An excess of fecal bile acids (BAs) is thought to be one of the mechanisms for diarrhea-predominant irritable bowel syndrome (IBS-D). However, the factors causing excessive BA excretion remain ...incompletely studied. Given the importance of gut microbiota in BA metabolism, we hypothesized that gut dysbiosis might contribute to excessive BA excretion in IBS-D. By performing BA-related metabolic and metagenomic analyses in 290 IBS-D patients and 89 healthy volunteers, we found that 24.5% of IBS-D patients exhibited excessive excretion of total BAs and alteration of BA-transforming bacteria in feces. Notably, the increase in Clostridia bacteria (e.g., C. scindens) was positively associated with the levels of fecal BAs and serum 7α-hydroxy-4-cholesten-3-one (C4), but negatively correlated with serum fibroblast growth factor 19 (FGF19) concentration. Furthermore, colonization with Clostridia-rich IBS-D fecal microbiota or C. scindens individually enhanced serum C4 and hepatic conjugated BAs but reduced ileal FGF19 expression in mice. Inhibition of Clostridium species with vancomycin yielded opposite results. Clostridia-derived BAs suppressed the intestinal FGF19 expression in vitro and in vivo. In conclusion, this study demonstrates that the Clostridia-rich microbiota contributes to excessive BA excretion in IBS-D patients, which provides a mechanistic hypothesis with testable clinical implications.
Irritable bowel syndrome (IBS) is one of the functional gastrointestinal disorders characterized by chronic and/or recurrent symptoms of abdominal pain and irregular defecation. Changed gut ...microbiota has been proposed to mediate IBS; however, contradictory results exist, and IBS-specific microbiota, metabolites, and their interactions remain poorly understood. To address this issue, we performed metabolomic and metagenomic profiling of stool and serum samples based on discovery (n = 330) and validation (n = 101) cohorts. Fecal metagenomic data showed moderate dysbiosis compared with other diseases, in contrast, serum metabolites showed significant differences with greater power to distinguish IBS patients from healthy controls. Specifically, 726 differentially abundant serum metabolites were identified, including a cluster of fatty acyl-CoAs enriched in IBS. We further identified 522 robust associations between differentially abundant gut bacteria and fecal metabolites, of which three species including Odoribacter splanchnicus, Escherichia coli, and Ruminococcus gnavus were strongly associated with the low abundance of dihydropteroic acid. Moreover, dysregulated tryptophan/serotonin metabolism was found to be correlated with the severity of IBS depression in both fecal and serum metabolomes, characterized by a shift in tryptophan metabolism towards kynurenine production. Collectively, our study revealed serum/fecal metabolome alterations and their relationship with gut microbiome, highlighted the massive alterations of serum metabolites, which empower to recognize IBS patients, suggested potential roles of metabolic dysregulation in IBS pathogenesis, and offered new clues to understand IBS depression comorbidity. Our study provided a valuable resource for future studies, and would facilitate potential clinical applications of IBS featured microbiota and/or metabolites.
Abstract
The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota is causatively linked ...with the development of both metabolic dysfunctions and gastrointestinal disorders, thus gut dysbiosis in IBS may contribute to the development of metabolic syndrome. Here, we show that human gut bacterium
Ruminococcus gnavus
-derived tryptamine and phenethylamine play a pathogenic role in gut dysbiosis-induced insulin resistance in type 2 diabetes (T2D) and IBS. We show levels of
R. gnavus
, tryptamine, and phenethylamine are positively associated with insulin resistance in T2D patients and IBS patients. Monoassociation of
R. gnavus
impairs insulin sensitivity and glucose control in germ-free mice. Mechanistically, treatment of
R. gnavus
-derived metabolites tryptamine and phenethylamine directly impair insulin signaling in major metabolic tissues of healthy mice and monkeys and this effect is mediated by the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Our findings suggest a causal role for tryptamine/phenethylamine-producers in the development of insulin resistance, provide molecular mechanisms for the increased prevalence of metabolic syndrome in IBS, and highlight the TAAR1 signaling axis as a potential therapeutic target for the management of metabolic syndrome induced by gut dysbiosis.
