Regulatory T Cells Restrict Permeability to Bacterial Antigen Translocation and Preserve Short‐Chain Fatty Acids in Experimental Cirrhosis

• Published in: Hepatology communications Vol. 2; no. 12; pp. 1610 - 1623
• Main Authors: Juanola, Oriol, Piñero, Paula, Gómez‐Hurtado, Isabel, Caparrós, Esther, García‐Villalba, Rocío, Marín, Alicia, Zapater, Pedro, Tarín, Fabián, González‐Navajas, José M., Tomás‐Barberán, Francisco A., Francés, Rubén
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins 01.12.2018; John Wiley and Sons Inc; Wolters Kluwer Health/LWW
• Subjects: Antigens; Bacterial infections; Cytokines; Dendritic cells; E coli; Fatty acids; Gene expression; Homeostasis; Immune system; Immunology; Inflammation; Liver cirrhosis; Lymphocytes; Metabolism; Microbiota; Microorganisms; Original; Permeability; Population
• ISSN: 2471-254X; 2471-254X
• DOI: 10.1002/hep4.1268

Intestinal permeability to translocation of bacterial products is increased in cirrhosis. Regulatory T cells (Tregs) remain central to the interplay between the host and microbial milieu. We propose that Tregs are involved in promoting gut barrier integrity and a balanced interaction with gut microbiota–derived short‐chain fatty acids (SCFAs). Carbon tetrachloride cirrhosis was induced in wild‐type and recombination activating gene 1 (Rag1)‐/‐ mice. Naive T cells and Treg cells were transferred into Rag1‐/‐ mice. Intestinal permeability was assessed in vivo after lipopolysaccharide (LPS) oral administration, and bacterial DNA presence was evaluated in mesenteric lymph nodes. Transcript and protein levels of tight‐junction (TJ) proteins were measured in colonic tissue. Intestinal T helper profile in response to Escherichia coli (E. coli) was determined by flow cytometry. SCFAs were measured by gas chromatography–mass spectrometry in colonic content before and after E. coli challenge. Rag1‐/‐ mice showed significantly increased permeability to LPS and bacterial DNA translocation rate compared with control mice. Naive T and Treg cotransfer significantly reduced gut permeability to bacterial antigen translocation and restored TJ protein expression in Rag1‐/‐ mice. Naive T and Treg replenishment in Rag1‐/‐ mice restrained proinflammatory differentiation of intestinal lymphocytes in response to E. coli. The main SCFA concentration resulted in significant reduction in Rag1‐/‐ mice after E. coli administration but remained unaltered after naive T and Tregs cotransfer. The reduced expression of SCFA receptors induced by E. coli was reestablished following naive T and Treg reconstitution in Rag1‐/‐ mice. Conclusion: The restriction of gut permeability, local inflammatory differentiation, and loss of bacteria‐derived SCFAs foster the value of Tregs in preventing bacterial translocation in cirrhosis. Increased intestinal permeability is key in the translocation of small bacterial antigens, which are associated with poor disease outcomes in cirrhosis. Treg cells help maintain an improved gut barrier integrity, restrict an exacerbated pro‐inflammatory Th commitment and preserve the most representative anti‐inflammatory SCFAs in experimental cirrhosis. Promoting Treg cells differentiation might prevent bacterial antigen translocation derived complications in advanced cirrhosis.