbazoles or tryptophan-enriched proteins have anti-inflammatory properties-partly via activation of aryl hydrocarbon receptors. The microbiota and its metabolic machinery produce a myriad of metabolites that serve as important messengers between the diet, microbiota, and host. Short-chain fatty acids affect immune responses and epithelial integrity via G-protein-coupled receptors and epigenetic mechanisms. By increasing our understanding of interactions between diet, immunity, and the microbiota, we might develop food-based approaches to prevent or treat many diseases. There now is scientific evidence to support the adage "we are what we eat," and this process begins in early life.

Lipocalin-2 ensures host defense against Salmonella Typhimurium by controlling macrophage iron homeostasis and immune response.

Lipocalin-2 (Lcn2) is an innate immune peptide with pleiotropic effects. Lcn2 binds iron-laden bacterial siderophores, chemo-attracts neutrophils and has immunomodulatory and apoptosis-regulating effects. In this study, we show that upon infection with Salmonella enterica serovar Typhimurium, Lcn2 promotes iron export from Salmonella-infected macrophages, which reduces cellular iron content and enhances the generation of pro-inflammatory cytokines. Lcn2 represses IL-10 production while augmenting Nos2, TNF-α, and IL-6 expression. Lcn2(-/-) macrophages have elevated IL-10 levels as a consequence of increased iron content. The crucial role of Lcn-2/IL-10 interactions was further demonstrated by the greater ability of Lcn2(-/-) IL-10(-/-) macrophages and mice to control intracellular Salmonella proliferation in comparison to Lcn2(-/-) counterparts. Overexpression of the iron exporter ferroportin-1 in Lcn2(-/-) macrophages represses IL-10 and restores TNF-α and IL-6 production to the levels found in wild-type macrophages, so that killing and clearance of intracellular Salmonella is promoted. Our observations suggest that Lcn2 promotes host resistance to Salmonella Typhimurium infection by binding bacterial siderophores and suppressing IL-10 production, and that both functions are linked to its ability to shuttle iron from macrophages.

The role of lipocalin-2 in liver regeneration.

BACKGROUND & AIMS: Various immune mediators such as interleukin-6 (IL-6) have been implicated in the process of liver regeneration. Lipocalin-2 (LCN2) has been recently characterized as a prototypic immune mediator produced by various cell types being involved mainly in host defence. In addition, numerous studies have demonstrated its clinical value as a biomarker. This study aimed at defining the role of LCN2 in liver regeneration. METHODS: We studied LCN2 expression in wild-type mice in a model of partial hepatectomy (PH). Furthermore, we evaluated liver regeneration after PH in LCN-deficient mice compared to littermate controls. Serum levels of LCN2 were assessed in a small group of patients undergoing hepatic resection. RESULTS: LCN2 is dramatically induced in livers and sera of wild-type mice after PH, whereas liver LCN2-receptor expression was decreased. Sham operations did not affect hepatic and serum LCN2 expression. Although LCN2-deficient mice exhibited increased baseline liver expression indices, LCN2-deficient mice did not differ from wild-type mice with respect to hepatic proliferation suggesting that this molecule is not involved in hepatic repair. Only serum IL-1ß levels were slightly lower in LCN(-/-) mice, whereas IL-6 serum levels did not differ between various tested animal groups. In humans undergoing hepatic resection, LCN2 levels increased significantly within 24 h following surgery. CONCLUSIONS: LCN2, although massively induced in mice after PH, is not relevant in murine hepatic regeneration. Further, human studies have to define whether LCN2 could evolve as biomarker after liver surgery.

Microbiota and diabetes: an evolving relationship.

The gut microbiota affects numerous biological functions throughout the body and its characterisation has become a major research area in biomedicine. Recent studies have suggested that gut bacteria play a fundamental role in diseases such as obesity, diabetes and cardiovascular disease. Data are accumulating in animal models and humans suggesting that obesity and type 2 diabetes (T2D) are associated with a profound dysbiosis. First human metagenome-wide association studies demonstrated highly significant correlations of specific intestinal bacteria, certain bacterial genes and respective metabolic pathways with T2D. Importantly, especially butyrate-producing bacteria such as Roseburia intestinalis and Faecalibacterium prausnitzii concentrations were lower in T2D subjects. This supports the increasing evidence, that butyrate and other short-chain fatty acids are able to exert profound immunometabolic effects. Endotoxaemia, most likely gut-derived has also been observed in patients with metabolic syndrome and T2D and might play a key role in metabolic inflammation. A further hint towards an association between microbiota and T2D has been derived from studies in pregnancy showing that major gut microbial shifts occurring during pregnancy affect host metabolism. Interestingly, certain antidiabetic drugs such as metformin also interfere with the intestinal microbiota. Specific members of the microbiota such as Akkermansia muciniphila might be decreased in diabetes and when administered to murines exerted antidiabetic effects. Therefore, as a 'gut signature' becomes more evident in T2D, a better understanding of the role of the microbiota in diabetes might provide new aspects regarding its pathophysiological relevance and pave the way for new therapeutic principles.

Adipose tissue and liver expression of SIRT1, 3, and 6 increase after extensive weight loss in morbid obesity.

BACKGROUND & AIMS: Severe obesity is associated with a state of chronic inflammation. Sirtuins (SIRT) are a family of conserved enzymes which are able to affect many metabolic and inflammatory pathways thereby potentially improving health and increasing lifespan. METHODS: We investigated the effect of weight loss on subcutaneous adipose tissue and liver mRNA and immunohistochemical expression of SIRT1, SIRT3, and SIRT6. Twenty-nine severely obese patients undergoing laparoscopic adjustable gastric banding (LAGB) were studied. Tissue samples were collected before and 6months after LAGB surgery. Tissue mRNA expression levels of SIRT1, SIRT3, and SIRT6 were correlated with clinical, biochemical, and histological parameters. In vitro, we studied sirtuin expression in native and stimulated monocytes, adipocytes, and hepatocytes. RESULTS: SIRT1, SIRT3, and SIRT6 mRNA expression was higher in the subcutaneous adipose tissue than in the liver. Weight loss resulted in a significant induction of SIRT1, SIRT3, and SIRT6 expression in the subcutaneous adipose tissue. In the liver, a significant increase after weight loss was observed, particularly for SIRT3 and SIRT6 mRNA expression; immunohistochemically, SIRT1 and SIRT3 expression was upregulated. Endotoxin and tumor necrosis factor-alpha suppressed SIRT1, SIRT3, and SIRT6 expression in human monocytes. The same stimuli suppressed total sirtuin deacetylase activity again, mainly in monocytes and less in adipocytes and hepatocytes. CONCLUSIONS: The relative abundance of adipose tissue mRNA expression of certain sirtuins exceeds its expression in the liver. Extensive weight loss increases sirtuin expression significantly both in adipose tissue and liver, probably as a consequence of reduced inflammation.