Dysbiosis in gut microbiota and abnormalities in bile acids have been linked to neurodegenerative diseases. While many studies have focused on the relationship between colonic bacteria and Alzheimer's disease (AD), this study propose that alterations in the small intestine microbiota may play a more critical role. This is because the small intestine is pivotal in recycling bile acids through enterohepatic circulation. This study uses amyloid precursor protein knock-in (APPNL-G-F/NL-G-F) transgenic mice to investigate the association between intestinal microbiota and bile acid metabolism. The results showed that the accumulation of beta-amyloid (Aβ) leads to a significant decrease in Lactobacillus johnsonii and a notable increase in bacteria of the genus Clostridium in the small intestine, which are important microorganisms for producing toxic bile acids. Extracellular vesicles (EVs) involved in bacterial interactions and bacteria-host interactions are currently a focus of research. Treatment with L. johnsonii-derived EVs at concentrations of 1010 and 1012/mL) inhibited the growth of Clostridium scindens and suppressed the production of toxic secondary lithocholic acid (TLA) at non-cytotoxic concentrations (108/mL). Furthermore, the removal of small RNA from L. johnsonii-derived EVs resulted in the loss of their ability to suppress TLA production. These results suggest that the small intestine microbiota may play a more critical role than the colonic microbiota in AD. Deterioration of small intestine microbiota led to the metabolism disruption of certain secondary bile acids, which have been reported to exacerbate AD pathology. The EVs released by L. johnsonii, which is abundant in the small intestine, can suppress toxic TLA and have the potential to be developed into health-promoting probiotics.

Starch digestibility and the content of resistant starch (RS) play a crucial role in human health, particularly in relation to glycemic responses, insulin sensitivity, fat oxidation, and satiety. This study investigates the impact of processing methods on potato starch digestibility and RS content, focusing on two modification techniques: autoclaving and high hydrostatic pressure (HHP), followed by retrogradation at different temperatures. The research employs a comprehensive approach to characterize structural changes in starch samples using X-ray diffraction (XRD), attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, and scanning electron microscopy (SEM). In turn, semi-dynamic in vitro digestion experiments based on the INFOGEST protocol were conducted to assess starch digestibility, while RS content was evaluated through enzymatic digestion of the non-RS fraction. SEM, XRD, and FTIR measurements reveal thermal processing appreciably affected starch architectures while HHP had a marginal effect. Further, the FTIR 1045/1022R ratio was found to be correlated with RS content measurements while reducing rapidly digestible starch (RDS). The findings led to the stipulation that thermal processing facilitates amylose leaching and granular disruption. In turn, retrogradation enabled the deposition of the amylose onto the disrupted structures which delineated their subsequent liability to enzymatic digestion. Conversely, HHP had minimal effects on granular architectures and amylose leaching. Overall, this research provides valuable insights for processing starch-based food products with the goal of increasing RS content, which may have significant implications for the food industry and nutritional science.

Liver metastasis is the leading cause of colorectal cancer (CRC)‑related mortality. Microbiota dysbiosis serves a role in the pathogenesis of colorectal liver metastases. Bile acids (BAs), cholesterol metabolites synthesized by intestinal bacteria, contribute to the metastatic cascade of CRC, encompassing colorectal invasion, migration, angiogenesis, anoikis resistance and the establishment of a hepatic pre‑metastatic niche. BAs impact inflammation and modulate the immune landscape within the tumor microenvironment by activating signaling pathways, which are used by tumor cells to facilitate metastasis. Given the widespread distribution of BA‑activated receptors in both tumor and immune cells, strategies aimed at restoring BA homeostasis and blocking metastasis‑associated signaling are of importance in cancer therapy. The present study summarizes the specific role of BAs in each step of colorectal liver metastasis, elucidating the association between BA and CRC progression to highlight the potential of BAs as predictive biomarkers for colorectal liver metastasis and their therapeutic potential in developing novel treatment strategies.

Bile salt hydrolase (BSH: EC.3.5.1.24) has been used as a biomarker for probiotics for an extended period. It is mostly present in the gut environment of vertebrates. Additionally, it influences the viability of probiotics. This biomarker is considered a promising nutritional supplement due to its unique ability to effectively address elevated blood cholesterol levels, a common issue in modern society. However, the commercialization of BSH has been limited by an incomplete understanding of the intestinal microbiota and the function of BSH. Hence, in this review, we aim to reveal the current advancements in BSH research and outline the necessary areas of investigation for future studies. The review highlights key findings related to the substrate affinity of BSH in probiotic bacteria and its BSH gene phylogeny that have been researched until today, suggesting further research regarding the differences in multiple BSH genes and corresponding differences in BSH affinity.

