The PI3K pathway as a therapeutic intervention point in inflammatory bowel disease

Abstract

With glucose being the preferred source of energy in activated T cells, targeting glycolysis has become an attractive therapeutic intervention point for chronic inflammatory bowel diseases (IBD). The switch to glycolysis is mediated by phosphoinositide‐3‐kinases (PI3K) which relay signals from surface receptors to the AKT pathway. We first confirmed by analysis of the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) that metabolism is shifted towards glycolysis in IBD patients as compared to non‐IBD donors. In contrast to non‐IBD donors, OCR correlated with ECAR (IBD: cor = 0.79, p = 2E‐10; non‐IBD: cor = 0.37, p = n.s.), in IBD patients. Second, we tested the PI3K inhibitor copanlisib as a potential therapeutic. Ex vivo, copanlisib suppressed the ECAR significantly in T cells activated by anti‐CD3 antibodies and significantly decreased ECAR rates in the presence of copanlisib (anti‐CD3: 58.24 ± 29.06; copanlisib: 43.16 ± 20.23, p < .000. In addition, copanlisib impaired the activation of CD4+ CD25+ T cells (anti‐CD3: 42.15 ± 21.46; anti‐CD3 + copanlisib: 26.06 ± 21.82 p = .013) and the secretion of cytokines (IFNγ: anti‐CD3: 6332.0 ± 5707.61 pmol/ml; anti‐CD3 + copanlisib: 6332.0 ± 5707.61, p = .018). In vivo, copanlisib significantly improved the histological scores (ethanol: 8.5 ± 3.81; copanlisib: 4.57 ± 2.82, p = .006) in the NSG‐UC mouse model. Orthogonal partial least square analysis confirmed the efficacy of copanlisib. These data suggest that the PI3K pathway provides an attractive therapeutic intervention point in IBD for patients in relapse. Targeting metabolic pathways have the potential to develop phase dependent therapies.

Stratifying macrophages based on their infectious burden identifies novel host targets for intervention during Crohn’s disease associated adherent-invasiveEscherichia coliinfection

“…The targets chosen; Adcy1, Pik3cb, Mlkl, Map2k1 and Itch, each represented a unique pathway in which they displayed the Signature 1 phenotype of increasing in direct response to bacterial burden within the cell. None of these genes had to date been associated with AIEC infection or used as a target to inhibit bacterial infection, although PIK3cb and MLKL had previously been suggested as targets for therapeutic intervention in IBD, while MAP2K1 has a currently approved kinase inhibitor targeted towards it for IBD treatment (Pierdomenico et al ., 2014; Bruckner et al ., 2020; Winkelmann et al ., 2021). ITCH has been directly implicated in pathogenesis of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mediated inflammatory disease and it is directly involved in ubiquitination and tagging of host proteins for proteasomal degradation, a system we have previously shown to be exploited during AIEC infection (Dunne et al ., 2013).…”

Feline Chronic Gingivostomatitis Diagnosis and Treatment through Transcriptomic Insights

“…In the work undertaken here, the Phosphatidylinositol 3-kinase/Ak strain transforming (PI3K/AKT) signaling pathway emerged as a significant molecular basis for disease with moderate activation (Z-score = 3.81) in the FCGS-affected group. Constitutive activation of the PI3K/AKT pathway has been observed in inflammatory and autoimmune diseases, viral infections, and autoinflammatory syndromes [ 18 , 19 , 20 , 21 ]. PI3K/AKT is known to influence immune cell function, such as the activity of myeloid cell populations, and contributes to the regulation of cytokine production, bringing to light once again the role of the innate immune system in this disease [ 22 ].…”

LncRNA-miRNA-mRNA Network Analysis Reveals the Potential Biomarkers in Crohn’s Disease Rats Treated with Herb-Partitioned Moxibustion

“…Based on previous findings, pyruvate metabolism and glycolysis/gluconeogenesis are critical for the development of inflammatory bowel disease. 63 , 64 In pathological states, the strong correlation between adipocytokine level and inflammation severity is demonstrated in IBD. 65 Decreased expression of PPAR gamma may cause persistent mucosal inflammation in colitis.…”