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Source of bile acids in the brain. Approximately 95% of the bile acids released into the intestine and transformed by the gut bacteria are re-absorbed at the brush border of the enterocytes. Bile acids are then transport via the portal circulation and taken up into hepatocytes by the basolateral bile acid transporters. A small amount of the bile acids in the enterohepatic circulation escape to the systemic circulation from where they can be taken up into the brain by passive diffusion or by active transport through the blood brain barrier (BBB). Additionally, the primary bile acids CA and CDCA can also be synthesized in the brain via the alternative pathway (involving the BA synthesis enzymes CYP27A1, CYP7B1 and CYP8B1) or via CYP46A1. Although the hepatic bile acid transporters are found in the BBB and in the brain, if they transport bile acids in the brain, and the directionality of their bile acid transport are unknown. CYP7A1 cholesterol 7α-hydroxylase, CYP8B1 12α-hydroxylase, CYP27A1 27-hydroxylase, CYP7B1 sterol 7α-hydroxylase, CYP46A1 cholesterol 24-hydroxylase, CA cholic acid, CDCA chenodeoxycholic acid, BBB blood brain barrier
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Bile acids are signalling hormones involved in the regulation of several metabolic pathways. The ability of bile acids to bind and signal through their receptors is modulated by the gut microbiome, since the microbiome contributes to the regulation and synthesis of bile acids as well to their physiochemical properties. From the gut, bacteria have b...
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There is ample scientific and clinical evidence of the effects of gut microbiota on the brain but no definitive evidence that the brain can affect changes in gut microbiota under the bi-directional gut-brain axis concept. As there is no pharmacotherapeutic intervention for the early stages of cognitive decline, research has focused on cognitive sti...
There is ample scientific and clinical evidence of the effects of gut microbiota on the brain but no definitive evidence that the brain can affect changes in gut microbiota under the bi-directional gut-brain axis concept. As there is no pharmacotherapeutic intervention for the early stages of cognitive decline, research has focused on cognitive sti...
Citations
... Gut bacteria are also involved, via their enzymatic machinery, in bile acid metabolism. Primary hepatic bile acids such as chenodeoxycholic acid and cholic acid produced in the liver from cholesterol (Monteiro-Cardoso et al., 2021), are subsequently converted into secondary bile acids by the microbiota. Deficits in the physiological intestinal balance may therefore lead to a decrease in the level of bile acids and subsequently an increase in cholesterol, which can be converted to neurotoxic oxysterols (J. ...
Autism spectrum disorder is a neurodevelopmental disorder characterized by a wide range of behavioral alterations, including impaired social interaction and repetitive behaviors. Numerous pharmacological interventions have been developed for autism spectrum disorder, often proving ineffective and accompanied by a multitude of side effects. The gut microbial alterations observed in individuals with autism spectrum disorder, including elevated levels of Bacteroidetes, Firmicutes, and Proteobacteria, as well as reduced levels of Bifidobacterium, provide a basis for further investigation. Recent preclinical studies have shown favorable outcomes with probiotic therapy, including improvements in oxidative stress, anti-inflammatory effects, regulation of neurotransmitters, and restoration of microbial balance. The aim of this review is to explore the potential of probiotics for the management and treatment of autism spectrum disorder, by investigating insights from recent studies in animals.
Lay abstract
Autism spectrum disorder is a neurodevelopmental disorder characterized by a wide range of behavioral alterations, including impaired social interaction and repetitive behaviors. Numerous pharmacological interventions have been developed for autism spectrum disorder, often proving ineffective and accompanied by a multitude of side effects. The gut microbiota is the reservoir of bacteria inhabiting our gastrointestinal tract. The gut microbial alterations observed in individuals with autism spectrum disorder, including elevated levels of Bacteroidetes, Firmicutes, and Proteobacteria, as well as reduced levels of Bifidobacterium, provide a basis for further investigation into the role of the gut microbiota in autism spectrum disorder. Recent preclinical studies have shown favorable outcomes with probiotic therapy, including improvements in oxidative stress, anti-inflammatory effects, regulation of neurotransmitters, and restoration of microbial balance. The aim of this review is to explore the potential of probiotics for the management and treatment of autism spectrum disorder, by investigating insights from recent studies in animals.