Interest in bile acids (BAs) is growing due to their emerging role as signaling molecules and their association with various diseases such as colon cancer and metabolic syndrome. Analyzing BAs requires chromatographic separation of isomers, often with long run times, which hinders BA analysis in large studies. Here, we present a high-throughput method based on liquid chromatography-tandem mass spectrometry to quantify BAs in mouse samples. After acidic protein precipitation in the presence of a comprehensive mixture of stable isotope-labeled internal standards (SIL-ISs), BAs are separated on a biphenyl column by gradient elution at basic pH. Quantification is performed using a six-point calibration curve. Except for the separation of β- and ω-muricholic acid (MCA) species, a rapid separation of 27 BA species was achieved in a run time of 6.5 min. Plasma quality controls (QCs) were used to evaluate intra- and inter-day precision. The CV was less than 10% for most BA species and exceeded 20% only for glycohyodeoxycholic (GHDCA) and taurohyodeoxycholic acid (THDCA) due to the lack of a corresponding SIL-IS. The limit of quantification (LoQ) was tested using diluted QCs and was found to be compromised for some BA species as a result of insufficient isotopic purity of the SIL-IS, leading to significant interference with the respective analyte. Finally, we tested the mouse sample material requirements for plasma, bile, and liver samples and determined BA concentrations in C57/BL6N wild-type mice. In conclusion, the LC-MS/MS method presented here permits a rapid and reproducible quantification of the major murine BAs.

The tumor microenvironment has recently been well-studied in various gastrointestinal cancers, including colorectal cancer (CRC). The gut microbiota, a collection of microorganisms in the human gastrointestinal tract, is one of the microenvironments associated with colon carcinogenesis. It has been challenging to elucidate the mechanisms by which gut microbiota contributes to carcinogenesis and cancer progression due to complex interactions with the host, including its metabolites and immune and inflammatory responses. Various studies described the influence of diet on reported changes in the composition and microbiota of gut bacteria and its association with CRC. In recent years, metagenomic techniques such as shotgun sequencing and genome-wide association studies focused on understanding the role of the microbiota and the metabolome on early CRCs and colon carcinogenesis to determine if there are modifiable or intervenable targets for CRC. In this review, we will attempt to provide an overview of gut microbiota related to CRC, with particular attention to the findings of recent studies.

The gut microbiota is a complex and dynamic ecosystem that plays a crucial role in human health and disease, including obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, and cancer. Chronic inflammation is a common feature of these diseases and is closely related to angiogenesis (the process of forming new blood vessels), which is often dysregulated in pathological conditions. Inflammation potentially acts as a central mediator. This abstract aims to elucidate the connection between the gut microbiota and angiogenesis in various diseases. The gut microbiota influences angiogenesis through various mechanisms, including the production of metabolites that directly or indirectly affect vascularization. For example, short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate are known to regulate immune responses and inflammation, thereby affecting angiogenesis. In the context of cardiovascular diseases, the gut microbiota promotes atherosclerosis and vascular dysfunction by producing trimethylamine N-oxide (TMAO) and other metabolites that promote inflammation and endothelial dysfunction. Similarly, in neurodegenerative diseases, the gut microbiota may influence neuroinflammation and the integrity of the blood-brain barrier, thereby affecting angiogenesis. In cases of fractures and wound healing, the gut microbiota promotes angiogenesis by activating inflammatory responses and immune effects, facilitating the healing of tissue damage. In cancer, the gut microbiota can either inhibit or promote tumor growth and angiogenesis, depending on the specific bacterial composition and their metabolites. For instance, some bacteria can activate inflammasomes, leading to the production of inflammatory factors that alter the tumor immune microenvironment and activate angiogenesis-related signaling pathways, affecting tumor angiogenesis and metastasis. Some bacteria can directly interact with tumor cells, activating angiogenesis-related signaling pathways. Diet, as a modifiable factor, significantly influences angiogenesis through diet-derived microbial metabolites. Diet can rapidly alter the composition of the microbiota and its metabolic activity, thereby changing the concentration of microbial-derived metabolites and profoundly affecting the host's immune response and angiogenesis. For example, a high animal protein diet promotes the production of pro-atherogenic metabolites like TMAO, activating inflammatory pathways and interfering with platelet function, which is associated with the severity of coronary artery plaques, peripheral artery disease, and cardiovascular diseases. A diet rich in dietary fiber promotes the production of SCFAs, which act as ligands for cell surface or intracellular receptors, regulating various biological processes, including inflammation, tissue homeostasis, and immune responses, thereby influencing angiogenesis. In summary, the role of the gut microbiota in angiogenesis is multifaceted, playing an important role in disease progression by affecting various biological processes such as inflammation, immune responses, and multiple signaling pathways. Diet-derived microbial metabolites play a crucial role in linking the gut microbiota and angiogenesis. Understanding the complex interactions between diet, the gut microbiota, and angiogenesis has the potential to uncover novel therapeutic targets for managing these conditions. Therefore, interventions targeting the gut microbiota and its metabolites, such as through fecal microbiota transplantation (FMT) and the application of probiotics to alter the composition of the gut microbiota and enhance the production of beneficial metabolites, present a promising therapeutic strategy.

