Nature Reviews Gastroenterology &Hepatology最新文献

A study published in Nature elucidates the genomic landscape of colorectal cancer (CRC). Researchers performed whole-genome sequencing of CRC samples from participants in the UK 100,000 Genomes Project. Analysis of the samples (n = 2,023) identified >250 putative driver genes of CRC and characterized subgroups of CRC. For example, the researchers clustered microsatellite-stable CRC into four distinct subgroups and also characterized rare CRC subgroups. In addition, they identified a potential role in CRC for the mutational signature SBS93, among others.

Ammonia levels are orchestrated by a series of complex interrelated pathways in which the urea cycle has a central role. Liver dysfunction leads to an accumulation of ammonia, which is toxic and is strongly associated with disruption of potassium homeostasis, mitochondrial dysfunction, oxidative stress, inflammation, hypoxaemia and dysregulation of neurotransmission. Hyperammonaemia is a hallmark of hepatic encephalopathy and has been strongly associated with liver-related outcomes in patients with cirrhosis and liver failure. In addition to the established role of ammonia as a neurotoxin in the pathogenesis of hepatic encephalopathy, an increasing number of studies suggest that it can lead to hepatic fibrosis progression, sarcopenia, immune dysfunction and cancer. However, elevated systemic ammonia levels are uncommon in patients with metabolic dysfunction-associated steatotic liver disease. A clear causal relationship between ammonia-induced immune dysfunction and risk of infection has not yet been definitively proven. In this Review, we discuss the mechanisms by which ammonia produces its diverse deleterious effects and their clinical relevance in liver diseases, the importance of measuring ammonia levels for the diagnosis of hepatic encephalopathy, the prognosis of patients with cirrhosis and liver failure, and how our knowledge of inter-organ ammonia metabolism is leading to the development of novel therapeutic approaches.

In a study published in Nature Medicine, researchers report an artificial intelligence (AI)-based digital pathology tool for scoring metabolic dysfunction-associated steatohepatitis (MASH; formerly known as nonalcoholic steatohepatitis (NASH)) histology. MASH clinical trial enrollment and endpoint assessment are based on histological criteria. The tool, which is termed AIM-MASH, produced predictions for steatosis grade and fibrosis stage that were comparable to consensus MASH Clinical Research Network grading and staging. The aim of the tool is to reduce variability in interpretation for trial outcomes, improve sensitivity of scoring systems and assist pathologists in histological review of clinical trials for MASH.

Chronic liver disease is a major cause of morbidity and mortality worldwide. Epidemiology, clinical phenotype and response to therapies for gastrointestinal and liver diseases are commonly different between women and men due to sex-specific hormonal, genetic and immune-related factors. The hepatic immune system has unique regulatory functions that promote the induction of intrahepatic tolerance, which is key for maintaining liver health and homeostasis. In liver diseases, hepatic immune alterations are increasingly recognized as a main cofactor responsible for the development and progression of chronic liver injury and fibrosis. In this Review, we discuss the basic mechanisms of sex disparity in hepatic immune regulation and how these mechanisms influence and modify the development of autoimmune liver diseases, genetic liver diseases, portal hypertension and inflammation in chronic liver disease. Alterations in gut microbiota and their crosstalk with the hepatic immune system might affect the progression of liver disease in a sex-specific manner, creating potential opportunities for novel diagnostic and therapeutic approaches to be evaluated in clinical trials. Finally, we identify and propose areas for future basic, translational and clinical research that will advance our understanding of sex disparities in hepatic immunity and liver disease.

Alterations in intestinal structure, mechanics and physiology underlie acute and chronic intestinal conditions, many of which are influenced by dysregulation of microbiome, peristalsis, stroma or immune responses. Studying human intestinal physiology or pathophysiology is difficult in preclinical animal models because their microbiomes and immune systems differ from those of humans. Although advances in organoid culture partially overcome this challenge, intestinal organoids still lack crucial features that are necessary to study functions central to intestinal health and disease, such as digestion or fluid flow, as well as contributions from long-term effects of living microbiome, peristalsis and immune cells. Here, we review developments in organ-on-a-chip (organ chip) microfluidic culture models of the human intestine that are lined by epithelial cells and interfaced with other tissues (such as stroma or endothelium), which can experience both fluid flow and peristalsis-like motions. Organ chips offer powerful ways to model intestinal physiology and disease states for various human populations and individual patients, and can be used to gain new insight into underlying molecular and biophysical mechanisms of disease. They can also be used as preclinical tools to discover new drugs and then validate their therapeutic efficacy and safety in the same human-relevant model.

New research has mapped neuroimmune interactions in the mouse gut, revealing that TRPV1-expressing nociceptor neurons (involved in visceral pain) control and suppress regulatory T (T_reg) cells in the gut, increasing susceptibility to colitis in mouse models. The findings potentially link pain signalling with immunomodulatory mechanisms in the gut.

In their screen, eight distinct neuronal subsets were activated in mice and mapped. Distinct immune perturbations were observed following this activation: nitrergic neurons (NOS1 expression) regulated T helper 17-like cells in the ileum; cholinergic neurons (express choline acetyltransferase) regulated ileal neutrophils; and nociceptor neurons (TRPV1 expression) regulated a range of cell types including type 2 innate lymphoid cells, activated CD8⁺ T cells, macrophages and RORγ T_reg cells. Examining the nociceptor neurons in more detail revealed that TRPV1⁺ neurons in the dorsal root ganglia suppressed RORγ⁺ T_reg cells in the colon via calcitonin gene-related peptide, which was mediated via the receptor RAMP1–CALCRL. Importantly, TRPV1⁺ neuron activation and subsequent downregulation of T_reg cells resulted in increased susceptibility to intestinal inflammation in mice (via Citrobacter infection and induction by administration of dextran sodium sulfate).

Globally, nearly half of deaths from cirrhosis and chronic liver diseases (CLD) and three-quarters of deaths from hepatocellular carcinoma (HCC) occur in the Asia-Pacific region. Chronic hepatitis B is responsible for the vast majority of liver-related deaths in the region. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common form of CLD, affecting an estimated 30% of the adult population. Compared with people of European descent, people from the Asia-Pacific region carry more genetic variants associated with MASLD and its progression. Alcohol is a fast-growing cause of CLD and HCC in Asia as a result of the rising per-capita consumption of alcohol. Drug-induced liver injury is under-recognized and probably has a high prevalence in this region. The epidemiological and outcome data of acute-on-chronic liver failure are heterogeneous, and non-unified definitions across regions contribute to this heterogeneity. CLDs are severely underdiagnosed, and effective treatments and vaccinations are underutilized. In this Review, we highlight trends in the burden of CLD and HCC in the Asia-Pacific region and discuss the rapidly changing aetiologies of liver disease. We examine the multiple gaps in the care cascade and propose mitigating strategies and future directions.