Key Advances in Gastroenterology & Hepatology

2023 was the most memorable year on record for obesity. The American Academy of Pediatrics recognized the complex, multifactorial nature of obesity and the broad range of treatments necessary to care for pediatric patients. The first-ever triple agonist and high-potency oral GLP1 agonist was introduced with unprecedented results.

In 2023, there were significant advancements in trials of interventions to reduce mortality and morbidity from alcohol-related liver disease, spanning the entire spectrum of disease: primary prevention to reduce overall alcohol-related harm, secondary prevention to attenuate fibrosis progression and tertiary prevention using antibiotics for severe alcohol-associated hepatitis.

Metastatic colorectal cancer is a heterogeneous disease associated with poor patient outcomes. Although the past decade has seen few first-line treatment advances, key studies published in 2023 established new options for late-line therapy of the disease with and without oncogenic drivers, thus expanding the continuum of care in metastatic colorectal cancer.

Important studies published in 2023 outlined new agents and strategies for the management of inflammatory bowel disease. Therapeutic ambitions for the management of inflammatory bowel disease were raised by the success of combinations of biologic agents in ulcerative colitis and early surgical resection in Crohn’s disease.

New light is being shed on the interactions between the gut microbiome, cancer cell signalling and the host immune response. With this knowledge, microbiota-based approaches for improving cancer prevention, prognostication and therapy have started to materialize and will contribute to reducing the global cancer burden.

In 2023, we witnessed advances in allocation policies and marginal donors, including living donors. Key improvements included the uncapped Model for End-stage Liver Disease 3.0 score, unveiled machine perfusion trials to standard deceased donors and lessons from the aborted living donor liver transplantations.

Enteric nervous system function is essential for survival. Studies published in 2023 have provided important novel insights into the mechanisms that regulate its development and maintenance, and demonstrate how it can be restored when these mechanisms fail.

Key studies published in 2022 further established the importance of alterations in the gut microenvironment and interactions with the enteric and central nervous systems in symptom generation in irritable bowel syndrome and suggested novel and clinically accessible therapeutic approaches for this large group of patients.

2022 was a proficuous year in both the nonalcoholic fatty liver disease (NAFLD) and obesity fields. Pharmacological treatment for obesity and NAFLD is moving forward, with the possibility of replacing bariatric surgery, artificial intelligence might help us access the histological effects of new drugs, and there were advances in personalized hepatocellular carcinoma screening in patients with NAFLD.

In 2022, we witnessed advances in the field of alcohol-related liver disease. Key developments included the discovery of novel proteomics-based biomarkers and potential therapeutic targets that regulate the recognition of molecules derived from gut microbiota to modulate liver injury. Additionally, there have been significant advances in refining selection for liver transplantation in severe alcohol-associated hepatitis.

Various pathways enable communication between the gut and brain, and this communication influences physiology and behaviour. Studies published in 2022 demonstrate how our understanding of several of these pathways is advancing rapidly.

The year 2022 was notable for substantial research progress related to pancreatic ductal adenocarcinoma (PDAC). The first single-cell and spatial transcriptomic atlases of PDAC were reported, a mechanism for how Schwann cells promote perineural invasion was explored, and, finally, the role of exercise in abrogating immunosuppression was shown.

The gut microbiome field is shifting from association to modulation. Microbiota-based treatments come in many shapes and sizes, ranging from dietary intervention to live bacterial products. Recent methodological advances are instrumental to developing innovative new treatment strategies in microbiome-linked pathologies.

Key studies published in 2022 highlight the emergence of several novel drugs for inflammatory bowel disease. Head-to-head trials and network meta-analyses have also been conducted to identify the sequencing of these treatments, but we still have a long way to go to achieve personalized medicine.

Key studies published in 2021 demonstrated mechanisms that drive macrophage–fibroblast pathogenicity in Crohn’s disease, developed multi-omics profiles to predict response to biological therapy, and suggested potential complementary treatments and new therapeutic agents in inflammatory bowel disease (IBD) therapy. These results represent important progress towards precision medicine for patients with IBD.

In 2021, our understanding of resistance to therapy in primary liver tumours improved drastically. By taking a holistic approach, three independent studies have characterized the tumour cell biodiversity across space, time and aetiologies in primary liver cancer, decoding the crosstalk between different cell types within the tumour ecosystem and their individual contributions to therapy resistance.

In 2021, transcriptome analysis of the mouse and human gut advanced our understanding of the cellular composition, development and surrounding non-neural context of the enteric nervous system (ENS). A role for the ENS in tuning regulatory T cell proportions contributed insights into the dependency between the ENS, immune system and microbiota.

Vaccination is a key intervention for the elimination of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections to fulfil the WHO’s 2030 global elimination goal. Innovations in 2021 promise to curb HBV transmission by reducing mother-to-child transmission and enhancing vaccine immunogenicity in at-risk adult groups. Additionally, an HCV vaccination trial was conducted, and there were also advances in our understanding of the immunology underpinning the lack of protection against HCV reinfection.

Important studies in 2021 demonstrated sophisticated developments in the study of liver fibrosis through omics. Cell-specific mapping, single-cell sequencing and deep-learning systems revealed complex intra-hepatic mechanisms and new computational platforms facilitating the research towards drug discovery in liver disease and in fibrosis.

2021 has been a productive year for fungal research. Key studies focused on intestinal inflammation and inflammatory bowel disease highlight antibody-mediated immunity in control of fungal commensalism, commensal and dietary fungi in intestinal inflammation and wound healing, and the therapeutic potential of transgenic yeast engineered to sense and target factors during intestinal inflammation.