An increasingly important role for gut microbiota in the initiation and progression of colorectal cancer (CRC) has been described. Even in the early stages of transformation, i.e., colorectal adenomas, changes in gut microbiota composition have been observed, and several bacterial species, such as pks+Escherichia coli and enterotoxigenic Bacteroides fragilis, have been proposed to drive colon tumorigenesis. In recent years, several strategies have been developed to study mucosa-associated microbiota (MAM), which is more closely associated with CRC development than lumen-associated microbiota (LAM) derived from fecal samples. This review summarizes the state of the art about the oncogenic actions of gut bacteria and compares the different sampling strategies to collect intestinal microbiota (feces, biopsies, swabs, brushes, and washing aspirates). In particular, this article recapitulates the current knowledge on MAM in colorectal adenomas and serrated polyps, since studying the intestinal microbiota associated with early-stage tumors can elucidate the molecular mechanisms underpinning CRC carcinogenesis.

Since the gut microbiota plays a crucial role in host metabolism and homeostasis, its alterations induced by xenobiotics such as pesticides, could pose a risk to host health. The pyrethroid insecticides were frequently detected in surface water (up to 13 mg/L worldwide), sediments, and agricultural products; additionally, some previous studies indicated that pyrethroid insecticides could cause disruption of gut homeostasis. Hence herein, the normally used pyrethroid lambda-cyhalothrin (LCT) was selected and studied for its effects on the intestinal microbial community and its related bile acid metabolism using mice as the model species. Results showed that the total amount of bile acids in plasma and fecal samples from LCT treated mice markedly increased compared to controls, which could be mainly ascribed to the significantly raised proportions of taurine conjugated bile acids in plasma, and the increase in fecal secondary bile acids. In gut microbial profiles, a significantly increased richness of Prevotellacea and a depletion of Lachnospiraceae were found at the family level upon the treatment with lambda-cyhalothrin. In conclusion, results obtained on bacterial and bile acid profiles corroborate that the treatment of mice with LCT could affect gut microbial community with accompanying changes in bile acid homeostasis.

There are studies with mixed conclusions about the role cholecystectomy plays as a risk factor for proximal colorectal cancer (CRC).

We performed a multicenter retrospective cohort study where the records of patients with CRC were reviewed. Data was collected regarding affected colon subsegment (cecum, ascending, transverse, descending, sigmoid, or rectum, which were also combined into proximal or distal colon), history and time since cholecystectomy, histopathology reports (TNM classification and clinical stage), and KRAS, NRAS, and BRAF mutation analysis. Univariate and multivariate analysis adjusting for age, smoking history, body mass index, sex, and family history of cancer were performed. Logistical regression for statistical analysis was used to estimate the odds ratio for the association between cholecystectomy and tumor location.

Four hundred four cases were obtained, of which 52 previously had cholecystectomy. The date of surgery was recorded in 43 patients, with a 5 y median and an interquartile range of 1.5-14 y prior to CRC diagnosis. Both crude and adjusted odds ratio (2.86 and 2.42, respectively) confirmed an associated risk for developing proximal CRC after cholecystectomy. When proximal CRC cases with previous cholecystectomy were directly compared against proximal CRC without cholecystectomy and distal CRC cases, the former had a higher distribution of prevalence for T3, T4b, N1b, M1a, and M1c. KRAS mutation also presented its highest prevalence in this group with 33%.

