Research areas

___hepatic

Immune modulation in Advanced Chronic Liver Disease

Liver cirrhosis is considered as a public health concern, being the fourth cause of death in Europe. Patients with cirrhosis are in risk of clinically relevant complications that worsen their prognosis. Disease progression is associated with an immunological dysfunction promoting bacterial complications, which become frequently relevant during cirrhosis progression. This microbial cargo constantly reaches the liver through the portal circulation, so that the hepatic immune system continuously faces gut-derived antigens that require an efficient clearance. 

Progressive and sustained liver damage pushes cirrhosis forward from a compensated towards a decompensated state, in which clinical complications arise and worsen patients’ prognosis. The dynamics of the immune response is then dissociated. On the one hand, progressive hepatocyte necrosis induces a hyper-activation of the systemic inflammatory response and the negative regulation of anti-inflammatory pathways. On the other hand, the increasing gut-derived antigenic burden compromises the immune surveillance activity and favors the exhaustion of immune cells functional capacity, leading to an immune deficient state (reduced phagocytic, respiratory burst and antimicrobial capacities, among others). 

With this background, our group is focused on the comprehension of the local and systemic inflammatory response underlying cirrhosis progression, including gut-derived antigenic load arriving through the gut-liver axis, and neurocognitive complications facilitated by the liver-brain axis during decompensated stages of disease. 

"Liver damage progresses along with an immune dysfunction and the microbiota dysbiosis".

Publications

Juanola O, Francés R, Caparrós E. Exploring the Relationship between Liver Disease, Bacterial Translocation, and Dysbiosis: Unveiling the Gut-Liver Axis. Visc Med. 2024 Feb;40(1):12-19. doi: 10.1159/000535962. Epub 2024 Jan 23. PMID: 38312368; PMCID: PMC10836950.
Martínez-López S, Ángel-Gomis E, Gómez-Hurtado I, Fernández-Iglesias A, Morante J, Gracia-Sancho J, Boix P, Cubero FJ, Zapater P, Caparrós E, Francés R. Cirrhosis-downregulated LSECtin can be retrieved by cytokines, shifts the TLR-induced LSECs secretome and correlates with the hepatic Th response. Liver Int. 2024 Apr;44(4):996-1010. doi: 10.1111/liv.15836. Epub 2024 Jan 31. PMID: 38293766.

Active projects

  • Prometeo 2021/033, Role of LSECtin in aging and the liver-brain axis in cirrhosis. Generalitat Valenciana. Rubén Francés. (Universidad Miguel Hernández de Elche). 01/01/2021-30/12/2024.
  • PI21/0082, Therapeutic targets and biomarkers from precision medicine in MAFLD (PreMed-MAFLD). Ministerio de Ciencia e Innovación. Rubén Francés. (IIS ISABIAL, Hospital General Universitario de Alicante). 01/01/2022-31/12/2023.
  • “CIBEREHD-BBN COLLABORATIVE PROJECTS 2023. Proof-of-concept study for in vivo delivering LSECtin-mRNA loaded lipid nanoparticles to hepatic antigen presenting cells. IP Rubén Francés”.

Completed projects

  • PID2019-107036RB-I00, LSECtin function in restricting the transition from innate to pathogenic adaptive CD4+ T cell response in cirrosis. Ministerio de Ciencia e Innovación. Rubén Francés. (Universidad Miguel Hernández de Elche). 01/01/2020-30/12/2022.
  • PI17/01617, Experimental study on the modulatory effect of the adrenergic system on hepatocarcinogenesis. Instituto de Salud Carlos III. Pedro Zapater Hernández. (Hospital General Universitario de Alicante). 2018-2020.
  • PI16/0967, Role of short-chain fatty acids in response to bacterial translocation and the associated haemodynamic alterations in cirrhosis. Rubén Francés Guarinos. (Hospital General Universitario de Alicante). 2017-2019.
  • Prometeo 2016/001, Targeting liver immunosurveillance recovery in cirrosis. Conselleria de Educación Generalitat Valenciana. Rubén Francés Guarinos. (Hospital General Universitario de Alicante). 2016-2019.
  • PI14/01090, Characterization of the interaction between immune system and sympathic nervous system and its relationship with the development of hepatocarcinoma in cirrhosis. Instituto de Salud Carlos III. Pedro Zapater Hernández. (Hospital General Universitario de Alicante). 2015-2017.
  • PI13/1443, Regulatory T cell induction as inflammatory control mechanism during selective intestinal decontamination as bacterial prophylaxis in cirrhosis. Instituto de Salud Carlos III. Rubén Francés Guarinos. (Hospital General Universitario de Alicante). 2014-2016.
  • PI11/00962, Sympathic nervous system activation in response to circulating bacterial DNA fragments in blood of patiens with cirrhosis and non-infected ascites. Instituto de Salud Carlos III. Pedro Zapater Hernández. (Hospital General Universitario de Alicante). 2012-2014.
  • PI10/0340, Role of IL-10 in the regulatory mechanisms of bacterial translocation, inflammatory response and microbiota changes in an experimental model of liver fibrosis induced by CCL4 in mice. Instituto de Salud Carlos III. Rubén Francés Guarinos. (Hospital General Universitario de Alicante). 2011-2013.

