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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. Here, the authors show a causal role for gut bacteria-derived metabolites tryptamine and phenethylamine in contributing to insulin resistance and the development of metabolic syndrome in patients with irritable bowel syndrome and type 2 diabetes.

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.

Background The gut microbiota is closely associated with gastrointestinal (GI) motility disorder, but the mechanism(s) by which bacteria interact with and affect host GI motility remains unclear. In this study, through using metabolomic and metagenomic analyses, an animal model of neonatal maternal separation (NMS) characterized by accelerated colonic motility and gut dysbiosis was used to investigate the mechanism underlying microbiota-driven motility dysfunction. Results An excess of intracolonic saturated long-chain fatty acids (SLCFAs) was associated with enhanced bowel motility in NMS rats. Heptadecanoic acid (C17:0) and stearic acid (C18:0), as the most abundant odd- and even-numbered carbon SLCFAs in the colon lumen, can promote rat colonic muscle contraction and increase stool frequency. Increase of SLCFAs was positively correlated with elevated abundances of Prevotella , Lactobacillus , and Alistipes . Functional annotation found that the level of bacterial LCFA biosynthesis was highly enriched in NMS group. Essential synthetic genes Fabs were largely identified from the genera Prevotella , Lactobacillus , and Alistipes . Pseudo germ-free (GF) rats receiving fecal microbiota from NMS donors exhibited increased defecation frequency and upregulated bacterial production of intracolonic SLCFAs. Modulation of gut dysbiosis by neomycin effectively attenuated GI motility and reduced bacterial SLCFA generation in the colon lumen of NMS rats. Conclusions These findings reveal a previously unknown relationship between gut bacteria, intracolonic SLCFAs, and host GI motility, suggesting the importance of SLCFA-producing bacteria in GI motility disorders. Further exploration of this relationship could lead to a precise medication targeting the gut microbiota for treating GI motility disorders.

With the widespread application of machine learning methods, the continuous improvement of forecast accuracy has become an important task, which is especially crucial for landslide displacement predictions. This study aimed to propose a novel prediction model to improve accuracy in landslide prediction, based on the combination of multiple new algorithms. The proposed new method includes three parts: data preparation, multi-swarm intelligence (MSI) optimization, and displacement prediction. In the data preparation, the complete ensemble empirical mode decomposition (CEEMD) is adopted to separate the trend and periodic displacements from the observed cumulative landslide displacement. The frequency component and residual component of reconstructed inducing factors that related to landslide movements are also extracted by the CEEMD and t-test, and then picked out with edit distance on real sequence (EDR) as input variables for the support vector regression (SVR) model. MSI optimization algorithms are used to optimize the SVR model in the MSI optimization; thus, six predictions models can be obtained that can be used in the displacement prediction part. Finally, the trend and periodic displacements are predicted by six optimized SVR models, respectively. The trend displacement and periodic displacement with the highest prediction accuracy are added and regarded as the final prediction result. The case study of the Shiliushubao landslide shows that the prediction results match the observed data well with an improvement in the aspect of average relative error, which indicates that the proposed model can predict landslide displacements with high precision, even when the displacements are characterized by stepped curves that under the influence of multiple time-varying factors.

The construction process of pile foundations can significantly disrupt the soil. Therefore, it is necessary to limit the degree of soil disturbance caused by pile foundation construction to an acceptable level. This paper examines the disturbance effects of pile driving on soft soil foundations, specifically analyzing the squeezing effect of squeezed soil piles and the unloading effect of non-squeezed soil piles. To investigate these effects, two typical squeezed soil piles, a hydrostatic pile, and a bag grouting pile, as well as a typical non-squeezed soil pile (a bored pile) are selected. Specifically, a novel construction method for numerical models, which simulates the mechanical processes of different pile types under standard grids, is proposed. Three crucial indicators—soil displacement field, stress field, and disturbance influence range—are chosen to compare the disturbance effects of three types of piles on the soil. Results indicate that the two types of squeezed soil piles cause significant disturbance to the soil displacement field, especially in the horizontal direction, while causing a relatively slight disturbance to the soil stress field. Among the two of them, the disturbance magnitude and range of the hydrostatic pile are greater than those of the bag grouting pile. For the non-squeezed soil pile, the soil displacement field changes minimally and the stress field remains basically unchanged during the pile driving process of the bored pile. To compare and quantify the disturbance effects of three types of piles on soil, the soil disturbance range in the horizontal direction of each pile is normalized by its radius. Results indicate that the horizontal disturbance values of maximum horizontal stress for all three types of piles are approximately 1/5 of the pile length above the pile tip, with normalized values of 7.6, 5.5, and 3.5, respectively. The maximum horizontal deformation disturbance range in the horizontal direction occurs near the ground surface and has normalized values of 15.2, 7.5, and 1.1 for the three types of piles, respectively. Therefore, the hydrostatic pile has the greatest disturbance effect, followed by the bag grouting pile and the bored pile. However, within the allowable range of disturbance in practical engineering, the optimal piling method can be selected by comprehensively considering factors such as the construction difficulty and economic costs.