... 41 Recent research explores the potential role of bile acids as a bridge between the gut microbiome and the brain, suggesting a pathway that could influence the patient's mental well-being. 42,43 The decreased abundance of bacteria belonging to Lachnospiraceae family in the COBMINDEX group at T2 and their positive correlation with PSS4 and GSI scores highlight Lachnospiraceae as an important therapeutic target that should be further explored particularly in the context of impaired bile acid metabolism and psychological distress which contribute to CD pathology. ...
Crohn’s disease (CD) is a chronic inflammatory bowel disease associated with psychological distress and intestinal microbial changes. Here, we examined whether a 3-month period of Cognitive Behavioral and Mindfulness with Daily Exercise (COBMINDEX) intervention, which improves the wellbeing and inflammatory state of CD patients, may also affect their gut microbiome. Gut microbiota, circulating inflammatory markers and hormones were analyzed in 24 CD patients before (T1) and after 3 months of COBMINDEX (T2), and in 25 age- and sex-matched wait-list control patients at the corresponding time-points. Microbiota analysis examined relative taxonomical abundance, alpha and beta diversity, and microbiome correlations with inflammatory and psychological parameters. At T1, CD patients exhibited a characteristic microbial profile mainly constituted of Proteobacteria (17.71%), Firmicutes (65.56%), Actinobacteria (8.46%) and Bacteroidetes (6.24%). Baseline bacterial abundances showed significant correlations with psychological markers of distress and with IFN$\gamma $γ. Following COBMINDEX, no significant changes in alpha and beta diversity were observed between both study groups, though a trend change in beta diversity was noted. Significant changes occurred in the abundance of phyla, families and genera only among the COBMINDEX group. Furthermore, abundance of phyla, families and genera that were altered following COBMNIDEX, significantly correlated with levels of cytokines and psychological parameters. Our results demonstrated that a short-term intervention of COBMINDEX was associated with changes in microbial indices, some of which are linked to psychological manifestations and systemic inflammation in CD patients. Psychological interventions to reduce chronic stress, such as COBMINDEX, appear to be beneficial in mitigating the pathobiology of CD patients, and may thus provide a useful adjunct to pharmacological therapy.
... Recent studies have shown that bile acids play a significant role in connecting the gut microbiome and the brain [25,26]. We hypothesized that fecal profiles of individual bile acids could be utilized as biomarkers to assess the psychological stressinduced behavioral impairments and subsequent changes of gut microbiota in an animal model. ...
... Even though susceptibility to psychological stress varies by mouse strain background [7] and diet composition [25], psychological stress generally alters the gut microbiota and increases the levels of secondary bile acids. Using omics approaches, we found that social defeat stress causes a decrease in immune response-related genes in the ileum. ...
The gut microbiota plays a crucial role in both the pathogenesis and alleviation of host depression by modulating the brain-gut axis. We have developed a murine model of human depression called the subchronic and mild social defeat stress (sCSDS) model, which impacts not only behavior but also the host gut microbiota and gut metabolites, including bile acids. In this study, we utilized liquid chromatography/mass spectrometry (LC/MS) to explore the effects of sCSDS on the mouse fecal bile acid profile. sCSDS mice exhibited significantly elevated levels of deoxycholic acid (DCA) and lithocholic acid (LCA) in fecal extracts, leading to a notable increase in total bile acids and 7α-dehydroxylated secondary bile acids. Consequently, a noteworthy negative correlation was identified between the abundances of DCA and LCA and the social interaction score, an indicator of susceptibility in stressed mice. Furthermore, analysis of the colonic microbiome unveiled a negative correlation between the abundance of CDCA and Turicibacter. Additionally, DCA and LCA exhibited positive correlations with Oscillospiraceae and Lachnospiraceae but negative correlations with the Eubacterium coprostanoligenes group. These findings suggest that sCSDS impacts the bidirectional interaction between the gut microbiota and bile acids and is associated with reduced social interaction, a behavioral indicator of susceptibility in stressed mice.
