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Preventing Negative Shifts in Gut Microbiota with Cannabis Therapy: Implications for Colorectal Cancer

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Despite the controversies surrounding the therapeutic use of cannabis in the treatment of several medical conditions, the fact remains that there is a scientific rationale for its use, particularly in the treatment of colorectal cancer (CRC). Constituents of cannabis such as CBD have demonstrated anti-cancer effects via endocannabinoid signaling. However, an additional positive aspect of cannabis use that may be overlooked is its potential role in preventing imbalances of the gut microbiota. Not only is this important for the treatment of several gastrointestinal disorders such as inflammatory bowel disease (IBD) and obesity, but it also has implications for the treatment of CRC. The impact of the endocannabinoid system on gut microbiota is a relatively new and emerging field wherein the interplay between cannabinoids and metabolic syndrome has been the focus thus far. This review aims to introduce the link between cannabis, obesity and CRC through alterations to gut microbiota, which is an exciting new direction of research. Here, we will outline the current understanding of the mechanism of action of cannabis on the endocannabinoid system as well as its therapeutic potential. We will also discuss the connection between imbalances in gut microbiota, the action of cannabis in correcting this occurrence and the potentially overlooked positive implications of preventing further negative changes to gut microbiota for the initiation of CRC.
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Preventing Negative Shifts in Gut Microbiota with
Cannabis Therapy: Implications for Colorectal Cancer
Regina-Veronicka Kalaydina1,2, Bessi Qorri1,2 and Myron R Szewczuk1*
1Department of Biomedical and Molecular Sciences, Queen’s University, Canada
2Contributing first authorship, Canada
Submission: October 03, 2017; Published: October 12, 2017
*Corresponding author: Myron R Szewczuk, Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6,
Canada, Tel: ; Fax +1 613 533 6796; Email:
Introduction
Recently, with the increased interest in the therapeutic
potential of MM, or cannabis (used interchangeably hereafter),
reports have suggested the existence of a relationship between
the endocannabinoid system, a naturally occurring system in
humans, and gastrointestinal (GI) tract function, proposing
that cannabinoids may also impact the gut microbiota [1].
The gut microbiota is a collection of microorganisms that
are involved in several homeostatic and immune functions
       
genotype and physiology, additional factors such as diet,
antibiotic use, smoking, exercise and stress have also been
implicated in contributing to the composition of individual gut
microbiota [1,3]. Since relative levels of gut microorganisms
have been previously associated with playing a crucial role
in the initiation and progression of colorectal cancer (CRC)
[2], the potential connection between the modulatory role of
cannabis, particularly as an anti-cancer agent [4], is perhaps not
  
the interactions of cannabis in rebalancing the GI tract microbiota and
the potential preventative action on the development of CRC. Here,
we will discuss how phytocannabinoids like cannabis may alter GI
tract characteristics and gut microbiota composition. We will also
cover the implications of the modulatory effects of cannabis on the

Endocannabinoids and the gut
Increased endocannabinoid system tone has been observed in

endocannabinoid levels in plasma and adipose tissue as well as
increased expression of the cannabinoid 1(CBD) receptor [6].
It has been reported that increased levels of endocannabinoids
acting primarily through the CB1 receptor serve a protective role
against epithelial damage and increased motility characteristic
       
cannabis as well, as it acts on the endocannabinoid system in a
similar manner to endogenous endocannabinoids via CB1 and
CB2 receptor signaling [6,7].
Mini Review
Volume 7 Issue 3 - 2017
DOI: 10.19080/ARGH.2017.07.555712
Adv Res Gastroentero Hepatol
Copyright © All rights are reserved by Myron R Szewczuk
Abstract
Despite the controversies surrounding the therapeutic use of cannabis in the treatment of several medical conditions, the fact remains

demonstrated anti-cancer effects via endocannabinoid signaling. However, an additional positive aspect of cannabis use that may be overlooked
is its potential role in preventing imbalances of the gut microbiota. Not only is this important for the treatment of several gastrointestinal
                    