BackgroundIrritable bowel syndrome, including the diarrhea-predominant subtype (IBS-D), is a prevalent disorder on a global scale. The pathogenesis of IBS-D involves changes in gastrointestinal ...motility and intestinal secretion, both of which were shown to be modulated by increased serotonin synthesis in the gut. While there is anecdotal evidence that gut microbiota may contribute to serotonin biosynthesis, the pathogenetic and molecular pathways involved are largely unknown. Knowledge of the molecular axis involved may allow the identification of novel bacterial and molecular targets for the development of better therapeutic options for IBS-D.MethodsWe applied metagenomics and metabolomics analysis to study the changes in gut microbiota and gut microbial metabolites. We conducted in vitro, ex vivo, and in vivo studies to examine the effects and underlying mechanisms of gut bacteria and their metabolites on 5-HT production and gastrointestinal transit.ResultsHerein, we identified a human gut bacterium Ruminococcus gnavus as a major factor that underlies the motility disorder in IBS-D. We showed that R. gnavus is highly enriched in IBS-D patients and positively correlated with the severity of diarrheal symptoms (IDDF2022-ABS-0035 Figure 1. The enrichment of Ruminococcus gnavus in IBS-D patients and its positive correlation with serum 5-HT level and diarrhea symptoms). Monocolonization of R. gnavus induces IBS-D-like symptoms including increased gastrointestinal transit and colonic secretion in pseudo-germ-free mice by stimulating the production of peripheral 5-HT (IDDF2022-ABS-0035 Figure 2. Monoassociation of Ruminococcus gnavus induces IBS-D-like symptoms and elevation of PEA level in pseudo-germ-free mice). Metabolically, we discovered that phenethylamine (PEA) derived from R. gnavus-mediated metabolism of dietary aromatic amino acids directly stimulates the 5-HT biosynthesis in intestinal enterochromaffin cells and this is mediated by its activation of a G-protein coupled receptor (TAAR1), thereby contributing to elevated GI transit and colonic secretion in IBS-D (IDDF2022-ABS-0035 Figure 3. PEA activates 5-HT production accelerate GI transit and increase colonic secretion in vitro and in vivo) (IDDF2022-ABS-0035 Figure 4. PEA stimulates 5-HT production via a TAAR1-dependent mechanism). More importantly, pharmacological inhibition of TAAR1 activation alleviates IBS-D-like symptoms in mice transplanted with fecal microbiota from IBS-D patients, a preclinical model of IBS-D (IDDF2022-ABS-0035 Figure 5. In vivo pea production by IBS-D associated bacteria enhance 5-HT synthesis and induce diarrhea like symptoms).Abstract IDDF2022-ABS-0035 Figure 1Abstract IDDF2022-ABS-0035 Figure 2Abstract IDDF2022-ABS-0035 Figure 3Abstract IDDF2022-ABS-0035 Figure 4Abstract IDDF2022-ABS-0035 Figure 5Abstract IDDF2022-ABS-0035 Figure 6ConclusionsOur studies provide a deeper understanding of how gut microbial metabolites derived from dietary amino acids affect 5-HT-dependent control of gut motility and have identified potential pathways predominantly mediated via the PEA/TAAR1 signaling axis for prophylactic and therapeutic treatments for IBS-D (IDDF2022-ABS-0035 Figure 6. Pathogenic role of gut microbiota-derived PEA in IBS-D).
Cinnamon protects against irritable bowel syndrome with diarrhea (IBS-D) in humans, but its efficacy and underlying mechanism of action remain poorly understood. Maternally separated (MS) IBS-D rat ...model and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced post-inflammatory IBS-D rat model are characterized by visceral hyperalgesia and diarrhea. This study used the two models to evaluate the effect of cinnamon extract (CE) on bowel symptoms. The MS rat model was also used to explore its underlying anti-IBS mechanism. cinnamon extract reduced defecation frequency and visceral hyperalgesia in MS rats in a dose-dependent manner and effectively improved visceral hyperalgesia in TNBS rats. The efficacy of cinnamon extract was comparable to the positive drug serotonin receptor 3 (5-HT3) selective antagonist, Ramosetron. Excessive 5-HT, a well-known pathogenic factor for IBS, in the colon and circulation of IBS rats was reduced after cinnamon extract intervention. Both, gene and protein levels of the colonic 5-HT synthetase, Tryptophan Hydroxylase 1 (Tph1), were also decreased in CE-treated IBS rats. In addition, a luciferase assay revealed that cinnamon extract and its major components, catechin, procyanidin B1/2, cinnamic acid, and cinnamyl alcohol, significantly inhibited
transcription activity
. These findings illustrated that aqueous cinnamon extract partially attenuated bowel symptoms in IBS models by directly inhibiting Tph1 expression and controlling 5-HT synthesis. This provides a scientific viewpoint for the use of cinnamon as a folk medication to treat IBS.
