I also did not know that, I was once treated by a GI at a university hospital who told me about a research project he had done where they gave CD patients Vitamin D, and registered the efficacy (using the CDAI score I think). He told me they concluded Vitamin D was as efficient in maintaining remission as the high dose of 5-ASA.
They did not study the mechanism, but reeding through the PubMed links you sent, it seems stimulating autophagy would be the reason.
So - does any of the established drugs like the biologics, Methotrexate and glucocorticosteroids have an impact on autophagy?
#WARNING: lengthy reply with lots of references.. :runaway:
I found a very interesting article,
Autophagy: a new target or an old strategy for the treatment of Crohn's disease?
quote:
"
Interestingly, as well as the promising introduction of direct autophagic modulators, several drugs already used in the treatment of Crohn's disease might exert at least part of their effect through the regulation of autophagy. However, whether this phenomenon contributes to or rather counteracts their therapeutic use, remains to be determined and might prove to be highly compound-specific . Here we review the complex and emerging role of autophagy modulation in the battle against Crohn's disease. Moreover, we discuss the potential benefits and deleterious effects of autophagic regulation by both new and clinically used drugs."
unfortunately the full article is not available without subscription.
Below are some articles I found dealing with autophagy and specific CD drugs. They sometime use the word "Apoptosis" which is also a programmed cell death and an important mechanism in the elimination of infected cells. It sounds a bit like autophagy, but I read that they can also be opposites, ind that autophagy can block the induction of apoptosis.
apoptosis and infliximab:
Downregulation of epithelial apoptosis and barrier repair in active Crohn’s disease by tumour necrosis factor α antibody treatment
In conclusion, we have shown a significant decrease in
epithelial cell apoptosis in CD patients after TNF-a antibody
therapy which was accompanied by an increase in epithelial
resistance. Tight junction protein expression did not contribute
to this barrier repair.
note: could this mean anti-TNFa drugs, while suppressing the inflammatory response and thus inducing a clinical improvement ("the parking lot effect" - patients getting infusions, and feeling improvement already when they exit the hospital), actually at the same time inhibit the body's attempts to clear an infection (eg. with AIEC or MAP?).
Another article, however, concludes the opposite, namely that infliximab increases apoptosis:
Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease
conclusions:
Conclusions: Our data indicate that infliximab treatment causes a rapid and specific increase in apoptosis of T lymphocytes in the gut mucosa. These findings may explain the rapid and sustained therapeutic effects of infliximab in Crohn's disease.
Infliximab induced activation dependent apoptosis of Jurkat T lymphocytes, possibly altering the Bax/Bcl-2 ratio. In patients with Crohn's disease, infliximab rapidly increased the number of apoptotic T cells in the inflamed mucosa, without affecting peripheral blood mononuclear cells. These data indicate that infliximab functions, in part, as an “immunotoxin” that specifically targets the mucosal T lymphocytes that are involved in the pathogenesis of Crohn's disease
On apoptosis and Methotrexate:
One way MTX works is that it is a competitive inhibitor of many enzymes that use folates, inhibiting synthesis of DNA, RNA, thymidylates, and proteins.
The article
Autophagy induction contributes to the resistance to methotrexate treatment in rheumatoid arthritis however, concludes that MTX also upregulates autophagy, at least in patients with rheumatoid arthritis:
Results:
MTX-induced apoptosis was increased in OA-FLS compared with RA-FLS. However, MTX stimulated the autophagy response in RA-FLS by inducing autophagosome formation, but not in OA-FLS. In RA-FLS, transfection with Beclin-1 small interfering RNA inhibited autophagy and increased susceptibility to MTX, which induces cell death. MTX upregulated autophagy through its ability to enhance the expression of HMGB1 and Beclin-1 rather than through the Akt/mTOR pathway.
Conclusions:
Autophagy induction contributes to resistance to MTX treatment in fibroblasts from patients with rheumatoid arthritis.
Another study on MTX that describe apoptosis:
Increased sensitivity to apoptosis induced by methotrexate is mediated by Jun N-terminal kinase
Results:
MTX does not directly induce apoptosis but rather ‘primes’ cells for markedly increased sensitivity to apoptosis via either mitochondrial or death receptor pathways by a Jun N-terminal kinase [JNK]-dependent mechanism. Increased sensitivity to apoptosis is mediated, at least in part, by MTX-dependent production of reactive oxygen species, JNK activation and JNK-dependent induction of genes whose protein products promote apoptosis. Supplementation with tetrahydrobiopterin blocks these methotrexate-induced effects. Subjects with rheumatoid arthritis on low-dose MTX therapy express elevated levels of the JNK-target gene, JUN.
Conclusions:
Our results support a model whereby methotrexate inhibits reduction of dihydrobiopterin to tetrahydrobiopterin resulting in increased production of ROS, increased JNK activity and increased sensitivity to apoptosis. The finding of increased JUN levels in subjects with RA taking low-dose MTX supports the notion that this pathway is activated by MTX, in vivo, and may contribute to efficacy of MTX in inflammatory disease.
Glucocorticosteriods (Prednisone) and apoptosis :
Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease
From the abstract:
Glucocorticoid hormones (GCH) induce apoptosis in PHA-primed peripheral blood T lymphocytes (PBL) and down-regulate membrane-bound proteins involved in the immune response.
Another one on glucocorticosteroids:
Recent insights into the mechanism of glucocorticosteroid-induced apoptosis
From the abstract:
Glucocorticosteroid hormones induce apoptosis in lymphocytes. Therefore, glucocorticoids are commonly used as immunosuppressive and chemotherapeutic agents
In summary, it does not seem far fetched to propose that upregulating autophagy and/or apoptosis may explain why usual CD drugs help inducing remission. Further, it makes the case for investing natural ways of stimulating these processes, to see if it can be done without the need for these drugs, in order to avoid the side effects.
Please note: I realise I may be mixing pears and apples in citing studies that describe either Autophagy or Apoptosis. Any thoughts on this?
Also, I realise I could be causing thread drift into the topic "CD and autophagy / apoptosis". Should we maybe start a new thread on this?? Kiny started one in 2012, but it is re. a specific article on autophagy and AIEC.
http://www.crohnsforum.com/showthread.php?t=44825