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Endocannabinoid system acts as a regulator of immune homeostasis in the gut.

ABSTRACT: Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1hi macrophages (M?), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1-/- or CB2-/- mice have fewer CX3CR1hi M? in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4+ cells, the Tr1 cells, in an IL-27-dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice [model of type 1 diabetes (T1D)] by transfer of CD4+ T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.

SUBMITTER: Acharya N

PROVIDER: S-EPMC5441729 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Endocannabinoid system acts as a regulator of immune homeostasis in the gut.

Acharya Nandini N Penukonda Sasi S Shcheglova Tatiana T Hagymasi Adam T AT Basu Sreyashi S Srivastava Pramod K PK

Proceedings of the National Academy of Sciences of the United States of America 20170424 19

Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocanna ...[more]

PMID: 28439004

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Project description:BackgroundThe recent identification of the endocannabinoid system in the gastrointestinal tract suggests a role in controlling intestinal inflammation. In addition, the gut chemosensing system has therapeutic applications in the treatment of gastrointestinal diseases and inflammation due to the presence of a large variety of receptors. The purposes of this study were to investigate the presence of markers of the endocannabinoid system and the chemosensing system in the pig gut and, second, to determine if thymol modulates these markers. One hundred sixty 28-day-old piglets were allocated into one of 5 treatment groups (n = 32 per treatment): T1 (control), T2 (25.5 mg thymol/kg feed), T3 (51 mg thymol/kg feed), T4 (153 mg thymol/kg feed), and T5 (510 mg thymol/kg feed). After 14 days of treatment, piglets were sacrificed (n = 8), and then duodenal and ileal mucosal scrapings were collected. Gene expression of cannabinoid receptors (CB1 and CB2), transient receptor potential vanilloid 1 (TRPV1), the olfactory receptor OR1G1, diacylglycerol lipases (DGL-α and DGL-β), fatty acid amine hydrolase (FAAH), and cytokines was measured, and ELISAs of pro-inflammatory cytokines levels were performed.ResultsmRNAs encoding all markers tested were detected. In the duodenum and ileum, the CB1, CB2, TRPV1, and OR1G1 mRNAs were expressed at higher levels in the T4 and T5 groups compared to the control group. The level of the FAAH mRNA was increased in the ileum of the T4 group compared to the control. Regarding the immune response, the level of the tumor necrosis factor (TNF-α) mRNA was significantly increased in the duodenum of the T5 group, but this increase was not consistent with the protein level.ConclusionsThese results indicate the presence of endocannabinoid system and gut chemosensing markers in the piglet gut mucosa. Moreover, thymol modulated the expression of the CB1, CB2, TRPV1, and OR1G1 mRNAs in the duodenum and ileum. It also modulated the mRNA levels of enzymes involved in the biosynthesis and degradation of endocannabinoid molecules. Based on these findings, the effects of thymol on promoting gut health are potentially mediated by the activation of these receptors.

Project description:The gut microbiota is an integral part of the host and has a functional potential in host physiology. Numerous scientific efforts have opened new horizons in gut microbiota research and enhanced the understanding of host-microbe interactions in vertebrates. However, evidence on the association between the gut microbiota and immunity in invertebrates, especially in shrimp, which is an important aquatic animal, is limited. Herein, we conducted a comprehensive analysis based on 16S rRNA gene sequencing and liquid chromatography-coupled mass spectrometry (LC-MS) to investigate the correlation between them. Comparing the gut microbiota among the four different species of shrimp, we found huge variations and determined a core gut microbiota composed of 55 microbes. The environmental challenge of white spot syndrome virus (WSSV) infection led to changes in core microbial structures, but the alteration of core microbiota among different shrimp followed the same trend and showed immune-related function in the prediction of its metabolic potential. In metabolomic analysis, nine significantly upregulated metabolites found after viral infection indicated that they have antiviral potential. Moreover, we found a tight correlation between them and almost half of the core microbiota. These data demonstrate that these metabolites are responsible for maintaining the immune homeostasis of the host and prove the function of the gut microbiota and the related metabolome in antiviral immunity of shrimp. IMPORTANCE Abundant gut microorganisms constitute a complex microecosystem with the intestinal environment of the host, which plays a critical role in the adjustment of various physiological states of the organism. Sequencing and mass spectrometry data collected from intestinal samples of shrimp after virus infection helped to investigate the special function of the microecosystem and suggested that the gut microbiota has a functional potential in maintaining immune homeostasis of the host under environmental challenge.

Project description:Microglia, which are tissue-resident macrophages in the brain, play a central role in the brain innate immunity and contribute to the maintenance of brain homeostasis. Lipopolysaccharide is a component of the outer membrane of gram-negative bacteria, and activates immune cells including microglia via Toll-like receptor 4 signaling. Lipopolysaccharide is generally known as an endotoxin, as administration of high-dose lipopolysaccharide induces potent systemic inflammation. Also, it has long been recognized that lipopolysaccharide exacerbates neuroinflammation. In contrast, our study revealed that oral administration of lipopolysaccharide ameliorates Alzheimer's disease pathology and suggested that neuroprotective microglia are involved in this phenomenon. Additionally, other recent studies have accumulated evidence demonstrating that controlled immune training with low-dose lipopolysaccharide prevents neuronal damage by transforming the microglia into a neuroprotective phenotype. Therefore, lipopolysaccharide may not a mere inflammatory inducer, but an immunomodulator that can lead to neuroprotective effects in the brain. In this review, we summarized current studies regarding neuroprotective microglia transformed by immune training with lipopolysaccharide. We state that microglia transformed by lipopolysaccharide preconditioning cannot simply be characterized by their general suppression of proinflammatory mediators and general promotion of anti-inflammatory mediators, but instead must be described by their complex profile comprising various molecules related to inflammatory regulation, phagocytosis, neuroprotection, anti-apoptosis, and antioxidation. In addition, microglial transformation seems to depend on the dose of lipopolysaccharide used during immune training. Immune training of neuroprotective microglia using low-dose lipopolysaccharide, especially through oral lipopolysaccharide administration, may represent an innovative prevention or treatment for neurological diseases; however more vigorous studies are still required to properly modulate these treatments.

Dataset Information

Endocannabinoid system acts as a regulator of immune homeostasis in the gut.

Publications

Endocannabinoid system acts as a regulator of immune homeostasis in the gut.

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