Research at the Llorente Lab
Llorente Lab
The Llorente lab (https://profiles.ucsd.edu/ana.llorenteizquierdo) at the University of California, San Diego, Division of Gastroenterology, Department of Medicine has a keen interest in understanding the complex interactions among the components of the intestinal mucosal barrier and their influence on the onset of liver disease. These components encompass the intestinal immune system, the microbiota, and the intestinal epithelium. These multifaceted interactions play a role in maintaining intestinal homeostasis and are crucially linked to the onset of liver diseases. Our research endeavors are dedicated to elucidating the molecular pathways and factors contributing to liver diseases, with the ultimate goal of identifying therapeutic alternatives.
We investigate the intricate components regulating intestinal homeostasis, such as the intestinal epithelium, microbiome, and immune system, to elucidate their impact on alcohol-associated liver disease (ALD), as well as metabolic dysfunction-associated steatotic and steatohepatitis liver disease (MASLD and MASH) and MASLD and alcohol use disorder (MetALD).
The Llorente, Hsu, Hartmann, and Schnabl labs enjoying a picnic at La Jolla Shores, 2024.
We study the implications of the gut-liver axis in preclinical animal models and patient biopsies using cutting-edge microbiomics and state-of-the-art technology, including single-cell RNA sequencing, metabolomics, metatranscriptomics, as well as intestinal and liver organoid cultures. We aim to find innovative strategies for treating liver diseases. The goal of the study is translational: to discover and propose alternative therapeutics.
The Llorente, Hsu, Hartmann, and Schnabl labs enjoying celebrating at the Israni Biomedical Research Facility. 2024
Research
Our goal
The Llorente lab has developed a research program focused on understanding the mechanisms that maintain intestinal homeostasis, with particular emphasis on the complex interactions between the intestinal microbiota and the mucosal immune system, and how these interactions contribute to the pathogenesis of liver disease. Their research is highly translational, with the ultimate goal of developing new therapeutic strategies for liver diseases.
Ethanol directly disrupts the components of the gastrointestinal mucosal barrier, playing a critical role in the pathogenesis of alcohol-associated liver disease (ALD) (Hepatology, 2024)
The Llorente lab’s research program is designed with the aim of making a positive societal impact. It is estimated that 1.5 billion individuals worldwide suffer from chronic liver disease. Obesity and alcohol consumption have become central liver disease risk factors. Alcohol, as a leading cause of liver disease, is associated with a wide spectrum of hepatic diseases, such as alcohol-associated steatosis, steatohepatitis, fibrosis, cirrhosis, and alcohol-associated hepatitis, and triggers weakening of the immune system, escalating the susceptibility to bacterial and viral infections.
Ethanol consumption significantly disrupts the gut-liver axis, promoting intestinal bacterial overgrowth, altering gut flora composition (dysbiosis), and breaking down the intestinal barrier to allow viable bacteria and toxic byproducts to escape into the liver via the portal vein (CMGH, 2015)
The intestinal microbiota plays a fundamental role in regulating host metabolism, immune function, mucosal barrier integrity, and protection against pathogens. Consequently, host–microbiome interactions have a profound impact on health and disease. This rapidly expanding field has opened new opportunities to develop preventive, diagnostic, and therapeutic strategies to combat liver and metabolic diseases.
The Llorente Laboratory aims to elucidate the mechanisms underlying host–intestinal microbiome interactions to identify innovative strategies for preventing and treating disease. Our research focuses on the development of microbiome-based approaches to restore intestinal homeostasis, improve host health, and mitigate liver and metabolic diseases.
Specifically, our research is designed to:
- Identify molecular targets: Discover molecular pathways and therapeutic targets for the development of novel treatments for liver and metabolic diseases.
- Develop diagnostic strategies: Define microbial components, metabolites, and host-derived biomarkers that promote or protect against disease, enabling the development of microbiome-based diagnostics, disease prediction strategies, and precision interventions.
- Develop therapeutic strategies to restore intestinal homeostasis: Identify and develop interventions that improve intestinal barrier function, modulate host–microbiome interactions, restore immune system responses, and promote microbial balance and intestinal homeostasis to prevent or treat disease.
- Develop nutritional strategies: Characterize dietary and environmental factors that influence host–microbiome interactions to prevent disease and promote long-term health.
Our research integrates mechanistic and translational approaches, including the development of advanced in vitro models to investigate molecular pathways, identify therapeutic targets, and accelerate the discovery of novel interventions.
Ultimately, the Llorente Laboratory seeks to translate fundamental discoveries into innovative strategies that improve disease prevention, diagnosis, and treatment. By advancing our understanding of host–microbiome interactions, we aim to reduce the burden of liver and metabolic diseases, improve patient care, and promote healthier lives.
ACCOMPLISHMENTS
The Llorente lab has a great reputation in the field of intestinal microbiome and its impact on chronic liver disease. Our publication in Nature Communications, 2017 demonstrated that gastric acid suppression contributes to alcohol-associated liver disease in mice and humans. This is mediated by the overgrowth of intestinal Enterococcus and its translocation to the liver.
Proton pump inhibitor (PPI) use is associated with increased cumulative risk of alcohol-associated liver disease (ALD) and is linked to elevated Enterococcus abundance in the gut microbiome of patients with alcohol use disorder (AUD) (Nature Communications, 2017)
We embarked on a mission to understand the role of Enterococcus in alcohol-related liver disease (Nature, 2019). We reported that alcohol-associated hepatitis in humans is associated with the presence of a pore-forming toxin called cytolysin produced by Enterococcus faecalis. We showed that cytolytic Enterococcus faecalis is a novel predictor of mortality in alcohol-associated hepatitis patients.
