Mounting evidence suggests that the gut microbiome impacts brain development and function. Gut-brain connections may be mediated by an assortment of microbial molecules that are produced in the gastrointestinal tract, which can subsequently permeate many organs, including sometimes the brain. Studies in animal models have identified molecular cues propagated from intestinal bacteria to the brain that can affect neurological function and/or neurodevelopmental and neurodegenerative conditions. Herein, we describe bacterial metabolites with known or suspected neuromodulatory activity, define mechanisms of signalling pathways from the gut microbiota to the brain and discuss direct effects that gut bacterial molecules are likely exerting on specific brain cells. Many discoveries are recent, and the findings described in this Perspective are largely novel and yet to be extensively validated. However, expanding research into the dynamic molecular communications between gut microorganisms and the CNS continues to uncover critical and previously unappreciated clues in understanding the pathophysiology of behavioural, psychiatric and neurodegenerative diseases.

Gut microbial molecules in behavioural and neurodegenerative conditions.

G-protein-coupled bile acid receptor, Gpbar1 (TGR5), is a member of G-protein-coupled receptor (GPCR) superfamily. High levels of TGR5 mRNA were detected in several tissues such as small intestine, stomach, liver, lung, especially in placenta and spleen. TGR5 is not only the receptor for bile acids, but also the receptor for multiple selective synthetic agonists such as 6α-ethyl-23(S)-methyl-cholic acid (6-EMCA, INT-777) and a series of 4-benzofuranyloxynicotinamde derivatives to regulate different signaling pathways such as nuclear factor κB (NF-κB), AKT and extracellular signal-regulated kinases (ERK). TGR5, as a metabolic regulator, is involved in energy homeostasis, bile acid homeostasis, as well as glucose metabolism. More recently, our group and others have extended the functions of TGR5 to more than metabolic regulation, which include inflammatory response, cancer and liver regeneration. These findings highlight TGR5 as a potential drug target for different diseases. This review summarizes the basic information of TGR5 and its new functions.

/pdf/tgr5-not-only-a-metabolic-regulator-3vpbw7wtj6.pdf

TGR5, Not Only a Metabolic Regulator

Bile acids are steroid acids found in the bile of mammals. The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is neuroprotective in different animal models of stroke and neurological diseases. We have previously shown that TUDCA has anti-inflammatory effects on glial cell cultures and in a mouse model of acute neuroinflammation. We show now that microglial cells (central nervous system resident macrophages) express the G protein-coupled bile acid receptor 1/Takeda G protein-coupled receptor 5 (GPBAR1/TGR5) in vivo and in vitro. TUDCA binding to GPBAR1/TGR5 caused an increase in intracellular cAMP levels in microglia that induced anti-inflammatory markers, while reducing pro-inflammatory ones. This anti-inflammatory effect of TUDCA was inhibited by small interference RNA for GPBAR1/TGR5 receptor, as well as by treatment with a protein kinase A (PKA) inhibitor. In the mouse model of acute neuroinflammation, treating the animals with TUDCA was clearly anti-inflammatory. TUDCA biased the microglial phenotype in vivo and in vitro toward the anti-inflammatory. The bile acid receptor GPBAR1/TGR5 could be a new therapeutic target for pathologies coursing with neuroinflammation and microglia activation, such as traumatic brain injuries, stroke, or neurodegenerative diseases. TUDCA and other GPBAR1/TGR5 agonists need to be further investigated, to determine their potential in attenuating the neuropathologies associated with microglia activation. J. Cell. Physiol. 232: 2231-2245, 2017. © 2016 Wiley Periodicals, Inc.

TUDCA: An Agonist of the Bile Acid Receptor GPBAR1/TGR5 With Anti-Inflammatory Effects in Microglial Cells.

Bile acids are synthesized from cholesterol and are known to be involved with the emulsification and digestion of dietary lipids and fat-soluble vitamins. Outside of this role, bile acids can act as cell signaling effectors through binding and activating receptors on both the cell membrane and nucleus. Numerous reports have investigated these signaling pathways in conditions where the liver is damaged. More recently, effort has been made to investigate the role of bile acids in diseases outside of those associated with liver damage. This review summarizes recent findings on the influences that bile acids can exert in normal neurological function and their contribution to diseases of the nervous system, with the intent of highlighting the role of these metabolites as potential players in neurological disorders.-McMillin, M., DeMorrow, S. Effects of bile acids on neurological function and disease.

Effects of bile acids on neurological function and disease.

Hypothalamic bile acid-TGR5 signaling protects from obesity.