MaZiRenWan (MZRW, also known as Hemp Seed Pill) is a Chinese Herbal Medicine which has been demonstrated to safely and effectively alleviate functional constipation (FC) in a randomized, ...placebo-controlled clinical study with 120 subjects. However, the underlying pharmacological actions of MZRW for FC, are still largely unknown. We systematically analyzed the bioactive compounds of MZRW and mechanism-of-action biological targets through a novel approach called "focused network pharmacology." Among the 97 compounds identified by UPLC-QTOF-MS/MS in MZRW extract, 34 were found in rat plasma, while 10 were found in rat feces. Hierarchical clustering analysis suggest that these compounds can be classified into component groups, in which compounds are highly similar to each other and most of them are from the same herb. Emodin, amygdalin, albiflorin, honokiol, and naringin were selected as representative compounds of corresponding component groups. All of them were shown to induce spontaneous contractions of rat colonic smooth muscle
. Network analysis revealed that biological targets in acetylcholine-, estrogen-, prostaglandin-, cannabinoid-, and purine signaling pathways are able to explain the prokinetic effects of representative compounds and corresponding component groups. In conclusion, MZRW active components enhance colonic motility, possibly by acting on multiple targets and pathways.
Saffron petal (SP) is an agricultural byproduct in the process of the crude drug saffron, accounting for 90% of the dry weight of saffron flowers. To promote the utilization of SP in the food and ...pharmaceutical industries, its anti-inflammatory activities were evaluated on LPS-activated RAW 264.7 cells and DSS-challenged colitic mice. The results indicated that the SP extract had a notable effect in alleviating the clinical manifestations of colitis, such as reduction in body weight, improvement in disease activity index, mitigation of colon shortening, and alleviation of colon tissue damage. Moreover, SP extract significantly suppressed macrophage infiltration and activation, evidenced by a decrease in colonic F4/80 macrophages and suppression of the transcription and secretion of colonic tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in DSS-challenged colitic mice. In vitro, SP extract also significantly suppressed nitric oxide production, COX-2 and iNOS expressions, and TNF-α and IL-1β transcription of activated RAW 264.7 cells. Network pharmacology-guided research identified that SP extract significantly downregulated Akt, p38, ERK, and JNK phosphorylation in vivo and in vitro. In parallel, SP extract also effectively corrected microbial dysbiosis by increasing the abundance of Bacteroides acidifaciens, Bacteroides vulgatus, Lactobacillus murinus, and Lactobacillus gasseri. These findings indicate that the effectiveness of SP extract in treating colitis is demonstrated by its ability to reduce macrophage activation, inhibit the PI3K/Akt and MAPK pathways, and regulate gut microbiota, suggesting that SP extract holds great potential as a therapeutic option for colitis.
Diarrhea-predominant irritable bowel syndrome (IBS-D), a globally prevalent functional gastrointestinal (GI) disorder, is associated with elevated serotonin that increases gut motility. While ...anecdotal evidence suggests that the gut microbiota contributes to serotonin biosynthesis, mechanistic insights are limited. We determined that the bacterium Ruminococcus gnavus plays a pathogenic role in IBS-D. Monocolonization of germ-free mice with R. gnavus induced IBS-D-like symptoms, including increased GI transit and colonic secretion, by stimulating the production of peripheral serotonin. R. gnavus-mediated catabolism of dietary phenylalanine and tryptophan generated phenethylamine and tryptamine that directly stimulated serotonin biosynthesis in intestinal enterochromaffin cells via a mechanism involving activation of trace amine-associated receptor 1 (TAAR1). This R. gnavus-driven increase in serotonin levels elevated GI transit and colonic secretion but was abrogated upon TAAR1 inhibition. Collectively, our study provides molecular and pathogenetic insights into how gut microbial metabolites derived from dietary essential amino acids affect serotonin-dependent control of gut motility.