Cholecystectomy was related to the development of proximal CRC in all its subsegments, seemingly associated with higher stages at diagnosis. Close surveillance should be considered in patients who undergo cholecystectomy.

Fructooligosaccharide (FOS) is a widely used prebiotic and health food ingredient, but few reports have focused on its risk to specific populations. Recently, it has been shown that the intake of inulin, whose main component is FOS, can lead to cholestasis and induce hepatocellular carcinoma in mice fed a high-fat diet (HFD); however, the molecular mechanism behind this is not clear. This study found that FOS supplementation induced abnormal enterohepatic circulation of bile acids in HFD-fed mice, which showed a significant increase in bile acid levels in the blood and liver, especially the secondary bile acids with high cytotoxicity, such as deoxycholic acid. The abundance of Clostridium, Bacteroides, and other bacteria in the gut microbiota also increased significantly. The analysis of the signaling pathway involved in regulating the enterohepatic circulation of bile acids showed that the weakening of the feedback inhibition of FXR-FGF15 and FXR-SHP signalling pathways possibly induced the enhancement of CYP7A1 activity and bile acid reabsorption in the blood and liver and led to an increase in bile acid synthesis and accumulation in the liver, increasing the risk of cholestasis. This study showed the risk of health damage caused by FOS supplementation in HFD-fed mice, which is caused by gut microbiota dysfunction and abnormal enterohepatic circulation of bile acids. Therefore, the application of FOS should be standardized to avoid the health risks of unreasonable FOS use in specific populations.

The intestinal microbiota comprises approximately 1013-1014 species of bacteria and plays a crucial role in host metabolism by facilitating various chemical reactions. Secondary bile acids (BAs) are key metabolites produced by gut microbiota.Initially synthesized by the liver, BA undergoes structural modifications through the activity of various intestinal microbiota enzymes, including eukaryotic, bacterial, and archaeal enzymes. These modified BA then activate specific receptors that regulate multiple metabolic pathways in the host, such as lipid and glucose metabolism, energy balance, inflammatory response, and cell proliferation and death. Recent attention has been given to intestinal flora disorders in diabetic kidney disease (DKD), where activation of BA receptors has shown promise in alleviating diabetic kidney damage by modulating renal lipid metabolism and mitochondrial production. Imbalances in the intestinal flora can influence the progression of DKD through the regulation of bile acid and its receptor pathways. This review aims to propose a mechanism involving the gut-BA-diabetes and nephropathy axes with the goal of optimizing new strategies for treating DKD.

Colorectal cancer (CRC) continues to be a major global health concern. Recent advances in molecular biology have highlighted the gut microbiota's role in CRC. This study investigates long-term (≥5 years) gut microbiota changes in patients postcholecystectomy, comparing them with CRC patients and healthy controls to assess their impact on CRC development.

Sixty participants were divided into three groups: 20 healthy controls, 20 postcholecystectomy (PCE) patients, and 20 CRC patients. Demographic data and stool samples were collected. Gut microbiota composition, abundance, and diversity were analyzed using high-throughput 16S rDNA sequencing.

Significant differences in microbial community, α-diversity ( P  < 0.05) and β-diversity ( P  = 0.006), were observed among the three groups. At the phylum level, Firmicutes abundance was significantly reduced in PCE and CRC groups compared with the control group ( P  = 0.002), while changes in other phyla were not significant ( P >0.05). At the genus level, Bacteroides , Dialister , and Parabacteroides increased progressively from control to PCE to CRC groups ( P  = 0.004, 0.001, and 0.002). Prevotella decreased across these groups ( P  = 0.041). Faecalibacterium and Roseburia abundances were reduced in PCE and CRC groups compared with controls ( P  = 0.001 and 0.003). The Random Forest algorithm identified Parabacteroides , Bacteroides , Roseburia , and Dialister as key distinguishing genera.

The gut microbiota of long-term (≥5 years) PCE patients significantly differs from that of controls and resembles that of CRC patients, suggesting a potential link between cholecystectomy and CRC development through key microbial changes.

