The gut and the liver are anatomically and physiologically connected, and this connection is called the "gut-liver axis," which exerts various influences on liver physiology and pathology. The gut microbiota has been recognized to trigger innate immunity and modulate the liver immune microenvironment. Gut microbiota influences the physiological processes in the host, such as metabolism, by acting on various signaling receptors and transcription factors through their metabolites and related molecules. The gut microbiota has also been increasingly recognized to modulate the efficacy of immune checkpoint inhibitors. In this review, we discuss recent updates on gut microbiota-associated mechanisms in the pathogenesis of chronic liver diseases such as NAFLD and NASH, as well as liver cancer, in light of the gut-liver axis. We particularly focus on gut microbial metabolites and components that are associated with these liver diseases. We also discuss the role of gut microbiota in modulating the response to immunotherapy in liver diseases.

Pain is a multidimensional condition of multiple origins. Determining both intensity and underlying cause are critical for effective management. Utilization of painkillers does not follow any guidelines relying on biomarkers, which effectively eliminates objective treatment. The aim of this study was to evaluate the use of serum cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as pain biomarkers. This work could significantly advance the diagnosis and treatment of pain.

We assessed the potential utility of serum COX-2 and iNOS as objective measures of pain in a sample of American patients. Pain was scaled between level 0-5 in accordance with the level reported by the patients. Blood samples were collected from 102 patients in the emergency room. Sandwich ELISA was used to determine the COX-2 and iNOS levels in the blood serum while statistical analysis was performed using Pearson product-moment correlation coefficients, Regression and Receiver Operating Characteristics (ROC) analyses. The biomarker results were also compared with self-reports of pain by the patients using conventional pain ratings and patients were asked to report the cause of the pain. Pain levels were clustered into four groups as 0 [self-reported 0], 1 [self-reported as 1], 2 [self-reported as 2 and 3] and 3 [self-reported as 4 and 5]. Co-expression of COX-2 and iNOS could significantly alter pain development and its sensitization. Therefore, iNOS dependent COX-2 levels were employed as categorized level.

Self-reported pain levels did not show a correlation with the serum level of COX-2 and iNOS. The lack of correlation is attributed to multiple reasons including patients' intake of painkillers prior to participation, painkiller intake habit, chronic diseases, and subjectivity of self-reported pain. Increased serum COX-2 levels were reported in relation to the subtypes of these health issues. Further, 83% of the patients who reported pain also showed the presence of COX-2 in serum, while only 53% of the patients showed the presence of iNOS in serum. Moderate relation was found between the clustered pain level and categorized COX-2 and iNOS- levels.

The findings support the requirement of further studies to use COX-2 and iNOS as prognostic biomarkers for objective quantification of pain at the clinical level.

The biosynthesis of prostaglandins and thromboxanes has been a focus of interest in the management of many liver diseases. Cyclooxygenases are the enzymes involved in the first step of the biosynthesis of these lipid mediators and selective inhibitors for these isoenzymes as well as pharmacological analogues of prostaglandins have been developed and are currently applied therapeutically. Here we discuss the implications of these enzymes in the onset of metabolic and lipid disorders in the liver and their potential role in the progression of the diseases towards fibrosis and hepatocellular carcinogenesis.