## 6 Therapeutic Potential of Cannabinoids in Gut Diseases
### Therapeutic Potential of Phytocannabinoids
#### 6.2.1 Therapeutic Potential of THC and CBD Infectious Diseases  
CBD has been shown to dose-dependently restore cell viability, TEER values, ZO-1, and occludin expression in Caco-2 cell cultures treated with TcdA. CBD also reversed the fall in RhoA GTP (the primary target for TcdA) expression and reversed the increase in expression of the pro-apoptotic Bax protein. All these protective effects were abolished by the CB1 antagonist AM251. This suggests that CBD may be helpful in clinical management of _Clostridium difficile_-associated colitis [95]. THC upregulated PPAR\(\gamma\) mRNA expression (which was reduced in SIV-infected individuals) when incubated ex vivo with intact colonic tissue of chronically SIV-infected rhesus macaques [94]. In mice with LPS-induced sepsis, CBD further reduced GIT motility, worsening septic ileus. This was prevented by the CB1 receptor antagonist AM251. CBD had no effect on GIT motility in healthy control mice. LPS also significantly upregulated CB1 receptor expression in the small intestine without affecting CB2 receptor expression. CBD reversed LPS-induced upregulation of FAAH activity, an effect that was unmodified by CB1 blockade. This suggests that CBD's exacerbation of septic ileus is due to FAAH inhibition and imbalance between endocannabinoid production and degradation, leading to endocannabinoid-induced inhibition of motility via CB1 receptor activation [105]. Therapeutic Potential of THC and CBD in Gastrointestinal Tract Motility  
In an in vivo study, THC was observed to dose-dependently decrease the frequency of transient lower esophageal sphincter relaxation episodes (which are the main mechanism of gastro-esophageal reflux) in both dogs and humans. Additionally, THC caused a dose-dependent decrease in postprandial acid reflux rates in dogs and a non-significant decrease in acid reflux episodes in humans. The CB1 receptor antagonist SR141716A reversed the effect of THC on transient lower esophageal sphincter relaxations (TLESR) [106]. A 4-weekrandomized controlled trial investigating the effect of CBD on clinical signs of diabetic or idiopathic gastroparesis showed improvements in symptom severity and frequency in the CBD group. CBD also caused delayed gastric emptying of solids in patients, but provided good clinical relief of symptoms despite this [107]. On the other hand, CBD provided no significant amelioration of symptoms in patients suffering from functional dysppepsia without delayed gastric emptying [108]. Similarly to CBD, THC also delayed gastric emptying in healthy subjects, as well as increasing fasting gastric volume in males. Colonic transit, however, was not affected [109]. In contrast, a later study documented a reduction in postprandial colonic motility and tone in response to THC in healthy subjects, alongside an increase in colonic sensitivity to distension [110]. Another possible interaction of cannabis use with gastric emptying was established in an epidemiological study which linked cannabis use to hospitalization with gastroparesis. This suggests that the delaying effect of cannabis on gastric emptying may cause dysmotility when used in excess [111]. There are case studies of THC being successfully used in clinical practice. One such example is the almost complete remission of symptoms related to failure to thrive secondary to intestinal dysmotility in a 58-year-old patient. When treated with dronabinol, the patient was able to maintain her nutritional status orally, which had previously been impossible [112]. Another such case is described for a 19-year-old patient suffering from chronic intestinal pseudo-obstruction, who had been dependent on parenteral nutrition since birth. After commencement of treatment with dronabinol, she experienced marked improvement in symptoms and subjective quality of life [113]. Therapeutic Potential of THC and CBD in Inflammatory Diseases  
In a murine model of DSS-induced colitis, CBD co-administered with fish oil at doses found to have no effect individually was able to effect several beneficial changes.