Circulating bile acid (BA) profiles change with lifestyle and are closely related to intestinal BA metabolisms such as deconjugation and conversion to secondary BAs. The composition of BA in the blood is involved in systemic nutrient metabolism and intestinal health. Herein, we explored the associations of lifestyle and physical fitness with the circulating BA profile of middle-aged men.

Data of 147 male participants (aged 50-64 years; BMI < 26 kg/m2; no medication for diabetes or dyslipidemia) from the Japan Multi-Institutional Collaborative Cohort study were analyzed. Serum concentrations of 15 types of BAs were examined for associations with variables on dietary habits, physical-activity habits, and physical fitness.

Green tea intake was positively associated with the deconjugation ratio of total BAs (p = 0.028) and negatively associated with secondary BA levels (free deoxycholic acid [DCA] (p = 0.078), glyco-DCA (p = 0.048), and tauro-DCA (p = 0.037)). In contrast, physical activity was negatively associated with the deconjugation ratio (p = 0.029) and secondary BA levels (free DCA (p = 0.098), and free lithocholic acid (p = 0.009)). Grip strength was also negatively associated with secondary BA levels (tauro-DCA (p = 0.041)) but was not associated with the deconjugation ratio. Energy and fat intake and skeletal muscle mass were not associated with the deconjugation ratio or secondary BA levels.

The study findings suggest that lifestyle-associated changes in serum deconjugated and secondary BAs indicate improvements in nutrient metabolism and the intestinal environment.

Marine organisms' lipid metabolism contributes to marine ecosystems by producing a variety of lipid molecules. Historically, research focused on the lipid metabolism of the organisms themselves. Recent microbiome studies, however, have revealed that gut microbial communities influence the amount and type of lipids absorbed by organisms, thereby altering the organism's lipid metabolism. This has highlighted the growing importance of research on gut microbiota. This review highlights mechanisms by which gut microbiota facilitate lipid digestion and diversify the lipid pool in aquatic animals through the accelerated degradation of exogenous lipids and the transformation of lipid molecules. We also assess how environmental factors and pollutants, along with the innovative use of probiotics, interact with the gut microbiome to influence lipid metabolism within the host. We aim to elucidate the complex interactions between lipid metabolism and gut microbiota in aquatic animals by synthesizing current research and identifying knowledge gaps, providing a foundation for future explorations.

Reflux bile acids are believed to promote esophageal adenocarcinoma (EAC), but the role of systemic bile acids is unknown. This study aimed to assess associations between systemic bile acids and stages of Barrett's esophagus (BE) progression.

Subjects with and without BE were enrolled in this multicenter cross-sectional study. Targeted serum bile acid profiling was performed, and a subset of subjects completed a validated food frequency questionnaire. RNA sequencing was performed on BE or gastric cardia tissue to assess bile acid associations with gene expression.

A total of 141 subjects were enrolled with serum bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia, 25 indefinite/low grade dysplasia, 23 high-grade dysplasia/EAC). Lower Healthy Eating Index score, older age, higher body mass index, and no proton pump inhibitor use were associated with increased levels of multiple bile acids. Global bile acid pools were distinct between non-BE and stages of BE neoplasia ( P = 0.004). Increasing cholic acid was associated with high-grade dysplasia/EAC compared with non-BE, even after adjusting for EAC risk factors (adjusted odds ratio 2.03, 95% confidence interval 1.11-3.71) as was the combination of unconjugated primary bile acids (adjusted odds ratio 1.81, 95% confidence interval 1.04-3.13). High cholic acid levels were associated with tissue gene expression changes including increased DNA replication and reduced lymphocyte differentiation genes.

Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes, proneoplastic effects of bile acids, and whether these bile acids, particularly cholic acid, represent potential biomarkers or viable therapeutic targets for advanced neoplasia in BE.

Increasing scientific evidence demonstrates that gut microbiota plays an essential role in the onset and development of Colorectal cancer (CRC). However, the mechanisms by which these microorganisms contribute to cancer development are complex and far from completely clarified. Specifically, the impact of gut microbiota-derived metabolites on CRC is undeniable, exerting both protective and detrimental effects. This paper examines the effects and mechanisms by which important bacterial metabolites exert detrimental effects associated with increased risk of CRC. Metabolites considered include heterocyclic amines and polycyclic aromatic hydrocarbons, heme iron, secondary bile acids, ethanol, and aromatic amines. It is necessary to delve deeper into the mechanisms of action of these metabolites in CRC and identify the microbiota members involved in their production. Furthermore, since diet is the main factor capable of modifying the intestinal microbiota, conducting studies that include detailed descriptions of dietary interventions is crucial. All this knowledge is essential for developing precision nutrition strategies to optimise a protective intestinal microbiota against CRC.

