Search

In this issue of Cancer Cell , Bell et al. identify the commensal bacterium Lactobacillus reuteri and its major metabolite reuterin as an important gatekeeper and promising target in colorectal cancerogenesis. They decipher a metabolic interplay in which L. reuteri is suppressed by metabolites from dysplastic intestinal epithelial cells which in turn are highly sensitive to the oxidative effects of the electrophile reuterin. [ABSTRACT FROM AUTHOR]

Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is released by various cell types and is an attractive biomarker of inflammation, ischemia, infection, and kidney damage. Both intestinal and metabolic inflammation, as observed in obesity and related disorders, are associated with increased LCN2 synthesis. While LCN2 in the intestinal tract regulates the composition of the gut microbiota and shows anti-inflammatory activities, it also exhibits proinflammatory activities in other experimental settings. In animal models of metabolic inflammation, type 2 diabetes mellitus (T2DM), or nonalcoholic steatohepatitis (NASH), increased LCN2 expression favors inflammation via the recruitment of inflammatory cells, such as neutrophils, and the induction of proinflammatory cytokines. A better understanding of this crucial marker of innate immunity might pave the way for targeting this pathway in future therapies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary Cholesterol metabolism is closely interrelated with cardiovascular disease in humans. Dietary supplementation with omega-6 polyunsaturated fatty acids including arachidonic acid (AA) was shown to favorably affect plasma LDL-C and HDL-C. However, the underlying mechanisms are poorly understood. By combining data from a GWAS screening in >100,000 individuals of European ancestry, mediator lipidomics, and functional validation studies in mice, we identify the AA metabolome as an important regulator of cholesterol homeostasis. Pharmacological modulation of AA metabolism by aspirin induced hepatic generation of leukotrienes (LTs) and lipoxins (LXs), thereby increasing hepatic expression of the bile salt export pump Abcb11. Induction of Abcb11 translated in enhanced reverse cholesterol transport, one key function of HDL. Further characterization of the bioactive AA-derivatives identified LX mimetics to lower plasma LDL-C. Our results define the AA metabolome as conserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans. [ABSTRACT FROM AUTHOR]

Highlights: [•] NAFLD is characterized by dysbiosis. [•] The intestinal microbiota contributes to NAFLD development. [•] Innate immunity plays a major role in NAFLD. [•] Proinflammatory cytokines are the driving forces for NASH. [Copyright &y& Elsevier]

Non-alcoholic fatty liver disease (NAFLD), the major cause of abnormal liver function in the western world, is often associated with obesity and diabetes. In obese individuals, fat accumulation in the abdominal region affects both lipid and glucose metabolism, and a liver loaded with fat is insulin resistant. Insulin resistance (IR) is often associated with chronic low-grade inflammation, and numerous mediators released from immune cells and adipocytes contribute to development of IR. Recent results showing an important role for these mediators in NAFLD are providing us with a better understanding of this highly prevalent disease with implications for novel therapy development. This review highlights new aspects in development of liver steatosis and the relevance of various cytokines and adipocytokines in NAFLD. [Copyright &y& Elsevier]

Abstract: The type I interferons interferon alpha (IFNα) and IFNβ are the first line of defense potently induced upon viral infection, and at the same time are immunomodulatory cytokines bridging innate and adaptive immunity. T cells secreting interleukin-17 (IL-17) have recently been identified to regulate neutrophil-mediated inflammation, and have been implicated in the pathogenesis of experimental colitis and human inflammatory bowel disease, and are considered to regulate the inflammatory response in these models. We therefore hypothesized that type I IFNs as sentinels of viral infection might counteract the development of Th17 cells. We studied the effects of IFNα on IL-17 mRNA and protein expression in human peripheral blood mononuclear cells (PBMC) and during differentiation of human and murine naïve T cells into Th17 cells. In patients with ulcerative colitis (UC) treated systemically with IFNα, we studied colonic expression of IL-17 before and 4 weeks after therapy. IFNα potently suppressed IL-17 production in PBMC both at the mRNA and protein level. Th17 differentiation of human and murine naïve T cells was markedly suppressed in the presence of IFNα. UC patients exhibited increased IL-17 expression in colonic tissue biopsies compared to healthy controls, which was down-regulated during IFNα therapy. IL-17 expression in colonic tissue correlated with clinical remission in these patients. Our data suggest that IFNα down-regulates IL-17 expression and Th17 differentiation in vitro and in vivo. As a corollary, these effects might play a role in the mode of action of type I IFNs in the treatment of various diseases. [Copyright &y& Elsevier]

Background & Aims: Portal fibrosis and linkage is a key feature of progressive disease in nonalcoholic steatohepatitis (NASH), but not simple steatosis. It is underappreciated and poorly understood. Fatty liver has impaired regeneration that induces a secondary replicative pathway using bipotential, periportal, hepatic progenitor cells (HPCs). We propose that activation of this pathway, with increased cell injury in NASH, also induces a periportal ductular reaction (DR) that could produce a profibrogenic stimulus. Methods: Biopsy specimens from 107 patients with nonalcoholic fatty liver disease and 11 controls were immunostained with cytokeratin-7 to quantify the DR and HPCs, and with p21 to assess hepatocyte replicative arrest. These results were correlated with clinicopathologic variables. Results: Patients with nonalcoholic fatty liver disease had expansion of HPCs, with a strong association between HPCs and the DR (rs = 0.582, P < .0001). In those with NASH (n = 69) there was an increased DR compared with simple steatosis, which correlated with the stage of fibrosis (rs = 0.510, P < .0001). The DR increased with the grade of NASH activity (rs = 0.478, P < .0001), grade of portal inflammation (rs = 0.445, P < .0001), and extent of hepatocyte replicative arrest (rs = 0.446, P < .0001). Replicative arrest was in turn associated with insulin resistance (rs = 0.450, P < .0001) and NASH activity (rs = 0.452, P < .0001). By multivariate analysis, the extent of DR (odds ratio [OR] = 17.9, P = .016), hepatocyte ballooning (OR = 8.1, P < .0001), and portal inflammation (OR = 3.3, P = .005) were associated independently with fibrosis. Conclusions: These findings suggest that an altered replication pathway in active NASH promotes a periportal DR, which in turn may provoke progressive periportal fibrogenesis. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a strong impact on microbial composition and provides risk for developing colorectal carcinoma (CRC). Large metagenomic studies in human CRC associated microbiome signatures with the colorectal adenoma-carcinoma sequence, suggesting a fundamental role of the intestinal microbiota in the evolution of gastrointestinal malignancy. Basic science established a critical function for the intestinal microbiota in promoting tumorigenesis. Further studies are needed to decipher the mechanisms of tumor promotion and microbial co-evolution in CRC, which may be exploited therapeutically in the future. [ABSTRACT FROM AUTHOR]