syndrome has been the focus thus far. This review aims to introduce the link between cannabis, obesity and CRC through alterations to gut
microbiota, which is an exciting new direction of research. Here, we will outline the current understanding of the mechanism of action of
cannabis on the endocannabinoid system as well as its therapeutic potential. We will also discuss the connection between imbalances in gut
microbiota, the action of cannabis in correcting this occurrence and the potentially overlooked positive implications of preventing further
negative changes to gut microbiota for the initiation of CRC.
Keywords: Gut microbiota; Colorectal cancer; Cannabis; Marijuana; Metabolic syndrome
Adv Res Gastroentero Hepatol 7(3): ARGH.MS.ID.555712 (2017) 001
Advanced Research in Gastroenterology & Hepatology
How to cite this article: Kalaydina RV, Qorri B, Szewczuk MR. Preventing Negative Shifts in Gut Microbiota with Cannabis Therapy: Implications for
Colorectal Cancer. Adv Res Gastroentero Hepatol 2017; 7(3): 555712. DOI: 10.19080/ARGH.2017.07.555712.
002
Cannabis is a phytocannabinoid acting on the
endocannabinoid system, an inherent communication network
of cannabinoid receptors and endogenous ligands ubiquitously
expressed in the body [4]. The most commonly studied active
9-tetrahydrocannabinol
(THC) and non-psychoactive cannabidiol (CBD), both of which
act on CB1 and CB2 receptors. Recent studies have reported that
cannabinoids modulate cholinergic neurotransmission within
the endocannabinoid system [8]. The CB1 receptor is primarily
expressed in the nervous system, found on neuronal cells, the
brain, endocrine tissues and other peripheral tissues [7]. In
contrast, CB2 receptors are more restricted in their distribution,
and are mainly found on some immune cells [9]. In the gut, the
CB1 receptor is implicated in enteric nervous system function
[8,10,11], expressed on epithelial cells, submucosal neurons,
and myenteric neurons [5], providing the means by which
cannabinoids modulate intestinal motility [11]. Activation of the
CB1 receptor on epithelial cells promotes wound healing, while
the corresponding receptor on submucosal neurons is associated
with decreased secretions. Interestingly, CB1 receptors on the
myenteric nerve plexus were found to inhibit motility in mouse
        
of CB2 receptors primarily on immune cells, their activation
       
cytokines such as tumor necrosis factor a (TNF-a) [5]. Taken
together, the presence of CB1 and CB2 receptors in the gut wall
has been implicated in the regulation of food intake, GI tract
     
emesis [10]. Bearing in mind that alterations in gut microbiota
have been associated with changes to endothelial membrane
 
there may be a link between cannabinoids and gut microbiota
composition with respect to slowing the initiation of CRC.
Gut microbiota composition
Human gut microbiota consists of four main phyla: Firmicutes,
Bacteroidetes, Actinobacteria, and Proteobacteria [12]. Of these,
Firmicutes and Bacteroidetes are of particular interest due to
their proposed role in obesity and progression of CRC [12,13].
   

Ley et al. [15] showing a 50% reduction in Bacteroidetes and a
corresponding increase in Firmicutes. Low calorie diet [16] and
    
ratio, and more recently, long-term THC intake has demonstrated
its ability to halt this shift in microbiota ratio [13].
A closer look at precisely how THC prevents further gut
microbiota dysbiosis reveals that vehicle-treated diet-induced
obese (DIO) mice receiving a high-fat diet demonstrated an
increased Firmicutes:Bacteroidetes ratio, while THC-treated
DIO mice did not experience a shift in this ratio [13]. In addition
to the change in microbiota composition, THC intake was also
accompanied by weight loss in DIO mice [13], as an increase
in Bacteroidetes has been associated with weight loss [16].
Although seemingly counterintuitive, the weight loss caused
by THC is due to its partial agonist effect and only occurs under
high endocannabinoid tone conditions [7,13]. THC acts at the
       
to full endogenous cannabinoid agonists [13]. As a result,
THC blocks the function of endogenous CB1 receptor agonists
that would otherwise promote hunger. Beyond that, the exact
mechanism behind THC’s ability to produce weight-loss under
high endocannabinoid tone remains to be elucidated. Moreover,
it remains to be determined whether the weight loss associated
with THC administration in DIO mice is a consequence of changes
to gut microbiota, or vice versa.
Given that obesity is a risk-factor for colorectal cancer,
it is perhaps not surprising that an increased Firmicutes:
Bacteroidetes ratio has also been correlated with disease
progression of colorectal cancer [12]. Gao et al. [18] eloquently
described the link between microbiota dysbiosis to sporadic
CRC, with CRC patients exhibiting markedly different microbial
structures compared to healthy individuals. Cancerous gut tissue
      