Excess body fat elevates colorectal cancer risk. While bariatric surgery (BRS) induces significant weight loss, its effects on the fecal stream and colon biology are poorly understood. Specifically, limited data exist on the impact of bariatric surgery (BRS) on fecal secondary bile acids (BA), including lithocholic acid (LCA), a putative promotor of colorectal carcinogenesis.

This cross-sectional case-control study included 44 patients with obesity; 15 pre-BRS (controls) vs. 29 at a median of 24.1 months post-BRS. We examined the fecal concentrations of 11 BA by liquid chromatography and gene abundance of BA-metabolizing bacterial enzymes through fecal metagenomic sequencing. Differences were quantified using non-parametric tests for BA levels and linear discriminant analysis (LDA) effect size (LEfSe) for genes encoding BA-metabolizing enzymes.

Total fecal secondary BA concentrations trended towards lower levels post- vs. pre-BRS controls (p = 0.07). Individually, fecal LCA concentrations were significantly lower post- vs. pre-BRS (8477.0 vs. 11,914.0 uM/mg, p < 0.008). Consistent with this finding, fecal bacterial genes encoding BA-metabolizing enzymes, specifically 3-betahydroxycholanate-3-dehydrogenase (EC 1.1.1.391) and 3-alpha-hydroxycholanate dehydrogenase (EC 1.1.1.52), were also lower post- vs. pre-BRS controls (LDA of - 3.32 and - 2.64, respectively, adjusted p < 0.0001). Post-BRS fecal BA concentrations showed significant inverse correlations with weight loss, a healthy diet quality, and increased physical activity.

Concentrations of LCA, a secondary BA, and bacterial genes needed for BA metabolism are lower post-BRS. These changes can impact health and modulate the colorectal cancer cascade. Further research is warranted to examine how surgical alterations and the associated dietary changes impact bile acid metabolism.

The critical role of the gut microbiome in gastrointestinal cancers is becoming increasingly clear. Imbalances in the gut microbial community, referred to as dysbiosis, are linked to increased risks for various forms of gastrointestinal cancers. Pathogens like Fusobacterium and Helicobacter pylori relate to the onset of esophageal and gastric cancers, respectively, while microbes such as Porphyromonas gingivalis and Clostridium species have been associated with a higher risk of pancreatic cancer. In colorectal cancer, bacteria such as Fusobacterium nucleatum are known to stimulate the growth of tumor cells and trigger cancer-promoting pathways. On the other hand, beneficial microbes like Bifidobacteria offer a protective effect, potentially inhibiting the development of gastrointestinal cancers. The potential for therapeutic interventions that manipulate the gut microbiome is substantial, including strategies to engineer anti-tumor metabolites and employ microbiota-based treatments. Despite the progress in understanding the influence of the microbiome on gastrointestinal cancers, significant challenges remain in identifying and understanding the precise contributions of specific microbial species and their metabolic products. This knowledge is essential for leveraging the role of the gut microbiome in the development of precise diagnostics and targeted therapies for gastrointestinal cancers.

