About the Lab

The Obesity, Diabetes and Metabolism (ODiM) Lab is a newly established research group hosted within the Biomedical Research Institute of Murcia (IMIB) (https://www.imib.es). Our lab is currently working on several research projects aimed at understanding the physiopathology of obesity and related metabolic diseases, with special interest in the study of type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD).

Why MASLD?

MASLD is currently the most prevalent cause of chronic liver disease worldwide, with an estimated global prevalence of over 30%. It’s projected that in the coming years, MASLD will surpass alcohol as the leading reason for liver transplantation in the general population. MASLD is directly linked to various extrahepatic comorbidities, including obesity, T2DM, dyslipidemia and chronic kidney disease, leading many researchers to view it as the hepatic manifestation of the metabolic syndrome.

The pathogenesis of MASLD has been the subject of extensive study over the past decade. However, the mechanisms driving its progression to MASLD remain only partially understood. Emerging evidence suggests that the physiopathology of MASLD is significantly influenced by various dietary and environmental factors. These factors may play a role in the development and progression of the disease by instigating alterations in gut microbiota and/or inducing epigenetic modifications, among other potential mechanisms.

In our lab, we aim to unravel the intricate relationship between the gut and the liver in the pathogenesis of MASLD and T2DM. We also investigate the potential impact of epigenetics and epitranscriptomic mechanisms on MASLD  and T2DM development and progression. Concurrently, we explore the therapeutic prospects of microbiota-targeted dietary interventions for patients with MASLD and other obesity-related metabolic disorders  such as T2DM.

We welcome applications from predoctoral and postdoctoral researchers who are interested in joining the ODiM Lab. If you’re interested, please submit a comprehensive CV and a letter detailing your research experience and your research proposal to: 

Dr. Bruno Ramos-Molina: bruno.ramos@imib.es (Group Leader)

Dr. María Ángeles Núñez Sánchez: mariaa.nunez@imib.es (Principal Investigator)

Research lines

1. Unveiling the role of gut microbiota and microbial metabolites in MASLD pathogenesis

The human gut microbiome is a diverse community comprising 10-100 trillion microorganisms that play various roles, including metabolic, protective, structural, and neurological functions within the host. Notably, the gut microbiota, through metabolite production and fermentation, modulates signaling pathways crucial for maintaining intestinal mucosal homeostasis. The composition of the gut microbiota can be influenced by various external factors. When the delicate balance between the gastrointestinal tract and resident microbiota is disrupted, it can lead to the development of both intestinal and extraintestinal diseases, including metabolic disorders such as type 2 diabetes mellitus (T2DM), dyslipidemia, and metabolic dysfunction-associated steatotic liver disease (MASLD).

One of our primary lab projects focuses on investigating the role of gut microbiome profiles in the pathogenesis of MASLD. We aim to understand how the gut microbiota-derived metabolome may be linked to the progression of simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, or even hepatocarcinoma (HCC). To achieve this, we are developing a multi-omic platform that combines metagenomics for determining gut microbiota composition and metabolomics for analyzing serum metabolites associated with the gut microbiota, such as short-chain fatty acids, bile acids and others.

2. Gut microbiota and MASH/fibrosis resolution after bariatric surgery

Currently, there are limited therapeutic options available for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). The most effective approach to date is weight loss. Bariatric surgery (BS), which leads to significant reductions in body weight in patients with severe obesity, is associated with substantial histopathological improvements in advanced stages of MASLD, including steatohepatitis (MASH) and liver fibrosis. Furthermore, BS is known to induce significant taxonomical and functional alterations in gut microbiota, which are believed to play a pivotal role in the metabolic improvements observed after BS. Additionally, emerging evidence underscores the potential link between changes in gut microbiota following BS and the resolution of MASH/fibrosis.

In this project, our objective is to investigate whether the resolution of MASH/fibrosis following BS is linked to specific alterations in the gut microbiota and microbial-derived metabolites. This prospective study involves a cohort of individuals with morbid obesity who are recruited for a bariatric intervention. We will utilize well-established metagenomic and metabolomic platforms in our laboratory for this research.

3. Evaluation of the epigenome, microbiome, and metabolome dynamics and their interaction with the adiposity increase in the maternal-infant axis

Childhood obesity has reached epidemic proportions globally and presents a significant public health challenge, accompanied by a substantial economic burden for its treatment. The World Health Organization (WHO) reports that in 2020, approximately 39 million children under the age of 5 were overweight or obese. The causes of childhood obesity are multifaceted, involving a complex interplay of genetics, environmental and developmental factors, and the gut microbiota. Nevertheless, it’s estimated that only around 20% of obesity risk can be attributed to genetic factors.

The “Developmental Origins of Health and Disease” hypothesis posits that the intrauterine environment plays a crucial role in influencing fetal development and future disease susceptibility. One of the mechanisms through which in utero exposures may induce metabolic changes is via epigenetic modifications, which, in turn, are influenced by environmental factors related to the mother during pregnancy, such as nutrition, physical activity, and lifestyle choices.”

This project’s goal is to characterize epigenetic changes within the maternal-infant axis that may be associated with the onset of obesity and metabolic disorders in early infancy. Identifying these alterations will enable the development of personalized preventive strategies against obesity and its associated comorbidities. To achieve this objective, we are employing a combination of various omics techniques, including epigenomics, metabolomics, and metagenomics.

4. Epitranscriptomic analysis in patients with MASLD/MASH: exploring diagnostic and therapeutic potential

Epitranscriptomic modifications are pivotal in RNA metabolism and can exert post-transcriptional influence on gene expression. Recent advances in Next-Generation Sequencing (NGS) have significantly enhanced the detection and mapping of RNA chemical modification sites, expanding the understanding of epitranscriptomics. Governed by these precise modifications, target RNAs undergo diverse fates, contingent on their temporal and spatial context. The most prevalent mRNA modification in eukaryotic cells is adenine methylation at the N6 position (m6A), which plays essential roles in various physiological processes, including embryogenesis, carcinogenesis, and neurogenesis.

Recent studies conducted in experimental models have raised the possibility of RNA methylation (m6A) playing a role in chronic liver disease including MASLD/MASH. The overarching aim of this project is to ascertain the epitranscriptomic profile associated with the presence of MASLD and MASH. Additionally, we aim to pinpoint epitranscriptomic modifications in liquid biopsy samples with diagnostic potential and assess whether modulating epitranscriptomic mechanisms could be a therapeutic avenue for the treatment of MASH by using human liver organoids derived from liver tissue samples of patients with obesity and MASLD.

5. Role of small intestine in type 2 diabetes mellitus and search for new therapeutic strategies

Type 2 diabetes mellitus (T2DM) is a common global health concern that is associated with a high number of comorbidities and mortality rates. The causes of T2DM are complex and involve genetic, metabolic, and environmental factors. In this regard, the small intestine plays a critical role in T2DM, as permeability is increased in this condition, allowing harmful substances into the bloodstream, triggering inflammation, which in turn can worsen insulin resistance. Additionally, gut microbiota imbalances, as well as alterations in their derived metabolites such as short-chain fatty acids (SCFAs) are also associated with increased permeability and inflammation. 

In this project our aim is to explore the mechanisms by which the small intestine contributes to T2DM progression and to evaluate the effectiveness of butyrate, a SCFA, in different T2DM-related parameters and intestinal permeability. For that purpose, we are establishing a state-of-the-art model of human intestinal organoids derived from small intestine samples of patients with obesity and T2DM.