Endogenous, as well as exogenous cannabinoids, have been widely recognized to regulate inflammation and mucosal permeability of the GI tract where they possibly interact with the gut microbiome. In this section, we have tried to pull together the known mechanisms through which cannabinoids control microbial dysbiosis and accompanying inflammation. The indispensable role of gut microbiota on immune regulation has been excellently validated by multiple investigations. For example, one such study demonstrated the ability of commensal segmented filamentous bacterium (SFB) to induce CD4⁺ T cells to produce IL-17 and IL-22 in the lamina propria of mice. SFB adhered to the Th17 cells and induced inflammation and production of antimicrobial defensins (77). In the gut, under normal circumstances, eCB system is regulated by CB1R. However, both CB1R and CB2R get activated during inflammation leading to anti-inflammatory cytokine production that suppresses inflammation and intestinal damage (78).

The crosstalk between eCB system and gut microbiota has been established with murine models of obesity where low-grade inflammation and increased eCB system tone are reported. Obese mice exhibited higher colonic CB1R colonic mRNA and the modulation of gut microbiota with the use of prebiotics reduced this scenario. Moreover, prebiotic treatment alleviated CB1R mRNA and concentration of AEA in genetically obese mice explaining the involvement of the gut microbial community on CB1R and eCB expression. The same study disclosed the maintenance of intestinal barrier integrity by eCB system (79). Reduction in the number of TJPs increases the space between epithelial cells promoting paracellular translocation of microbial metabolites from the intestinal lumen to circulation and other organs, and elevated LPS levels impair adipogenesis and promote inflammation (79). THC administration has been reported to reduce LPS levels in mice while increasing TJPs. THC mediated CBR modulation reduced plasma LPS levels by altering the distribution and localization of TJPs which led to improved gut barrier function (65, 70).

Microbial-derived SCFAs, neurotransmitters, and amino acids take part in the immune, endocrinal, and neuronal signaling pathways via binding to host receptors (80, 81). Multiple investigations have validated the potential of AEA and THC to enhance the levels of SCFAs and AMPs in murine models of inflammation (64–67). SCFAs are produced in the colon by fermentation and subsequent degradation of undigested dietary fibers by gut harboring bacteria and they contribute to the regulation of both innate and adaptive immunity of the host. Acetate and propionate, produced by Bacteroidetes, and butyrate, produced by Firmicutes are the major SCFAs involved in host-bacterial communications (82). Blocking of histone deacetylases (HDAC) and activation of GPCRs are two main signaling pathways modulated by microbial SCFAs (80–82). Interestingly, GPCRs such as GPR43 and GPR109A are expressed by adipose tissue macrophages and dendritic cells (DCs). The binding of SCFAs to these receptors induces K⁺ efflux and membrane hyperpolarization which in turn stimulates NLRP3 inflammasome in primed macrophages to produce IL-18 (83, 84). Butyrate-dependent activation of GPR109A induces apoptosis of colon cancer cells. Furthermore, these receptor/ligand complexes inhibit nuclear factor-kappaB (NF-κB) activation in the colon of mice (85). Butyrate enhanced the function of human TGFβ1 in the intestinal epithelial cells (IECs) which in turn directed the accumulation of Treg cells in the lumen, and the study suggested inhibition of HDAC as the major mechanism behind this activity. Butyrate-induced HDAC inhibition down-regulated the generation of LPS-triggered pro-inflammatory cytokines such as IL-6 and IL-12 (86, 87). Another study demonstrated that butyrate enhanced the expression of AMPs, LL-37, and CAP-18 by IECs in rabbits (88). In a similar manner, activation of genes encoding host defense peptides in HD11 macrophages and monocytes has been observed in chickens following butyrate consumption (89). Succinate, another SCFA produced by the gut bacteria, Prevotella copri was shown to be involved in gut gluconeogenesis and improved glucose homeostasis (90). Once transported into circulation, SCFAs exert their effect on distant organs as well. For example, circulating propionate modified bone marrow hematopoiesis by increasing levels of macrophages and DCs precursors. The phagocytic DCs invaded the lung but lacked Th2 effector cell differentiation ability and controlled inflammation (91). SCFAs, as evident from numerous studies, represent the most important connecting link between gut microbiome and host immune homeostasis.

