Oral caffeine administration ameliorates acute colitis by suppressing chitinase 3-like 1 expression in intestinal epithelial cells.
BACKGROUND
The initial trigger of inflammatory bowel disease (IBD) can be partly attributed towards the interaction and invasion of intestinal epithelial cells (IECs) and submucosal compartments. Identifying safe and economical methods to block these interactions may help prevent the onset of early colitis. Chitinase 3-like 1 (CHI3L1) is an inducible host protein that facilitates bacterial attachment and invasion on/into IECs. Therefore, we test the hypothesis of inhibiting CHI3L1 using the pan-chitinase inhibitor caffeine to reduce the likelihood of early colitis onset.


METHODS
IEC lines were treated with caffeine (2.5 or 5 mM) and analyzed for CHI3L1 expression and the impact on bacterial invasion. In vivo, mice were treated with 2.5 mM caffeine and induced with 3.5 % dextran sulfate sodium (DSS)-mediated colitis and subsequently analyzed colitis development.


RESULTS
In vitro, caffeine treatment in IEC lines down-regulated CHI3L1 mRNA expression, which resulted in the reduction of bacterial invasion in a caffeine dose-dependent manner. In vivo, mice treated with caffeine displayed a delayed response towards DSS-induced colitis, characterized by lower body weight loss, clinical and histological scores. Bacterial translocation into other organs and pro-inflammatory cytokines production were also reduced in the caffeine-treated mice with DSS-induced colitis. Caffeine treatment also resulted in the loss of CHI3L1-associated AKT signaling pathway activation both in vitro and in vivo.


CONCLUSIONS
Development of acute colitis is reduced upon caffeine treatment. The mechanism involves the down-regulation of CHI3L1 expression and its associated bacterial interaction effect. Therefore, caffeine is proposed as a safe and economical candidate for successful IBD management.
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, GRJ 825D, 55 Fruit Street, Boston, MA, 02114, USA.
In-Ah
IA
Lee
Daren
D
Low
Alan
A
Kamba
Victoria
V
Llado
Emiko
E
Mizoguchi
D000208:Acute Disease; D054392:Adipokines / Q000037:antagonists & inhibitors* / Q000235:genetics; D000284:Administration, Oral; D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D000071451:Chitinase-3-Like Protein 1; D003092:Colitis / Q000188:drug therapy* / Q000503:physiopathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D037102:Lectins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism
D054392:Adipokines; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins; D012333:RNA, Messenger; D002110:Caffeine; D016264:Dextran Sulfate