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•Ruminococcus gnavus enriched in IBS-D patents produces phenethylamine and tryptamine•Phenethylamine and tryptamine stimulate serotonin biosynthesis in the gut via TAAR1•Monocolonizing mice with R. gnavus increases serotonin and induces IBS-D symptoms•TAAR1 inhibition alleviates IBS-D symptoms in mice transplanted with IBS-D microbiota
Zhai et al. identify gut microbe Ruminococcus gnavus as a major factor that underlies gut motility disorder in IBS-D. Ruminococcus gnavus drives the development of IBS-D via the breakdown of dietary essential amino acids that stimulate serotonin biosynthesis in the gut.
CDD-2103 is an herbal prescription used to treat ulcerative colitis (UC). This study aimed to uncover its mechanism by integrating metabolomics and serum-feces pharmacochemistry-based network ...pharmacology.
A DSS-induced chronic colitis mice model was used to evaluate the anti-colitis effect of CDD-2103. Serum and feces metabolomics were conducted to identify differential metabolites and pathways. In the serum-feces pharmacochemistry study, biological samples were collected from rats treated with CDD-2103. Then, network pharmacology was utilized to predict the targets of the identified compounds. Critical genes were extracted through the above-integrated analysis. The interactions between targets, CDD-2103, and its compounds were validated through molecular docking, immunoblotting, and enzyme activity assays.
CDD-2103 alleviated ulcerous symptoms and colonic injuries in colitis mice. Metabolomics study identified differential metabolites associated with tryptophan, glycerophospholipid, and linoleic acid metabolisms. The serum-feces pharmacochemistry study revealed twenty-three compounds, which were subjected to network pharmacology analysis. Integration of these results identified three key targets (AHR, PLA2, and PTGS2). Molecular docking showed strong affinities between the compounds and targets. PTGS2 was identified as a hub gene targeted by most CDD-2103 compounds. Immunoblotting and enzyme activity assays provided further evidence that CDD-2103 alleviates UC, potentially through its inhibitory effect on cyclooxygenase-2 (COX-2, encoded by PTGS2), with alkaloids and curcuminoids speculated as crucial anti-inflammatory compounds.
This integrated strategy reveals the mechanism of CDD-2103 and provides insights for developing herbal medicine-based therapies for UC.
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•CDD-2103 herbal prescription effectively treats chronic colitis in mice by reducing ulcerous symtoms, colonic injuries, and inflammation.•An integrated platform of metabolomics and serum-feces pharmacochemistry-based network pharmacology is proposed to uncover the action mechanisms of CDD-2103.•CDD-2103 compounds strongly bind to three targets, regulating metabolic pathways, with key metabolites serving as diagnostic and therapeutic biomarkers.•The platform can be applied to study other herbs or formulas, providing insights into natural medicine mechanisms.
Gastrodia Rhizoma is a Traditional Chinese Medicine applied in the treatment of stroke, numbness of limb, headache and dizziness. However, its clinical effect is threatened by sulfur‐fumigation used ...in the process of storage. This article employs content determination coupled with high‐performance liquid chromatography fingerprint to investigate the effect of sulfur‐fumigation on Gastrodia Rhizoma so as to evaluate the quality of Gastrodia Rhizoma. The result was that most active ingredient in Gastrodia Rhizoma decreased after sulfur‐fumigation and the fingerprints analyzed by mathematical statistics between sulfur‐fumigated Gastrodia Rhizoma and unfumigated Gastrodia Rhizoma have substantial differences, which reveals that sulfur‐fumigation has a significant influence on the quality of Gastrodia Rhizoma. The conclusion of hierarchical clustering analysis, principal component analysis and partial least squares could validate each other, which implies that the method of mathematical statistics applied for assessing the quality of Gastrodia Rhizoma is effective and stable. The method not only affords a viable strategy for distinguishing Gastrodia Rhizoma whether sulfur‐fumigated or not and assessment of the quality of Gastrodia Rhizoma, but also provides a reference for other herbal medicine that suffers from sulfur‐fumigation.
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