when compared to healthy tissue (30.54%), which mirrors
the elevated Firmicutes shown to accompany obesity in DIO
mice. Additionally, cancerous tissue contained lower levels of
Bacteroidetes (12.77%) in comparison to healthy tissue (19.1%)
[13]. This is particularly interesting because Gram-negative
bacteria in the Bacteroidetes phylum predominantly produce
short-chain fatty acids (SCFAs) acetate and propionate, both of
which are closely related to obesity by playing roles in cholesterol
synthesis and reducing intake of food, respectively [19].
Preventing the Firmicutes:Bacteroidetes ratio from increasing
may be of critical importance as colon cancer is thought to be
bacterially induced (or associated) [12] in accordance with one
of the major mechanisms of colon cancer initiation. According
to this model, gut microbiota dysbiosis leads to increased

and hyperproliferation, all of which contribute directly to
       
summarized in Figure 1 below. This is accomplished by means of

metabolites, disruptions to tissue barriers and translocation of
microbes, which are all common under conditions of dysbiosis
[12]. As a result, rebalance of gut microbiota dysbiosis early in
disease onset may be critical to preventing the progression of
colorectal cancer.
Together, these data suggest that by virtue of interfering with
the appetite-stimulating property of endocannabinoids, cannabis
may prove to be an alternate therapeutic approach in promoting
weight loss in obese individuals, thereby lowering their risk
of developing CRC. Since cannabis has a well-established role
in maintaining the integrity of the endothelial membrane and
        
cannabis to halt negative changes to gut microbiota in obese
individuals may be a novel way to target CRC prevention.
Advanced Research in Gastroenterology & Hepatology
How to cite this article: Kalaydina RV, Qorri B, Szewczuk MR. Preventing Negative Shifts in Gut Microbiota with Cannabis Therapy: Implications for
Colorectal Cancer. Adv Res Gastroentero Hepatol 2017; 7(3): 555712. DOI: 10.19080/ARGH.2017.07.555712.
003
Figure 1: Mechanism of bacteria-associated (or induced) colon cancer and CB1 receptors. Through an increase of bacterial toxins,
a decrease in benecial bacterial metabolites and increased microbial translocation, gut dysbiosis results in increased endothelial
permeability and chronic inammation, which can be initiators of colorectal cancer.
Cannabis: a guardian of endothelial membrane
integrity and an anti-inflammatory agent
It has been previously reported that perturbation in gut
microbiota can result in increased tight junction permeability
  
breaches to the epithelial barrier result in commensal bacteria
   
[12]. Consequently, Toll-like receptors (TLRs) and Nod-like
receptors (NLRs) can recognize select pathogenic molecular
motifs [2]. This detection results in the activation of the MAPK,
      
     a is
 
on account of its induction of interleukein 8 (IL-8) in human
colonic epithelial cells. Both TNF-a and IL-8 play key roles in
the maintenance of intestinal immune homeostasis [5]. Under
     
and chemokine production, proliferation and recruitment
        
       

     
      
adhesion and migration, and inducing apoptosis of activated
immune cells [6]. Taken together, both CB1 and CB2 receptors
are involved in protective roles in intestinal conditions with an
      
     
in the gut by maintaining barrier integrity and inducing
regenerative processes [6].
THC and CBD have also been shown to restore endothelial
membrane permeability directly, with THC and CBD
administration enhancing the recovery speed of cells treated
with ethylenediaminetetraacetic acid (EDTA) to induce
increased permeability [21]. Furthermore, all cannabinoids (i.e.,
endocannabinoids, and exogenous cannabinoids, THC and CBD)
increased zona occludens-1 mRNA expression in cells with EDTA-
induced increased permeability. This is particularly relevant
because zona occludens-1 is a tight junction protein, which
suggests that THC and CBD may restore the epithelial integrity of
tight junctions with increased permeability in a similar manner
to endocannabinoids mentioned previously [21].
Moreover, CBD has also been shown to counteract intestinal


colitis revealed that CBD improved signs of colon injury via
reduction of edema in the mucosa and submucosa, and induction

was found to be associated with the down-regulation of inducible
nitric oxide synthase (iNOS) expression and modulation of
       
reactive oxygen species (ROS) production and lipid peroxidation
in intestinal epithelial cells in a concentration dependent manner
[22]. In preventing oxidative stress, CBD has been shown to be
associated in mucosal protection, which can prevent TLRs and
NLRs from recognizing molecular motifs in pathogens and thus