The gastrointestinal tract is where the majority of gut microbiota settles; therefore, the composition of the gut microbiota and the changes in metabolites, as well as their modulatory effects on the immune system, have a very important impact on the development of gastrointestinal diseases. The purpose of this article was to review the role of the gut microbiota in the host environment and immunometabolic system and to summarize the beneficial effects of botanical active ingredients on gastrointestinal cancer, so as to provide prospective insights for the prevention and treatment of gastrointestinal diseases. A literature search was performed on the PubMed database with the keywords "gastrointestinal cancer", "gut microbiota", "immunometabolism", "SCFAs", "bile acids", "polyamines", "tryptophan", "bacteriocins", "immune cells", "energy metabolism", "polyphenols", "polysaccharides", "alkaloids", and "triterpenes". The changes in the composition of the gut microbiota influenced gastrointestinal disorders, whereas their metabolites, such as SCFAs, bacteriocins, and botanical metabolites, could impede gastrointestinal cancers and polyamine-, tryptophan-, and bile acid-induced carcinogenic mechanisms. GPRCs, HDACs, FXRs, and AHRs were important receptor signals for the gut microbial metabolites in influencing the development of gastrointestinal cancer. Botanical active ingredients exerted positive effects on gastrointestinal cancer by influencing the composition of gut microbes and modulating immune metabolism. Gastrointestinal cancer could be ameliorated by altering the gut microbial environment, administering botanical active ingredients for treatment, and stimulating or blocking the immune metabolism signaling molecules. Despite extensive and growing research on the microbiota, it appeared to represent more of an indicator of the gut health status associated with adequate fiber intake than an autonomous causative factor in the prevention of gastrointestinal diseases. This study detailed the pathogenesis of gastrointestinal cancers and the botanical active ingredients used for their treatment in the hope of providing inspiration for research into simpler, safer, and more effective treatment pathways or therapeutic agents in the field.

Colorectal cancer (CRC) continues to be a significant contributor to global morbidity and mortality. Emerging evidence indicates that disturbances in gut microbial composition, the formation of reactive oxygen species (ROS), and the resulting inflammation can lead to DNA damage, driving the pathogenesis and progression of CRC. Notably, bacterial metabolites can either protect against or contribute to oxidative stress by modulating the activity of antioxidant enzymes and influencing signaling pathways that govern ROS-induced inflammation. Additionally, microbiota byproducts, when supplemented through probiotics, can affect tumor microenvironments to enhance treatment efficacy and selectively mediate the ROS-induced destruction of CRC cells. This review aims to discuss the mechanisms by which taxonomical shifts in gut microbiota and related metabolites such as short-chain fatty acids, secondary bile acids, and trimethylamine-N-oxide influence ROS concentrations to safeguard or promote the onset of inflammation-mediated CRC. Additionally, we focus on the role of probiotic species in modulating ROS-mediated signaling pathways that influence both oxidative status and inflammation, such as Nrf2-Keap1, NF-κB, and NLRP3 to mitigate carcinogenesis. Overall, a deeper understanding of the role of gut microbiota on oxidative stress may aid in delaying or preventing the onset of CRC and offer new avenues for adjunct, CRC-specific therapeutic interventions such as cancer immunotherapy.

5-aminosalicylic acid (5-ASA) is a first-line treatment for maintaining colitis remission. It is a highly effective, safe, and well-tolerated drug with anti-inflammatory and chemo-preventive properties. While patients with primary sclerosing cholangitis (PSC) with concomitant ulcerative colitis are treated with 5-ASA, the molecular mechanisms underlying the drug's chemo-preventive effects are not entirely understood. We previously reported that bile acids and lipopolysaccharide-induced miR-155 expression was associated with downregulating mismatch repair (MMR) proteins in CACO-2 cell lines. Therefore, in this investigation, a set of in vitro functional studies was performed to show the possible mechanisms behind the epigenetic relationship between miR-155 and 5-ASA's prevention of high microsatellite instability (MSI-H). In transient transfection with miR-155Mimic, which behaves like endogenous miRNA, we confirmed the relationships between miR-155 and its target MMR in three human intestinal epithelial cell lines: CACO-2, NCM460D and HT-29. We have shown, for the first time, that 5-ASA modulates MLH1, MSH2, MSH6 in miR-155 transfected cells. These findings underline that chemoprotective 5-ASA therapy can effectively attenuate the expression of miR-155 and potentially prevent a development of MSI-H in a subset of colorectal cancers associated with PSC.

The incidence of Barrett esophagus (BE) and Gastroesophageal Adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BA) support fat digestion and undergo microbial metabolization in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. The capacity of inhibiting cancer-related processes when activated, make FXR an appealing therapeutic target. In this work, we assess the role of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression.

Here we show that high fat diet (HFD) accelerated tumorigenesis in L2-IL1B mice (BE- and GEAC- mouse model) while increasing BA levels and enriching gut microbiota that convert primary to secondary BA. While upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine organoids and L2-IL1B mice with the FXR agonist obeticholic acid (OCA) deacelerated GEAC progression.