Important colorectal cancer (CRC) studies in 2021, including a new standard of care for first-line treatment of MSI-H–dMMR metastatic CRC, single-cell and spatial analysis of primary tumours and investigations of diet in preclinical models of cancer initiation, have provided novel insights into the CRC immune microenvironment.

In this Review, Danne and colleagues describe the roles of neutrophils in inflammatory bowel disease, as well as their functions in host–microbiota interactions.

This Review discusses how the maternal gut microbiome in pregnancy influences the developing immune system and proposes avenues for future research.

Gut microbiota has a vital role in mechanisms involved in overweight and obesity, including host metabolism and energy expenditure. This Review describes the physiology of white and brown adipose tissue and provides timely insights into the gut microbiota–adipose tissue axis.

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory disease (IMID). Here, the authors review evidence on the preclinical phase of IBD, outlining and describing the proposed at-risk, initiation and expansion phases. Overlap with other IMIDs is discussed alongside the possible future directions for research into preclinical IBD.

This Perspective explores the relationship between screening endoscopy and colorectal cancer incidence, examining available evidence and offering insights into the discrepancies between real-world and trial evidence alongside potential pitfalls with interpreting the data.

In this Review, Murphy and Zaki discuss changes in the incidence and mortality of colorectal cancer, including trends by age and birth cohort, and consider the contributions of early-life exposures and emerging risk factors.

In this Review, Arrese and colleagues discuss the intersection of nonalcoholic fatty liver disease and alcohol-related liver disease, including their pathophysiology, clinical management and suggestions for future research.

The importance of commensal fungi in health and disease is becoming increasingly clear. In this Review, Ost and Round discuss the involvement of the mycobiota in intestinal diseases, and consider potential opportunities to target fungi and their interactions for therapeutic purposes.

Nonalcoholic fatty liver disease (NALFD) prevalence, including in children and adolescents, is rising worldwide. This Review offers a comprehensive overview of the lifestyle interventions available for NAFLD, including dietary and physical-activity strategies.

IL-12 and IL-23 have been implicated in inflammatory bowel disease. In this Review, Vande Casteele and colleagues summarize the mechanistic role of IL-12 and IL-23 in inflammatory bowel disease, and discuss the clinical development of drugs targeting IL-12 and/or IL-23.

Macrophages are critical for maintaining intestinal homeostasis, yet are implicated in chronic intestinal inflammation. This Review provides detailed insights into the biology of macrophages in the context of inflammatory bowel disease and discusses future perspectives.

The treatment landscape of inflammatory bowel disease (IBD) is constantly evolving, including among pregnant women and those who wish to become pregnant. This Review provides a detailed update on the management of patients with IBD during pregnancy and breastfeeding.

In this Review, Huang et al. highlight global trends in the epidemiology of cirrhosis, including contributions of various aetiologies of liver disease, and consider what needs to be done to address projected increases in the burden of cirrhosis.

The therapeutic landscape of metastatic colorectal cancer (mCRC) is changing. This Review provides a comprehensive overview discussing the current mCRC advances in precision oncology and suggests a treatment strategy for mCRC with rare genomic alterations.

Global alcohol consumption has increased in the past two decades and is projected to increase further. In this Review, Loomba and colleagues discuss the global epidemiology of alcohol-associated cirrhosis and hepatocellular carcinoma, including risk factors, trends and projections.

The influence of nerves on cancer is beginning to be understood. This Review discusses emerging insights into the role of the nervous system in gastrointestinal cancer and of nerves as components of the tumour microenvironment, highlighting underlying mechanisms and its potential as a therapeutic target.

Archaea are an overlooked member of the human gut microbiota. This Perspective discusses key characteristics of archaea, their role in human health and physiology, and the clinical relevance of methanogenic archaea in the human gastrointestinal tract.

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.

This Review covers the discovery of Akkermansia muciniphila and its association with health and disease, including metabolic diseases. Insights into underlying mechanisms for how A. muciniphila improves health are given as are comparisons with other next-generation beneficial microorganisms.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide and screening is useful for early diagnosis. This Review outlines currently available CRC screening options worldwide (including colonoscopy and stool-based tests). Key features of each modality and new screening tests under development are described.

In this Review, O’Toole and colleagues discuss the composition and function of the gut microbiome as it relates to ageing and ‘unhealthy’ ageing as well as the potential for microbiome-directed interventions to encourage ‘healthy’ ageing.

Attaining mucosal healing without immunosuppression is an attractive option for the treatment of inflammatory bowel disease (IBD). This Review describes the mechanisms of mucosal healing and how they might be altered in IBD and discusses potential therapeutic approaches to promote mucosal healing and regeneration.

Intestinal immune cell trafficking is a tightly regulated process involved in health and disease. This Review discusses the sphingosine 1-phosphate modulators as therapeutic agents in targeting leukocyte trafficking and inflammation in inflammatory bowel disease.

Mechanosensation — detecting mechanical forces and converting them into physiological responses — is important for normal gastrointestinal tract function. Mechanosensation abnormalities are frequently found in gastrointestinal diseases. This Review describes the physical properties of the gut relevant for mechanosensing, as well as the mechanosensory molecules, cells and circuits involved in gastrointestinal tract mechanosensation.

Ceresa et al. discuss machine perfusion technologies for liver preservation and transplantation, including the potential of hypothermic and normothermic machine perfusion to improve preservation time and organ quality, as well as the future applications of perfusion technologies.