In light of the accumulating evidence implicating the
     
maintenance of the endothelial membrane, regeneration, and
its anti-oxidant effects, it follows that cannabis has shown to
have anti-tumoral action both in vitro and in vivo. Additionally,
CBD was found to exert anti-proliferative effects in colorectal
carcinoma cells, most likely via indirect activation of CB1
receptors by means of raising endocannabinoid levels [4]. It has
been shown that CBD exerts chemo-preventive effects in the
Advanced Research in Gastroenterology & Hepatology
How to cite this article: Kalaydina RV, Qorri B, Szewczuk MR. Preventing Negative Shifts in Gut Microbiota with Cannabis Therapy: Implications for
Colorectal Cancer. Adv Res Gastroentero Hepatol 2017; 7(3): 555712. DOI: 10.19080/ARGH.2017.07.555712.
004
AOM (azoxymethane) model of colon carcinogenesis [4]. Several
studies have suggested that cannabinoids inhibit angiogenesis by
preventing endothelial cell migration via acting on both CB1 and
CB2 receptors [23]. In addition to anti-cancer effects, cannabis
may have an overlooked role in inducing weight-loss via altering
gut microbiota, which may further decrease the susceptibility of
obese patients in developing CRC.
Conclusion
Cannabis has been shown to play a protective role on the
       
prevents further exacerbation of the Firmicutes:Bacteroidetes
ratio found in obesity, resulting in weight-loss, suggests that
cannabis may play a role in CRC prevention as well. Further
studies are warranted to establish whether THC can stop the
increase in the Firmicutes:Bacteroidetes ratio in mouse models of

on CRC disease progression. Additionally, it is necessary to clarify
whether preventing an increase in the Firmicutes:Bacteroidetes
microbiota ratio is responsible for weight loss, or whether weight

      

at an increased risk of developing CRC. However, a drawback
of the therapeutic utility of cannabis remains, due to THC
exerting psychoactive effects through cerebral CB1 receptors.
        
has a similar effect on gut microbiota, as CBD does not exhibit
    
antioxidant and immunomodulatory effects, making it an
attractive therapy. Therefore, further studies are needed to
determine whether CBD has the same effect on gut microbiota
with respect to the balance of Firmicutes:Bacteroidetes to
evaluate its application in halting the progression of the obese
         
disease onset.
Acknowledgements
This work was supported in part by grants to MR Szewczuk
from the Natural Sciences and Engineering Research Council
of Canada (NSERC), a private sector cancer funding from the
Josefowitz Family and Encyt Technologies, Inc. to MR Szewczuk.
R Kalaydina is a recipient of the Queen’s Graduate Award
(QGA). B Qorri is a recipient of the QGA and the 2017 Terry Fox
Research Institute Transdisciplinary Training Program in Cancer
Research.
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Advanced Research in Gastroenterology & Hepatology
How to cite this article: Kalaydina RV, Qorri B, Szewczuk MR. Preventing Negative Shifts in Gut Microbiota with Cannabis Therapy: Implications for
Colorectal Cancer. Adv Res Gastroentero Hepatol 2017; 7(3): 555712. DOI: 10.19080/ARGH.2017.07.555712.
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DOI: 10.19080/ARGH.2017.07.555712
... The impact of the endocannabinoid system on gut microbiota is a relatively new and emerging field wherein the interplay between cannabinoids and metabolic syndrome has been the focus so far. Recent data have suggested that Δ 9 -THC prevents further exacerbation of the Firmicutes:Bacteroidetes ratio typically found in obesity, resulting in weight-loss, indicating that Cannabis may play a role in CRC prevention as well [54]. Further studies are needed to determine whether CBD has the same effect on gut microbiota with respect to the balance of Firmicutes:Bacteroidetes to evaluate its application in halting the progression of the obese microbiota profile present in CRC, with the hopes of delaying this disease onset [54]. ...
... Recent data have suggested that Δ 9 -THC prevents further exacerbation of the Firmicutes:Bacteroidetes ratio typically found in obesity, resulting in weight-loss, indicating that Cannabis may play a role in CRC prevention as well [54]. Further studies are needed to determine whether CBD has the same effect on gut microbiota with respect to the balance of Firmicutes:Bacteroidetes to evaluate its application in halting the progression of the obese microbiota profile present in CRC, with the hopes of delaying this disease onset [54]. ...
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