... Most primary BAs are reabsorbed in the terminal ileum and transported back to the liver, while a subset of primary BAs is metabolized by the gut microbiota into secondary BAs, many of which are also reabsorbed. Recent studies have highlighted the role of BAs in the gut-brain axis [27], as the gut microbiota is actively involved in BA metabolism, and BAs may interact with specific receptors present in neurons and influence brain function in physiology and pathology [28]. This suggests a potential pathway through which early life stress-induced alterations in BAs may influence brain function and behavior. ...
The rat model of perinatal stress (PRS), in which exposure of pregnant dams to restraint stress reduces maternal behavior, is characterized by a metabolic profile that is reminiscent of the “metabolic syndrome”. We aimed to identify plasma metabolomic signatures linked to long-term programming induced by PRS in aged male rats. This study was conducted in the plasma and frontal cortex. We also investigated the reversal effect of postpartum carbetocin (Cbt) on these signatures, along with its impact on deficits in cognitive, social, and exploratory behavior. We found that PRS induced long-lasting changes in biomarkers of secondary bile acid metabolism in the plasma and glutathione metabolism in the frontal cortex. Cbt treatment demonstrated disease-dependent effects by reversing the metabolite alterations. The metabolomic signatures of PRS were associated with long-term cognitive and emotional alterations alongside endocrinological disturbances. Our findings represent the first evidence of how early life stress may alter the metabolomic profile in aged individuals, thereby increasing vulnerability to CNS disorders. This raises the intriguing prospect that the pharmacological activation of oxytocin receptors soon after delivery through the mother may rectify these alterations.
... The role of brain serotonin in controlling mood, sleep, and stress response is comparatively well studied (Berger et al., 2009;Strasser et al., 2016), while we have not fully comprehended the role of peripheral serotonin (El-Merahbi et al., 2015). The SBAs are another major microbial metabolite that cannot cross the BBB, although preliminary indications suggest certain roles for SBAs in modulating the brain functions (Monteiro-Cardoso et al., 2021). ...
Meta-organisms encompassing the host and resident microbiota play a significant role in combatting diseases and responding to stress. Hence, there is growing traction to build a knowledge base about this ecosystem, particularly to characterize the bidirectional relationship between the host and microbiota. In this context, metabolomics has emerged as the major converging node of this entire ecosystem. Systematic comprehension of this resourceful omics component can elucidate the organism-specific response trajectory and the communication grid across the ecosystem embodying meta-organisms. Translating this knowledge into designing nutraceuticals and next-generation therapy are ongoing. Its major hindrance is a significant knowledge gap about the underlying mechanisms maintaining a delicate balance within this ecosystem. To bridge this knowledge gap, a holistic picture of the available information has been presented with a primary focus on the microbiota-metabolite relationship dynamics. The central theme of this article is the gut-brain axis and the participating microbial metabolites that impact cerebral functions.
... Our study suggests a possible link between diverse endogenous bile acids and mitophagy regulation by modulation of FXR activity. This offers a perspective on how the gut microbiota, recognized for synthesizing secondary bile acids, might affect tissue and neuronal health [69][70][71] . Interestingly, we discovered that UA, a human gut microbiome-derived metabolite noted for inducing mitophagy and improving mitochondrial function 8 , modulates FXR activity, similar to our identified molecule, MIC. ...
