Drug decreases gut leakiness associated with ulcerative colitis

Andy

Andy

Retired committee member
A research team led by biomedical scientists at the University of California, Riverside, has found that a drug approved by the FDA to treat rheumatoid arthritis and ulcerative colitis can repair permeability defects in the gut's epithelium.

Affecting roughly 1 million Americans, ulcerative colitis is a chronic inflammatory bowel disease of the large intestine in which the lining of the colon becomes inflamed and leaky. Affecting more than 2 million Americans, rheumatoid arthritis is an autoimmune disease in which the body's immune system attacks the joints.

The study is the first to show the drug, tofacitinib, also called Xeljanz, has a direct effect on cells lining the gut by correcting defects that occur in inflammation. Until now, the effects of tofacitinib on intestinal epithelial cell functions were largely unknown.
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https://medicalxpress.com/news/2019-12-drug-decreases-gut-leakiness-ulcerative.html
 
M.E. is to my best knowledge often associated with leaky gut. Which is why there's such an emphasis on the gut. But much more promising and measured jak-inhibitors are already in the final stages of testing(upaciditinib, filgotinib). And if I recall correctly, trials on m.e. are already underway or at least funded for those drugs.
 
The study talked about in the article above.

The JAK-Inhibitor Tofacitinib Rescues Human Intestinal Epithelial Cells and Colonoids from Cytokine-Induced Barrier Dysfunction
Background

Alterations to epithelial tight junctions can compromise the ability of the epithelium to act as a barrier between luminal contents and the underlying tissues, thereby increasing intestinal permeability, an early critical event in inflammatory bowel disease (IBD). Tofacitinib (Xeljanz), an orally administered pan-Janus kinase (JAK) inhibitor, was recently approved for the treatment of moderate to severe ulcerative colitis. Nevertheless, the effects of tofacitinib on intestinal epithelial cell functions are largely unknown. The aim of this study was to determine if JAK inhibition by tofacitinib can rescue cytokine-induced barrier dysfunction in intestinal epithelial cells (IECs).

Methods
T84 IECs were used to evaluate the effects of tofacitinib on JAK-signal transducer and activator of transcription (STAT) activation, barrier permeability, and expression and localization of tight junction proteins. The impact of tofacitinib on claudin-2 promoter activity was assessed in HT-29 IECs. Tofacitinib rescue of barrier function was also tested in human colonic stem cell-derived organoids.

Results
Pretreatment with tofacitinib prevented IFN-γ-induced decreases in transepithelial electrical resistance (TER) and increases in 4 kDa FITC-dextran permeability (FD4), partly due to claudin-2 transcriptional regulation and restriction of ZO-1 rearrangement at tight junctions. Although tofacitinib administered after IFN-γ challenge only partially normalized TER and claudin-2 levels, FD4 permeability and ZO-1 localization were fully recovered. The IFN-γ-induced FD4 permeability in primary human colonoids was fully rescued by tofacitinib.

Conclusions
These data suggest differential therapeutic efficacy of tofacitinib in the rescue of pore vs leak-tight junction barrier defects and indicate a potential contribution of improved epithelial barrier function to the beneficial effects of tofacitinib in IBD patients.
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Paywall, https://academic.oup.com/ibdjournal/advance-article-abstract/doi/10.1093/ibd/izz266/5637473
Sci hub, https://sci-hub.se/10.1093/ibd/izz266
 
Interestingly the drug, tofacitinib, is talked about in this paper.

JAK/STAT Blockade Alters Synovial Bioenergetics, Mitochondrial Function, and Proinflammatory Mediators in Rheumatoid Arthritis
Objective

To examine the effects of tofacitinib on metabolic activity, mitochondrial function, and proinflammatory mechanisms in rheumatoid arthritis (RA).

Methods
Ex vivo RA synovial explants and primary RA synovial fibroblasts (RASFs) were cultured with 1 μM tofacitinib. RASF bioenergetics were assessed using an XF24 analyzer, and key metabolic genes were assessed by reverse transcription–polymerase chain reaction (RT‐PCR) analysis. Mitochondrial function was assessed using specific cell fluorescent probes and by mitochondrial gene arrays. Mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay, and lipid peroxidation was quantified by enzyme‐linked immunosorbent assay (ELISA). The effect of tofacitinib on spontaneous release of proinflammatory mediators from RA whole tissue synovial explants was quantified by ELISAs/MSD multiplex assays, and metabolic markers were quantified by RT‐PCR. Finally, RASF invasion, matrix degradation, and synovial outgrowths were assessed by transwell invasion/Matrigel outgrowth assays and ELISA.

Results
Tofacitinib significantly decreased mitochondrial membrane potential, mitochondrial mass, and reactive oxygen species production by RASFs and differentially regulated key mitochondrial genes. Tofacitinib significantly increased oxidative phosphorylation, ATP production, and the maximal respiratory capacity and the respiratory reserve in RASFs, an effect paralleled by a decrease in glycolysis and the genes for the key glycolytic enzymes hexokinase 2 (HK2), glycogen synthase kinase 3α (GSK‐3α), lactate dehydrogenase A, and hypoxia‐inducible factor 1α. Tofacitinib inhibited the effect of oncostatin M (OSM) on interleukin‐6 (IL‐6) and monocyte chemotactic protein 1 and reversed the effects of OSM on RASF cellular metabolism. Using RA whole tissue synovial explants, we found that tofacitinib inhibited the key metabolic genes for glucose transporter 1, 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3, 3′‐phosphoinositide–dependent protein kinase 1, HK2, and GSK‐3α, the proinflammatory mediators IL‐6, IL‐8, IL‐1β, intercellular adhesion molecule 1, vascular endothelial growth factor, and TIE‐2, and RASF outgrowth from synovial explants, RASF invasion, and matrix metalloproteinase 1 activity.

Conclusion
This study demonstrates that JAK/STAT signaling mediates the complex interplay between inflammation and cellular metabolism in RA pathogenesis.
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Open access, https://onlinelibrary.wiley.com/doi/full/10.1002/art.40569
 
Solstice said:
M.E. is to my best knowledge often associated with leaky gut. Which is why there's such an emphasis on the gut. But much more promising and measured jak-inhibitors are already in the final stages of testing(upaciditinib, filgotinib). And if I recall correctly, trials on m.e. are already underway or at least funded for those drugs.
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do you have a link for that information? could not find anything! ty!
 
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