5.0 Cannabinoid activity and Gut inflammation
The GI tract is rich in components of the endocannabinoid system. In
addition to the classical CB1 and CB2receptors, the gut also expresses G protein-coupled receptor 55 (GPR55),
a cannabinoid-responsive non-CB1/CB2receptor, which upon activation leads to increased intracellular calcium
concentration (Grill et al., 2018). This mechanism has been shown to
involve Gq, G12, actin, RhoA,
phospholipase C and calcium released from inositol 1,4,5-triphosphate
receptor (IP3R)-gated stores (Lauckner et al., 2008). Within the GI
system, CB2 is largely expressed on immune cells whereas
CB1 is largely expressed on cholinergic neurons (Sibaev
et al., 2009; Schmole et al., 2015). Moreover, the gut also contains
enzymes of the endocannabinoid system including diacylglycerol lipase
and N-acyl phosphatidylethanolamine-specific phospholipase D, FAAH and
MAGL (Grill et al., 2018).
By examining the role of endocannabinoids in maintaining gut integrity,
it is most apparent that these endogenous ligands have multiple
regulatory roles including, maintaining the integrity of the epithelial
barrier, regulating gut microbiota and keeping the immune cells tolerant
to commensals (Cani et al., 2016; Karwad et al., 2017). The latter is
achieved through regulation of the expansion of the regulatory T cell
(Treg) subset Tr1 and the presence of CX3CR1hi, an
immunosuppressive macrophage population (Acharya et al., 2017). Thus, it
is unsurprising that changes in the levels of endocannabinoids and
endocannabinoids-like lipids are implicated in inflammatory bowel
disease (IBD) and colorectal cancer (Di Sabatino et al., 2011; Chen et
al., 2015). It however remains to be determined if such variations
correlate with disease progress (Grill et al., 2018).
Functional data from animal models shows alterations in the components
of the endocannabinoid system during experimental intestinal
inflammation (Massa et al., 2004; D’Argenio et al., 2006). It has been
shown that, pharmacological activation of CB1 and
CB2 attenuates experimental colitis (Kimball et al.,
2006; Storr et al., 2009), while pharmacological antagonism or genetic
ablation of these receptors worsens gut inflammation (Massa et al.,
2004; Storr et al., 2008). This is evident from studies that
demonstrated that increased levels of anandamide and 2-AG, following
inhibition of FAAH or MAGL or genetic deficiency in genes that encodes
these enzymes, is protective against experimental colitis such as
dextran sodium sulfate (DSS)-induced colitis or trinitrobenzene sulfonic
acid (TNBS)-induced colitis (Pagano et al., 2016; Shamran et al., 2017;
Zhao et al., 2017).
Synthetic analogs of endocannabinoids as well as phytocannabinoids have
been shown to ameliorate gut inflammation in animal models of intestinal
inflammation (Grill et al., 2018). In a study by Jamontt et al. (2010),
both the psychotropic Δ9-THC and the non-psychotropic
cannabidiol reduced colonic injury in a rat model of TNBS-induced
colitis. Cannabidiol, however, has very low affinity on
CB1 and CB2, and is antagonistic on
GPR55 (Ryberg et al., 2007). In addition, cannabidiol acts on PPARγ (De
Filippis et al., 2010) and TRPV1 (De Petrocellis et al., 2011) expressed
in the gut. It also inhibits the activity of FAAH and has been shown to
ameliorate intestinal inflammation in dinitrobenzene sulfonic acid
(DNBS)-induced colitis in mice (Borrelli et al., 2009). Significant
reduction in intestinal inflammation by cannabidiol appears to be a
combined effect with other compounds in Cannabis sativa rather
than a single effect (Pagano et al., 2016). Moreover, O-1602, an analog
of cannabidiol and a GPR55 agonist, has been shown to protect against
intestinal damage in experimental colitis. This effect, however, was not
mediated by GPR55, and by extrapolation, not by CB1 or
CB2 since O-1602 lacks affinity for CB1and CB2 (Ryberg et al., 2007). Several other
phytocannabinoids, endocannabinoids, endocannabinoid-like substances and
synthetic endocannabinoid analogs have been demonstrated to inhibit
intestinal inflammation in various models of experimental colitis. Table
1 summarizes these ligands and the mechanisms involved in the inhibition
of inflammatory processes in the GIT.
By employing the use of chronic ileitis model, Leinwand et al. (2017)
identified upregulation of CB2 and anandamide in
actively inflamed ileum of TNFΔARE/+ mice compared
with controls. In TNFΔARE/+ mice, CB2mRNA was relatively expressed 11-fold more on Tregs as compared to T
effector cells, while in wild-type mice, there was a 2.4-fold increase
in its expression on Tregs compared to T effector cells. The authors
reported that GP-1a, a previously classified CB2receptor agonist, acts at CB2 as an inverse agonist,
thus allows the receptor to resensitize. This finding is also supported
by a previous study by Soethoudt et al. (2017), where GP-1a was shown to
actively inhibit the reuptake of anandamide and also act as an inverse
agonist at the CB2 receptors in vitro . GP-1a
however did not stimulate CB1 receptors. The inverse
agonism at CB2 enhances the activation of Treg-expressed
CB2 receptors by endocannabinoids, with subsequent
increase in Treg suppressive function and associated increase in IL-10
secretion (Leinward et al., 2017). As opposed to active inflammation,
CB2R was downregulated in both chronically inflamed
TNFΔARE/+ mice and in Crohn’s disease patients.
Activation of CB2 receptors inhibited ileitis in mice,
thus establishing the protective effect of the endocannabinoid system in
intestinal inflammation (Leinward et al., 2017).
Table 1. Other cannabinoid receptor ligands in murine models of
intestinal inflammation