Autophagy–lysosomal function is crucial for maintaining healthy lifespan and preventing age-related diseases. The transcription factor TFEB plays a key role in regulating this pathway. Decreased TFEB expression is associated with various age-related disorders, making it a promising therapeutic target. In this study, we screened a natural product library and discovered mitophagy-inducing coumarin (MIC), a benzocoumarin compound that enhances TFEB expression and lysosomal function. MIC robustly increases the lifespan of Caenorhabditis elegans in an HLH-30/TFEB-dependent and mitophagy-dependent manner involving DCT-1/BNIP3 while also preventing mitochondrial dysfunction in mammalian cells. Mechanistically, MIC acts by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12/FXR, which, in turn, induces mitophagy and extends lifespan. In conclusion, our study uncovers MIC as a promising drug-like molecule that enhances mitochondrial function and extends lifespan by targeting DAF-12/FXR. Furthermore, we discovered DAF-12/FXR as a previously unknown upstream regulator of HLH-30/TFEB and mitophagy.
... In many, mainly chronic, neurologic disorders, bile acid metabolism has been found to be altered, and bile acids can be detected in quantifiable and even rather high concentrations in cerebrospinal fluid and/or brain parenchyma [13][14][15][16][17]. Furthermore, even therapeutic/anti-inflammatory effects of bile acids have been described [16][17][18][19][20][21][22]. However, most of the above findings are based on experimental animal data, which limits transferability to humans due to the different spectrum of bile acids in rodents (e.g., the presence of muricolic, murideoxycholic, and hyodeoxycholic acid, which do not exist in the human organism). ...
... The occurrence of bile acids in the CSF has already been described in animal expe ments [7,9,18]. However, data from these experimental animal models are first and fo most hypothesis-generating and probably not inevitably transferable to humans. ...
... The occurrence of bile acids in the CSF has already been described in animal experiments [7,9,18]. However, data from these experimental animal models are first and foremost hypothesis-generating and probably not inevitably transferable to humans. ...
(1) Background: Bile acids, known as aids in intestinal fat digestion and as messenger molecules in serum, can be detected in cerebrospinal fluid (CSF), although the blood–brain barrier is generally an insurmountable obstacle for bile acids. The exact mechanisms of the occurrence, as well as possible functions of bile acids in the central nervous system, are not precisely understood. (2) Methods: We conducted a single-center observational trial. The concentrations of 15 individual bile acids were determined using an in-house LC-MS/MS method in 54 patients with various acute and severe disorders of the central nervous system. We analyzed CSF from ventricular drainage taken within 24 h after placement, and blood samples were drawn at the same time for the presence and quantifiability of 15 individual bile acids. (3) Results: At a median time of 19.75 h after a cerebral insult, the concentration of bile acids in the CSF was minute and almost negligible. The CSF concentrations of total bile acids (TBAs) were significantly lower compared to the serum concentrations (serum 0.37 µmol/L [0.24, 0.89] vs. 0.14 µmol/L [0.05, 0.43]; p = 0.033). The ratio of serum-to-CSF bile acid levels calculated from the respective total concentrations were 3.10 [0.94, 14.64] for total bile acids, 3.05 for taurocholic acid, 14.30 [1.11, 27.13] for glycocholic acid, 0.0 for chenodeoxycholic acid, 2.19 for taurochenodeoxycholic acid, 1.91 [0.68, 8.64] for glycochenodeoxycholic acid and 0.77 [0.0, 13.79] for deoxycholic acid; other bile acids were not detected in the CSF. The ratio of CSF-to-serum S100 concentration was 0.01 [0.0, 0.02]. Serum total and conjugated (but not unconjugated) bilirubin levels and serum TBA levels were significantly correlated (total bilirubin p = 0.031 [0.023, 0.579]; conjugated bilirubin p = 0.001 [0.193, 0.683]; unconjugated p = 0.387 [−0.181, 0.426]). No correlations were found between bile acid concentrations and age, delirium, intraventricular blood volume, or outcome measured on a modified Rankin scale. (4) Conclusions: The determination of individual bile acids is feasible using the current LC-MS/MS method. The results suggest an intact blood–brain barrier in the patients studied. However, bile acids were detected in the CSF, which could have been achieved by active transport across the blood–brain barrier.