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 Tph1 transcription activity in vitro . 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.

Pile groups are frequently employed to reinforce soft soil foundations, while the piling process frequently disturbs the adjacent foundation. The shielding effect, which prevents the transmission of disturbances from pile installation, is indispensable for minimizing engineering disturbances and optimizing pile group construction techniques. However, current research focuses predominantly on characterizing the phenomenon of shielding, with a limited exploration of the mechanism. To eliminate the limitation, a numerical investigation of the shielding mechanism of pile groups in a pile–soil system is performed this study. Using the finite difference program FLAC3D and the cavity expansion theory, a three-dimensional numerical model of a pile–soil foundation was created. During the sequential penetration of piles, the response characteristics of the soil surrounding the piles were investigated. Displacement field was first investigated to determine the presence of shielding effects in the pile group and then highlighted the effective role of the existing piles in controlling deformation. Furthermore, through a combined analysis of the stress and strain fields during piling, the mechanism of the shielding effect induced by pile construction is proposed, which is attributed to the direct obstruction effect of piles and the “soil arching effect” created by the soil between piles. The former is reflected by the direct barrier of the existing pile to the soil displacement induced via the installation of the new piles. The latter is reflected by the obstruction of soil between two existing piles to the displacement of soil passing through the two existing piles. This research provides a comprehensive understanding of the mechanical behavior of the pile–soil system and has practical implications for controlling disturbances and optimizing construction techniques in piling engineering projects.

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.

Background Dysregulation of gut microbiota–host bile acid (BA) co-metabolism is a critical pathogenic factor of diarrhea-predominant irritable bowel syndrome (IBS-D). Traditional Chinese Medicine (TCM), instructed by pattern differentiation, is effective in treating IBS-D, in which liver depression and spleen deficiency (LDSD) is the most prevalent pattern. Still, it is unclear the linkage between the LDSD pattern and the BA metabolic phenotype. Purpose This study aimed to uncover the biological basis of the LDSD pattern from the BA metabolic perspective. Methods Patients with IBS-D completed questionnaires regarding the irritable bowel severity scoring system (IBS-SSS), stool frequency, Stool Bristol scale, and Self-Rating Scales of mental health. Fasting blood and morning feces were collected to analyze the gut metagenome and BA-related indices/metabolites. Results IBS-D patients with LDSD had a higher incidence of BA overexcretion (41% vs. 23% non-LDSD) with significant elevations in fecal total BAs and serum BA precursor 7α-hydroxy-4-cholesten-3-one levels. Compared to controls or non-LDSD patients, LDSD patients had a featured fecal BA profile, with higher proportions of deoxycholic acid (DCA), 7-ketodeoxycholic acid, and lithocholic acid. It is consistent with the BA-metabolizing genomic changes in the LDSD gut microbiota characterized by overabundances of 7-dehydroxylating bacteria and BA-inducible genes ( baiCD/E/H ). The score of bowel symptoms (stool frequency and abdominal pain) showing greater severity in the LDSD pattern were positively correlated with bai -expressing bacterial abundances and fecal DCA levels separately. Conclusion We clarified a differed BA metabolic phenotype in IBS patients with LDSD, which closely correlates with the severity of bowel symptoms. It demonstrates that gut microbiota and host co-metabolism of BAs would provide crucial insight into the biology of the LDSD pattern and its internal relationship with IBS progression.

Many plant‐derived bioactive molecules with low solubility and permeability can cause hepatocyte injury. However, the mechanism by which they induce hepatic damage without passive diffusion into the hepatic circulatory system remains unclear. This study demonstrate that indirubin, the main component of indigo naturalis with poor aqueous solubility, predisposes mice with chronic colitis to hepatic injury. This closely mimics the hepatic damage commonly observed in ulcerative colitis patients treated with indigo naturalis. Upon administration, indirubin is detected in the plasma, Peyer's patches, and hepatic tissue, with its distribution linked to macrophage infiltration into the liver. Ablation of macrophages significantly reduces indirubin accumulation and attenuates elevated hepatic transaminases in mice with chronic colitis. Mechanistically, macrophages internalize and transport indirubin aggregates from Peyer's patches through the circulatory system to the livers. This internalization activates the NLRP3 inflammasome, leading to the formation of macrophage extracellular traps (METs), which contribute to oxidative stress‐induced liver injury. The study identifies indirubin as a potentially toxic component of indigo naturalis that provokes METs‐mediated oxidative damage. Additionally, the findings reveal a novel transport pathway for poorly soluble molecules to reach the liver via uptake by macrophages within Peyer's patches. Plant‐derived bioactive molecules with low solubility and permeability induce hepatocyte injury, though the mechanisms driving their hepatic effects remain poorly understood. This study identifies a novel transport pathway in which poorly soluble indirubin accumulates in the liver via macrophage‐mediated uptake in Peyer's patches, exacerbating hepatic injury in chronic colitis mice. This process mirrors clinical observations in ulcerative colitis patients using such herb.