Hepatic encephalopathy (HE) is a serious neurological complication of acute and chronic liver failure. Expression of the neurosteroid/bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) has been demonstrated in the brain and is thought to be neuroprotective. However, it is unknown how TGR5 signaling can influence the progression and associated neuroinflammation of HE. HE was induced in C57Bl/6 mice via intraperitoneal injection of azoxymethane (AOM) and tissue was collected throughout disease progression. TGR5 expression was elevated in the frontal cortex following AOM injection in mice. The cellular localization of TGR5 was found in both neurons and microglia in the cortex of C57Bl/6 mice. Central infusion of the TGR5 agonist, betulinic acid, prior to AOM injection delayed neurological decline, increased cortical cyclic adenosine monophosphate concentrations, reduced microglia activation and proliferation, and reduced proinflammatory cytokine production. Betulinic acid treatment in vitro reduced the neuronal expression of chemokine ligand 2, a chemokine previously demonstrated to contribute to HE pathogenesis. Lastly, treatment of the microglia cell line EOC-20 with conditioned media from betulinic acid-treated primary neurons decreased phagocytic activity and cytokine production. Together, these data identify that activation of TGR5, which is up-regulated during HE, alleviates neuroinflammation and improves outcomes of AOM-treated mice through neuron and microglia paracrine signaling.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.13243

TGR5 signaling reduces neuroinflammation during hepatic encephalopathy

Cholangiocarcinoma is an aggressive cancer of the bile ducts with limited treatment options and a high mortality rate. Patients with cancer have over a twofold higher rate of depression than the general population and are prescribed selective serotonin reuptake inhibitors (SSRIs) to manage their depression. However, serotonin has been demonstrated to promote the proliferation of cancer cells. In this mouse xenograft study, we provide evidence that the SSRIs sertraline and fluoxetine lead to increased serotonin bioavailability that results in a proliferation of cholangiocarcinoma cells. Cholangiocarcinoma cell proliferation was not observed in vitro, indicating that the effects of SSRIs are due to increased serotonin levels in noncancerous cells of the body. These novel findings on the effect of SSRIs in promoting the growth of cholangiocarcinoma support the notion that these antidepressants should be used cautiously in this patient population. Introduction Cancer of the bile ducts, or cholangiocarcinoma, is an extremely aggressive tumor that has very poor prognosis and limited treatment options [1] [2]. Cholangiocarcinomas accounts for around 15% of all liver cancers and causes 2% of all cancer deaths worldwide [3]. Despite aggressive treatment, survival rates are low, generally only 6 months from diagnosis, as 90% of patients are not eligible for surgery-, and the cancer is relatively resistant to chemotherapy. The high mortality rate from cholangiocarcinoma is due in part to the late diagnosis, as the clinical manifestations of this cancer (such as abdominal pain, pruritus, weight loss, etc.) occur after the cancer is quite advanced [4]. Serotonin, or 5-hydroxytryptamine (5-HT), is synthesized via the decarboxylation and hydroxylation of tryptophan by the enzymes tryptophan hydroxylase and decarboxylase [5]. Serotonin can then generate a wide variety of intracellular effects as there are 16 receptor subtypes, with all but one being G protein–coupled receptors that lead to the activation of secondary messenger systems [6]. The uptake of serotonin from the extracellular space into the cell via serotonin transporters terminates serotonin receptormediated signaling [7]. Predominantly, it is the enzyme monoamine oxidase A that degrades serotonin once it is inside the cell [8]. Serotonin has been classified as a growth factor for several different nontumorigenic cell types as well as in a variety of cancer cells, including small cell lung carcinoma, choriocarcinoma, bladder cancer, prostate cancer, hepatocellular carcinoma, and breast cancer [9] [10] [11] [12] [13] [14] [15]. Similarly, cholangiocarcinoma produces increased amounts of serotonin, [16] which exerts growth-promoting effects in vitro and in vivo. This increased biogenic amine production is due to the coordinated increase in synthesis and the epigenetic silencing of monoamine oxidase A [16] [17] [18]. Cancer patients have a variety of stressors (physiological, monetary, and psychological) that result in clinical depression at rates much higher than the general population [19]. The incidence of depression in the general population has been reported to be between 5% and 6%, whereas in cancer patients this jumps to 12.9%, with another 16.5% displaying subclinical depressive symptoms [20] [21]. The use of SSRIs for the management of depressive symptoms has becomemore common in recent years with antidepressant use increasing nearly 400% in the time period of 2005–2008 when compared to 1988–1994 [22]. As SSRI antidepressants work through inhibiting serotonin transporter activity, The specific serotonin reuptake inhibitors sertraline and fluoxetine promote tumor growth in a mouse xenograft model of cholangiocarcinoma DOI: 10.19185/matters.201706000003 Matters (ISSN: 2297-8240) | 2 their use leads to increased serotonin bioavailability. The effects of SSRI use on cholangiocarcinoma growth have not yet been determined. Objective The objective of this study was to assess the effects of the SSRIs sertraline and fluoxetine on cholangiocarcinoma growth using a xenograft tumor model in mice.

The specific serotonin reuptake inhibitors sertraline and fluoxetine promote tumor growth in a mouse xenograft model of cholangiocarcinoma

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TGR5 signaling reduces neuroinflammation during hepatic encephalopathy

The specific serotonin reuptake inhibitors sertraline and fluoxetine promote tumor growth in a mouse xenograft model of cholangiocarcinoma