... Elementary BAs are converted from cholesterol in the liver, released into the intestinal lumen during the digestion of chyme by the organism, and converted to secondary BAs such as deoxycholic acid (DCA) and lithocholic acid (LCA) by uncoupling and dehydroxylation in the presence of bile salt hydrolase-expressing intestinal microorganisms such as Clostridium spp., Lactobacillus spp., Enterococcus spp., and so on [103]. Recent research has revealed that in addition to affecting lipid metabolism and inflammatory response, BAs also play a role in regulating appetite and energy homeostasis [104], where farnesoid X receptor (FXR) and takeda G-protein-coupled receptor 5 (TGR5) act as crucial receptors to mediate BAs' function. ...
With the increasing prevalence of energy metabolism disorders such as diabetes, cardiovascular disease, obesity, and anorexia, the regulation of feeding has become the focus of global attention. The gastrointestinal tract is not only the site of food digestion and absorption but also contains a variety of appetite-regulating signals such as gut-brain peptides, short-chain fatty acids (SCFAs), bile acids (BAs), bacterial proteins, and cellular components produced by gut microbes. While the central nervous system (CNS), as the core of appetite regulation, can receive and integrate these appetite signals and send instructions to downstream effector organs to promote or inhibit the body’s feeding behaviour. This review will focus on the gut-brain axis mechanism of feeding behaviour, discussing how the peripheral appetite signal is sensed by the CNS via the gut-brain axis and the role of the central “first order neural nuclei” in the process of appetite regulation. Here, elucidation of the gut-brain axis mechanism of feeding regulation may provide new strategies for future production practises and the treatment of diseases such as anorexia and obesity.
... cholenoic acid, can undergo 7α-hydroxylation and multistep conversions that end with the production of CDCA. The BA synthetic pathways are also present in other highly metabolic organs such as the brain (Parker et al., 2020;Monteiro-Cardoso et al., 2021) and the murine and human placenta (Russell, 2003;Ontsouka et al., 2023). Regardless of the synthetic pathway implicated, the final steps in BA biogenesis involve the enzymatic actions of BA-CoA synthase and BA CoA: amino acid N-acyltransferase (BAAT). ...
... Noticeably, the placenta is also a steroidogenic organ capable of the synthesis of diverse hormones such as progesterone using cholesterol as a precursor molecule (Karahoda et al., 2021). Interestingly, there is evidence that also extrahepatic tissues (e.g., the brain) are capable of synthesizing BAs and therefore contribute to the serum BA pool (Pan et al., 2017;Monteiro-Cardoso et al., 2021). In the context of Frontiers in Physiology frontiersin.org ...
... The apparent discrepancy between placental tissues and cell-based data could have resulted from a dilution effect occurring in placental tissue, which contains a myriad of cell types. The findings reported by (Ontsouka et al., 2023) are in line with studies where another extrahepatic organ -the brain -was found to exhibit BA biogenetic capabilities (Pan et al., 2017;Monteiro-Cardoso et al., 2021). To date, the majority of studies focused on investigating the role of the placenta exclusively as an interface across which BAs are transported between the mother to the fetus (Sewell et al., 1980;Itoh et al., 1982;Colombo et al., 1985;Meng et al., 1997;St-Pierre et al., 2000;Tribe et al., 2010;Geenes et al., 2014;Liu et al., 2021;Ontsouka et al., 2021). ...