___intestinal

Specific cellular response to biologic treatments in IBD

Inflammatory bowel disease (IBD) includes both ulcerative colitis and Crohn’s disease, entities considered immune-mediated, systemic diseases with a chronic course during which flare and remission stages are present. Its incidence and prevalence are increasing over time, both in Western countries and especially in developing countries. The aetiology of CD is multifactorial. It is considered the result of a deregulated immune response to the intestinal microbiota in genetically predisposed individuals, which arises from the confluence between host genetics and external environmental influences, causing a constant inflammatory environment in these patients.

The use of anti-TNF-α has significantly improved the therapeutic outcomes in IBD. Biologic therapies have expanded in the last years to other molecules, interfering with different and specific aspects of the immune responses. Despite this array of possibilities, improving efficacy of treatments still constitutes a goal required to reduce the number of patients non-responding or showing loss of response to those therapies. 

Our line of translational research in IBD focuses on the identification, control, and recovery of mechanisms of immune activity in the context of intestinal inflammation, with special attention to its relationship with the microbiome. We are also interested in the evaluation of the immunologic impact of biologic therapeutic strategies to improve their efficacy in IBD patients. On the other hand, the group also maintains a line of clinical research in IBD focused on the development of extraintestinal manifestations and patients’ quality of life.

Active projects

  • PI21/01702. Chemokine and chemokine receptor expression profile in response to biologic therapy in ileal tissue of patients with Crohn’s disease. Instituto de Salud Carlos III. Ana Gutiérrez (ISABIAL, Hospital General Universitario de Alicante). 2022-2024.
  • NIVELART. Correlation between serum levels of biologic drugs and articular extraintestinal manifestations in patients with Crohn’s disease. Grupo Español de Trabajo en Crohn y Colitis Ulcerosa (GETECCU) and Sociedad Valenciana de Patología Digestiva (SVPD). Ana Gutiérrez (ISABIAL, Hospital General Universitario de Alicante).
  • ChemokIBD. Biologic therapy-restricted transcriptional chemotactic profile in Crohn’s disease. Asociación Española de Gastroenterología (AEG). Rubén Francés (Universidad Miguel Hernández de Elche). 2021-2023.

Completed projects

  • UGP-19-241. Functional characterization of type 2 innate lymphoid cells in inflammatory progression to fibrosis in Crohn’s disease. ISABIAL. Ana Gutiérrez Casbas. (ISABIAL, Hospital General Universitario de Alicante). 2019-2021
  • CROHNSX. Biologic markers of fertility and sexual dysfuntion in patients with Crohn’s disease. Grupo Español de Trabajo en Crohn y Colitis Ulcerosa (GETECCU) and Fresenius Kali. Ana Gutiérrez Casbas. (ISABIAL, Hospital General Universitario de Alicante). 2019-2021.
  • EIIMIGRA. Immigrant IBD population in Spain. Grupo Español de Trabajo en Crohn y Colitis Ulcerosa (GETECCU). Ana Gutiérrez Casbas. (ISABIAL, Hospital General Universitario de Alicante). 2018-2020
  • BACTEC-26. IL26-mediated immune response to bacterial translocation in patients with Crohn’s disease. Asociación Española de Gastroenterología (AEG). Rubén Francés (ISABIAL, Hospital General Universitario de Alicante). 2016-2018.
  • ADATHEC. Bacterial DNA blood translocation and NOD2 gene mutations: Combined efficacy in predicting relapse at short-term in patients with Crohn’s disease. Abbvie International. Rubén Francés. 2012-2016