Bile acid metabolism is another activity implemented by a variety of gut microbes harboring the gut. Microbes convert primary bile acid to secondary and tertiary bile acids via various mechanisms that include deconjugation of glycine and taurine by bile salt hydrolase, de-hydroxylation as well as dehydrogenation and epimerization of cholesterol core (92). Members of the genera Bifidobacterium, Clostridium, and Lactobacillus are reported to efficiently metabolize primary bile acids (92, 93). Secondary bile acid metabolism and prevention of bile acid production in the liver by activating nuclear receptor farnesoid X receptor (FXR) in the ileum by gut microbiota controls liver inflammation. Also, intestinal microbiota decreases the levels of pro-inflammatory cytokines which are involved in reducing the transcription of FXR target genes (94). Proteins and peptides in the diets are digested to free amino acids as a result of microbial fermentation and major amino acid of such kind is tryptophan. Tryptophan metabolites are another set of biologically active metabolites generated by intestinal bacteria that affect intestinal epithelial barrier integrity as well as the organogenesis of intestinal lymphoid follicles. Members of the phylum Firmicutes convert tryptophan to tryptamine and other indole derivatives (95, 96). A recent study showed that tryptamine can attenuate neuroinflammation in the murine model of MS (97). Lactobacillus strains were found to efficiently metabolize Tryptophan to its derivatives which act as aryl hydrocarbon receptor (AhR) ligands in the colitis mouse model (98). These metabolites, mostly indoles, act as AhR agonists and regulate type-1 IFN signaling in astrocytes leading to suppression of central nervous system (CNS) inflammation (99). AhR signaling mediates IL-22 production in the gut by activating innate lymphoid cell 3 (ILC3) (100). In addition, AhR has been shown to play a vital role in the development of ILC and intraepithelial lymphocytes (100, 101). How AhR activation leads to suppression of inflammation has been the topic of recent reviews (102, 103). Figure 1 illustrates a summary of cannabinoid mediated microbiome modulation and the immunomodulatory mechanism of microbial metabolites.

While most of the studies that we have reviewed above have shown an association between the administration of cannabinoids and suppression of inflammation to changes in the microbiota, one can question whether these studies merely indicate a relationship between these events or whether the cannabinoid-mediated alterations in the microbiota are actually responsible for inducing attenuation of inflammation. The association between microbial changes seen following exposure to cannabinoids and the consequent impact of such changes in immunomodulation can only be proven through fecal microbiota transplants (FMT).

There is evidence to suggest the role of microbiota on eCB signaling through use of FMT. Multiple studies reported that FMT-mediated microbial dysbiosis can modify eCB signaling (104, 105). One study clearly investigated the impact of FMT from conventionally raised mice to germ-free mice. Endocannabinoidome gene expression and lipidomics were analyzed by transcriptomics and LC-MS/MS before and after FMT. Age-dependent endocannabinoidome gene expression and lipid variations in the germ-free mice were reversed following FMT from age-matched conventionally raised donor mice (106). In another study, FMT from murine models of EAE disease treated with THC and CBD, into antibiotics treated, microbe depleted mice demonstrated that the recipient mice showed decreased EAE disease severity (70). A similar kind of study was conducted in a murine model of SEB-mediated ARDS. The microbiota transplanted from THC-treated ARDS mice into antibiotic-treated, microbiome-depleted recipient mice showed better survival from ARDS than those that received FMT from the control group. FMT from THC-treated groups caused a decrease in inflammatory CD4⁺ and CD8⁺ T cells and an increase in immune suppressive MDSCs and Tregs in the lungs (65). Such studies clearly demonstrate that endogenous and exogenous cannabinoids can promote beneficial microbiota in the gut that can attenuate inflammatory diseases even in distal organs.