To date, the discussion concerning bile acids (BAs) during gestation is almost exclusively linked to pregnancy complications such as intrahepatic cholestasis of pregnancy (ICP) when maternal serum BA levels reach very high concentrations (>100 μM). Generally, the placenta is believed to serve as a protective barrier avoiding exposure of the growing fetus to excessive amounts of maternal BAs that might cause detrimental effects (e.g., intrauterine growth restriction and/or increased vulnerability to metabolic diseases). However, little is known about the precise role of the placenta in BA biosynthesis, transport, and metabolism in healthy pregnancies when serum BAs are at physiological levels (i.e., low maternal and high fetal BA concentrations). It is well known that primary BAs are synthesized from cholesterol in the liver and are later modified to secondary BA species by colonic bacteria. Besides the liver, BA synthesis in extrahepatic sites such as the brain elicits neuroprotective actions through inhibition of apoptosis as well as oxidative and endoplasmic reticulum stress. Even though historically BAs were thought to be only “detergent molecules” required for intestinal absorption of dietary fats, they are nowadays acknowledged as full signaling molecules. They modulate a myriad of signaling pathways with functional consequences on essential processes such as gluconeogenesis -one of the principal energy sources of the fetus- and cellular proliferation. The current manuscript discusses the potential multipotent roles of physiologically circulating BAs on developmental processes during gestation and provides a novel perspective in terms of the importance of the placenta as a previously unknown source of BAs. Since the principle “not too much, not too little” applicable to other signaling molecules may be also true for BAs, the risks associated with fetal exposure to excessive levels of BAs are discussed.
... Despite the original belief that solely the enterohepatic axis determines the serum BA levels [4], evidence suggests other potential sources (e.g., the brain [5,6]) that can influence the serum BA concentrations and provoke functional effects. In the context of pregnancy, previous studies have shown that serum BA levels are higher in pregnant compared to nonpregnant mice and women [7,8]. ...
... A gender-balanced cohort of human placentas (n = 6 females, n = 6 males) was used. CYP46A1, another alternative BA synthesis pathway ( [5]), was undetectable in the human placenta, while it was expressed in human livers ( Figure 1A,B and Table 1). Cyp46a1 was also found in extrahepatic tissues in mice (Figure 2A,B), suggesting a speciesand tissue-specific importance of the CYP46A1/Cyp46a1-related pathway. ...
... Cyp46a1 was also found in extrahepatic tissues in mice (Figure 2A,B), suggesting a speciesand tissue-specific importance of the CYP46A1/Cyp46a1-related pathway. CYP39A1/Cyp39a1, an oxysterol 7α-hydroxylase and critical enzyme required in the alter- CYP46A1, another alternative BA synthesis pathway ( [5]), was undetectable in the human placenta, while it was expressed in human livers ( Figure 1A,B and Table 1). Cyp46a1 was also found in extrahepatic tissues in mice (Figure 2A,B), suggesting a species-and tissue-specific importance of the CYP46A1/Cyp46a1-related pathway. ...
Bile acids (BAs) are natural ligands for several receptors modulating cell activities. BAs are synthesized via the classic (neutral) and alternative (acidic) pathways. The classic pathway is initiated by CYP7A1/Cyp7a1, converting cholesterol to 7α-hydroxycholesterol, while the alternative pathway starts with hydroxylation of the cholesterol side chain, producing an oxysterol. In addition to originating from the liver, BAs are reported to be synthesized in the brain. We aimed at determining if the placenta potentially represents an extrahepatic source of BAs. Therefore, the mRNAs coding for selected enzymes involved in the hepatic BA synthesis machinery were screened in human term and CD1 mouse late gestation placentas from healthy pregnancies. Additionally, data from murine placenta and brain tissue were compared to determine whether the BA synthetic machinery is comparable in these organs. We found that CYP7A1, CYP46A1, and BAAT mRNAs are lacking in the human placenta, while corresponding homologs were detected in the murine placenta. Conversely, Cyp8b1 and Hsd17b1 mRNAs were undetected in the murine placenta, but these enzymes were found in the human placenta. CYP39A1/Cyp39a1 and cholesterol 25-hydroxylase (CH25H/Ch25h) mRNA expression were detected in the placentas of both species. When comparing murine placentas and brains, Cyp8b1 and Hsd17b1 mRNAs were only detected in the brain. We conclude that BA synthesis-related genes are placentally expressed in a species-specific manner. The potential placentally synthesized BAs could serve as endocrine and autocrine stimuli, which may play a role in fetoplacental growth and adaptation.
