p38γ and p38δ as biomarkers in the interplay of colon cancer and inflammatory bowel diseases

descripción no proporcionada por scopusThis research was funded by the MCIN/AEI/10.13039/501100011033 (PID2019-108349RB100 and SAF2016-79792R) to AC and JJSE; Villum Foundation, grant no. 13152 to KA; by Agencia Estatal de Investigación (PID2019-104867RBI00/AEI/10.13039/501100011033) and the Instituto de Salud Carlos III- Fondo Europeo de Desarrollo Regional (CIBERONC/CB16/12/00273 and ICI20/00057) to AM and AB. PF received MCIN FPI fellowship (BES-2017-080139)

Alternative p38MAPKs as biomarkers in the interplay of colon cancer and inflammatory bowel diseases

Trabajo presentado en el 44º Congreso Nacional de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Málaga (España) del 06 al 09 de septiembre de 2022.Chronic inflammation in inflammatory bowel disease (IBD) is a risk factor for Colorectal cancer (CRC) development, but our understanding of this interplay at a molecular level is still limited. p38γ and p38δ, are central in the development of mouse colitis-associated CRC (CAC) by modulating the inflammatory immune response. However, their implication in human CRC and IBD is not well defined. In this study we perform an integrative analysis of p38γ and p38δ mRNA and protein expression and activation in human patients; using human CRC derived organoids and plasma samples, as well as data from different human CRC and IBD mRNA databases. We found that, p38δ levels were decreased, whereas p38γ expression and phosphorylation were significantly increased in CRC compared to normal colon samples. This increase correlated with the expression of genes implicated in inflammation. Examine of p38γ/p38δ in IBD patients showed that p38γ mRNA and protein levels were increased in Crohn’s disease and ulcerative colitis patients. Contrary, p38δ mRNA was significantly decreased. We also investigated the expression of miRNAs, miR-128-2, miR133a and miR-155, implicated in inflammation and cancer development. In mouse model of colitis and CAC, miR128-2 level was regulated by p38γ/p38δ. In the plasma of IBD and CRC patients, miR128-2 was increased compared to healthy donors, and this correlated with p38γ and p38δ levels. Our results show an opposite regulation of p38γ and p38δ in both CRC and IBD; and suggest that p38γ acts as a link between colitis and CRC by favouring an inflammatory environment that promotes tumour development. We provided evidence that p38γ/p38δ, together with miR-128-2, can be useful as biomarkers, and as potential treatment targets, for colitis and early-stage CRC

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M.S.Richard Dagenhar

Gut microbiome–based therapeutics in inflammatory bowel disease

Abstract Inflammatory bowel disease (IBD), including both ulcerative colitis and Crohn's disease, is a chronic inflammatory disease of the gastrointestinal tract that is thought to arise from a combination of environmental, genetic and immunological factors. The gut microbiome, a diverse ecosystem of microorganisms residing in the digestive tract, has been proposed to play a role in the pathogenesis of IBD. There is an unmet clinical need for microbiome‐based therapies. This review will discuss the landscape of microbiome‐based therapeutics in IBD. Microbiome‐targeted therapeutics, such as antibiotics, pre‐/probiotics and faecal microbiota transplant (FMT), are based on the premise that restoring a healthy gut microbiome can attenuate mucosal inflammation. Antibiotics work directly to impede growth or eradicate specific gut microorganisms. Antibiotics may play a role in inducing clinical remission and treating refractory pouchitis and may be associated with immunogenicity to anti‐TNF biologics in IBD. Prebiotics are the molecular metabolic building blocks for commensal gut bacteria. Probiotics artificially introduce gut microorganisms thought to be beneficial to the local microenvironment and maybe be associated with symptom relief in IBD. FMT similarly introduces bacteria found in higher proportions of healthy persons, though in a more direct manner than probiotics. FMT has been associated with increased rates of clinical remission in IBD, but heterogeneity in FMT response may be influenced by IBD subtype, FMT donor selection and delivery protocols. Current evidence suggests that microbiome‐targeted therapeutics may have some benefit for IBD. Several studies are underway exploring the targeting of specific gut microbes or microbial pathways as therapy in IBD