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In this Viewpoint article, we asked a selection of scientists and clinicians in the gut microbiota field to provide their opinions on the major advances in and future directions for research, and the challenges and solutions for translating gut microbiome research to the clinic.

In this Review, the authors discuss the role of the main IL-1 family members in gastrointestinal and liver diseases, focusing on preclinical and clinical research. Opportunities for therapeutic interventions are also outlined.

Here the authors report that hepatic loss of GTPase-activating protein-binding protein1 (G3BP1) exacerbates MASLD and MASH pathogenesis in a study with male mice. Mechanistically, G3BP1 interacts with SNARE proteins and promotes autophagosome-lysosome fusion, and facilitates nuclear translocation of the transcription factor TFE3.

The intestinal microbiome has an important role in health and disease; however, the long-term effects of lifestyle choices on microbiome alterations are incompletely understood. Here, based on extensive lifestyle and medical data collected over 26 years, Si et al. demonstrate that long-term life history can predict current enterotype in older adults.

Tilg et al. explore how metabolic dysfunction, altered gut microbiome and dysregulated innate and adaptive immunity contribute to NAFLD and how the interplay between these factors mediates disease progression.

The gut–liver axis is of crucial importance in health and disease. TM6SF2 is a genetic risk factor for metabolic dysfunction-associated steatotic liver disease. Zhang, Yu et al. reveal that intestinal TM6SF2 critically affects the gut–liver axis.

Glucagon-like peptide 1 receptor agonists are effective pharmacotherapies for the treatment of obesity and related disorders. In metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis, semaglutide improved liver histology over 72 weeks. In another new study, tirzepatide was superior to semaglutide in reducing body weight in individuals with obesity.

The association between NAFLD and diabetes mellitus has garnered increasing attention in the past few years. In this Review, Tilg and colleagues explore in detail the molecular mechanisms linking NAFLD and diabetes mellitus, and discuss clinical aspects arising from the interaction of both diseases.

Severe acute malnutrition is a life-threatening disease affecting millions of children. A recent study has now identified an immature gut microbiome as an important contributing factor in children with kwashiorkor. The condition was transmissible into gnotobiotic mice by combining stool transplantation and region-specific diet. In addition, antibiotics reduce mortality in children with kwashiorkor.

Adipose tissue produces several inflammatory mediators, including the adipocytokines adiponectin, leptin and resistin. Here, recent advances in our understanding of the role of these adipocytokines in inflammation and immunity are discussed, highlighting the importance of these mediators in obesity-associated diseases.

Chronic consumption of alcohol can cause a spectrum of liver abnormalities, ranging from simple steatosis to steatohepatitis, cirrhosis and hepatocellular carcinoma. Alcoholic liver disease is still the most common cause of liver cirrhosis in the Western world. This Review focuses on the current management of patients with alcoholic liver disease, with emphasis on alcoholic steatohepatitis and cirrhosis.

The gut microbiota is involved in the development of colorectal cancer. Here, the authors analyse the faecal microbiomes of healthy subjects and of patients with colorectal cancer or benign adenoma, revealing microbial genes, strains and functions enriched in each group.

Gut commensal bacteria and their metabolites can contribute to metabolic diseases. Qiao, Liu et al. reveal that expansion of Parabacteroides merdae attenuates experimental atherosclerosis.

Nonalcoholic fatty liver disease is an increasingly recognized health problem. Its presentation ranges from simple steatosis to its inflammatory representation of nonalcoholic steatohepatitis. This Review considers various modalities that have been tried for nonalcoholic fatty liver disease, such as weight loss and/or exercise, thiazolidinediones, metformin, lipid-lowering agents and antioxidants, as well as considering treatments that are on the horizon.

Lactulose is used to treat patients with hepatic encephalopathy but this prebiotic can also increase intestinal Bifidobacteria, thereby reducing systemic infection, growth of multidrug-resistant bacteria and mortality that often accompanies chronic liver disease.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent liver disease worldwide, mainly because of the massive parallel global increase in obesity. Extensive public-health and political efforts will be needed in the near future to counteract this disturbing development.