Fecal cytolysin (a cytolytic exotoxin secreted by Enterococcus faecalis) is an important microbial marker linked to severity and mortality in alcohol-associated hepatitis. Duan Y*, Llorente C*, et al. Nature, 2019
We further demonstrated the use of specific bacteriophages as a novel therapeutic strategy to reduce ethanol-induced liver injury in mice.
Targeted bacteriophages can destroy cytolysin-producing Enterococcus faecalis (Nature, 2019)
The high impact of this publication is evidenced by the numerous editorials that discussed our contribution to the field, which were published in prestigious journals such as Nature, Science, Cell, Nature Reviews Microbiology, Nature Reviews Gastroenterology & Hepatology, Nature Reviews Drug Discoveries, Liver International, Gut, Trends in Microbiology, Translational Research, and Molecular Cell. This work yielded a patent titled “Biomarker and Treatment of Target for Alcohol Hepatitis” (WO2019191508). The patent describes methods of detecting and monitoring the progression of liver disease, assessing the risk of mortality in humans, and methods of treating liver disease, further emphasizing the impact of our research. Our pioneering research has paved the way for the current commercialization efforts to bring these innovative therapies to clinical trials, where they can make a tangible difference in saving lives.
Our team has also explored the role of intestinal α1-2-fucosylation in obesity and steatohepatitis using murine models (CMGH, 2021). We found that reducing α1-2-fucosylation protected mice from these conditions by altering the intestinal microbiome and bile acid metabolism. This suggests potential therapeutic avenues for managing obesity and steatohepatitis by targeting α1-2-fucosylation.
Among other achievements, the Llorente lab pioneered an innovative technique involving the isolation of the myenteric and submucosal plexuses from the mouse gastrointestinal tract and their subsequent co-culture with small intestinal organoids (Cells, 2024 ).
Enteric Nervous System and Intestinal Organoid Co-Culture Model (Cells, 2024)
Enteric Nervous System and Intestinal Organoid Co-Culture Model (Cells, 2024)
The Llorente lab’s current efforts are nicely summarized here:
Behind The Paper (Springer Nature)
The Gut–Liver Axis in Liver Disease:
- Microbiome
- Cellular Components of the Intestine
- The Immune System.
- The Enteric Nervous System (ENS).
- The Intestinal Epithelium.
- Goblet Cell Dysfunction in ALD
Goblet cell functions. Adapted from eGastroenterology, 2024Our work revealed that chronic alcohol exposure impairs goblet cell-associated antigen passages (GAPs), specialized structures that educate intestinal immune cells and maintain antimicrobial protection. By reducing mAChR4-dependent GAP formation, alcohol weakens mucosal immunity, promotes bacterial translocation, and accelerates liver injury.
We identified the mAChR4–GAP–APC–ILC3–IL-22–REG3 pathway as a critical protective circuit in the gut–liver axis. Restoring this pathway through IL6ST/gp130 signaling or mAChR4 activation re-establishes intestinal immune surveillance, limits microbial translocation, and protects against ethanol-induced liver disease. These findings position goblet cells and GAP formation as key therapeutic targets for ALD, with potential implications for both liver disease and alcohol use disorder (Nature, 2025). This work established mAChR4 as a translational target and led to two patent applications related to alcohol-associated liver disease and MASLD.
GAPs deliver luminal antigens to lamina propria antigen-presenting cells, educating the intestinal immune system and stimulating REG3B/G antimicrobial peptides. Adapted from Behind The Paper | Nature, 2025.
Our current efforts have demonstrated that Muc2 deficiency enhances GAP formation and confers protection against ALD, whereas GAP closure exacerbates disease. Targeting GC-specific mAChR4 to restore GAPs represents a promising therapeutic strategy for ALD (Hepatology, 2026).
Muc2 deficiency enhances GAP formation and confers protection against ALD (Hepatology, 2026)
Our current findings show that non-absorbable antibiotics worsen alcohol-associated liver disease in gastric acid-suppressed mice (Gut Microbes, 2026). We found that gastric acid-suppressive medications (like PPIs) allow Gram-positive bacteria, especially cytolysin-producing Enterococcus faecalis, to expand in the gut and translocate to the liver, worsening liver injury. Surprisingly, treating this dysbiosis with non-absorbable antibiotics targeting Gram-positive bacteria didn't fix the problem; it backfired by increasing bacterial translocation and making liver injury worse. In patients with alcohol-associated hepatitis, PPI use was linked to Enterococcus overgrowth and higher 30-day mortality, but this pattern didn't hold in cirrhosis or MASLD, showing that the gut's response to acid suppression really depends on the underlying liver disease.
On the therapeutic side, we identified two promising strategies to neutralize the bacterial toxin cytolysin itself, using dipalmitoylphosphatidylcholine (DPPC) and a Caspase-1 inhibitor, pointing toward more precise, toxin-targeted treatments instead of broad microbiota suppression.
PPI use in alcohol-associated liver disease allows Gram-positive E. faecalis to overgrow. Shockingly, broad non-absorbable antibiotics worsen this by causing other bacteria to invade, escalating liver injury. Precise, toxin-targeted treatments are needed, not broad suppression. (Gut Microbes, 2026).
The Llorente lab has published manuscripts in high-impact journals such as Nature, Journal of Hepatology, Hepatology, Nature Communications, Journal of Clinical Investigation, Cell Host & Microbe, among others:
https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/