A new report in Science by Ma and colleagues uncovers the interplay of microbiota-controlled bile acid metabolism and immune responses in the context of primary and metastatic liver tumours in mice. Their findings shed light on the gut–liver axis in hepatic malignancies.

Two new position papers convincingly propose that nonalcoholic fatty liver disease needs a new name — metabolic associated fatty liver disease (MAFLD). A new name for this disease affecting nearly one billion people globally is overdue, as knowledge gained from the past decades has assuringly demonstrated that MAFLD is a purely metabolic disorder.

Liver resident CD8 T cells have an essential role in immunopathology in a mouse model of nonalcoholic steatohepatitis, by becoming auto-aggressive following sequential transcriptional and metabolic activation steps .

Dietary lipids are linked to the development of inflammatory bowel diseases through unclear mechanisms. Here, the authors report that dietary polyunsaturated fatty acids trigger intestinal inflammation resembling aspects of Crohn’s disease, which is restricted by glutathione peroxidase 4 in the intestinal epithelium.

Inflammation is a hallmark of obesity and driver of various associated pathologies. Here the authors show that mice overexpressing the anti-inflammatory cytokine IL-37 are protected from the metabolic consequences of a high-fat diet, and that plasma levels of IL-37 correlate with insulin sensitivity in humans.

This Review outlines how Western-style diets contribute to the rising incidence of chronic, noncommunicable diseases by converging on key mechanisms, including gut microbial rarefaction and chronic inflammation.

Here, the authors describe how metabolic disorders, such as type 2 diabetes and nonalcoholic fatty liver disease, are driven by alterations in the composition of the intestinal microbiota and its metabolites, which translocate from the gut across a disrupted intestinal barrier and contribute to metabolic inflammation.

This Review discusses how adipose tissue can regulate host immune function via the release of adipokines, including adiponectin, leptin and various cytokines. These adipokines contribute to immune responses and metabolic inflammation and can have both beneficial and detrimental effects on host physiology. In obesity, adipokine release can promote insulin resistance and cardiovascular diseases; as such, there is interest in targeting these mediators for therapy of various metabolic disorders.

Experimental and clinical evidence supports a role of metabolic perturbation in the development of gut inflammation in inflammatory bowel disease (IBD). This Review discusses the role of diet and metabolic inflammation in IBD, outlining key concepts and highlighting the links between metabolism and inflammation in IBD.

Stefan Kiechl and colleagues show that blockade of receptor activator of nuclear factor-κB (RANKL) signaling in hepatocytes by cell type–specific genetic deletion of its receptor promotes greater insulin sensitivity in both a genetic and a nutritional model of type 2 diabetes. They also show epidemiological evidence that elevated serum concentrations of soluble RANKL are a risk factor for the development of this disease.

Non-alcoholic liver disease (NAFLD) is now metabolic dysfunction-associated steatotic liver disease (MASLD), emphasizing the key metabolic factors of obesity, insulin resistance, vascular dysfunction and dyslipidaemia. Here, we discuss impacts on the existing body of clinical and preclinical liver disease research and on research moving forward.

Cardiovascular disease is the leading cause of death in NAFLD. In this Review, the authors explore the evidence that NAFLD affects not only the coronary arteries but also all other cardiac structures, thereby potentially increasing risk of cardiomyopathy, cardiac arrhythmias, conduction defects and valvular calcification.

This Review outlines the current understanding of IL-12 and IL-23 biology in IBD, as well as the roles of major downstream cytokines, including IL-17. The authors also discuss how emerging knowledge influences the development of therapeutic strategies in IBD.

A combination of cell line, transgenic mouse and human genetic data implicates a proinflammatory function of Dickkopf1 across malignant and non-malignant cells.

Netea and colleagues provide a general guide to the cellular and humoral contributors to inflammation as well as the pathways that characterize inflammation in specific organs and tissues.