We provide a novel concept of GEAC carcinogenesis being accelerated via the diet-microbiome-metabolome axis and FXR inhibition on progenitor cells. Further, FXR activation protected with OCA ameliorated the phenotype in vitro and in vivo, suggesting that FXR agonists have potential as differentiation therapy in GEAC prevention.

Cancers are causing millions of deaths and leaving a huge clinical and economic burden. High costs of cancer drugs are limiting their access to the growing number of cancer cases. The development of more affordable alternative therapy could reach more patients. As gut microbiota plays a significant role in the development and treatment of cancer, microbiome-targeted therapy has gained more attention in recent years. Dietary and natural compounds can modulate gut microbiota composition while providing broader and more accessible access to medicine. Tea compounds have been shown to have anti-cancer properties as well as modulate the gut microbiota and their related metabolites. However, there is no comprehensive review that focuses on the gut modulatory effects of tea compounds and their impact on reshaping the metabolic profiles, particularly in cancer models. In this review, the effects of different tea compounds on gut microbiota in cancer settings are discussed. Furthermore, the relationship between these modulated bacteria and their related metabolites, along with the mechanisms of how these changes led to cancer intervention are summarized.

The etiology of cancers is multifactorial, with certain bacteria established as contributors to carcinogenesis. As the understanding of carcinogenic bacteria deepens, interest in cancer treatment through bacterial eradication is growing. Among emerging antibacterial platforms, cell membrane-coated nanoparticles (CNPs), constructed by enveloping synthetic substrates with natural cell membranes, exhibit significant promise in overcoming challenges encountered by traditional antibiotics. This article reviews recent advancements in developing CNPs for targeting carcinogenic bacteria. It first summarizes the mechanisms of carcinogenic bacteria and the status of cancer treatment through bacterial eradication. Then, it reviews engineering strategies for developing highly functional and multitasking CNPs and examines the emerging applications of CNPs in combating carcinogenic bacteria. These applications include neutralizing virulence factors to enhance bacterial eradication, exploiting bacterium-host binding for precise antibiotic delivery, and modulating antibacterial immunity to inhibit bacterial growth. Overall, this article aims to inspire technological innovations in developing CNPs for effective cancer treatment through oncogenic bacterial targeting.

Colorectal cancer (CRC) is one of the most life-threatening neoplasias in terms of incidence and mortality worldwide. Vitamin D deficiency has been associated with an increased risk of CRC. 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the most active vitamin D metabolite, is a pleiotropic hormone that, through its binding to a transcription factor of the nuclear receptor superfamily, is a major regulator of the human genome. 1,25(OH)2D3 acts on colon carcinoma and stromal cells and displays tumor protective actions. Here, we review the variety of molecular mechanisms underlying the effects of 1,25(OH)2D3 in CRC, which affect multiple processes that are dysregulated during tumor initiation and progression. Additionally, we discuss the epidemiological data that associate vitamin D deficiency and CRC, and the most relevant randomized controlled trials of vitamin D3 supplementation conducted in both healthy individuals and CRC patients.

The gut microbiota plays a critical role in the progression of human diseases, especially cancer. In recent decades, there has been accumulating evidence of the connections between the gut microbiota and cancer immunotherapy. Therefore, understanding the functional role of the gut microbiota in regulating immune responses to cancer immunotherapy is crucial for developing precision medicine. In this review, we extract insights from state-of-the-art research to decipher the complicated crosstalk among the gut microbiota, the systemic immune system, and immunotherapy in the context of cancer. Additionally, as the gut microbiota can account for immune-related adverse events, we discuss potential interventions to minimize these adverse effects and discuss the clinical application of five microbiota-targeted strategies that precisely increase the efficacy of cancer immunotherapy. Finally, as the gut microbiota holds promising potential as a target for precision cancer immunotherapeutics, we summarize current challenges and provide a general outlook on future directions in this field.

While the human gut microbiota has a significant impact on gut health and disease, understanding of the roles of gut microbes, interactions, and collective impact of gut microbes on various aspects of human gut health is limited by the lack of suitable in vitro model system that can accurately replicate gut-like environment and enable the close visualization on causal and mechanistic relationships between microbial constitutents and the gut. , In this study, we present a scalable Gut Microbiome-on-a-Chip (GMoC) with great imaging capability and scalability, providing a physiologically relevant dynamic gut-microbes interfaces. This chip features a reproducible 3D stratified gut epithelium derived from Caco-2 cells (µGut), mimicking key intestinal architecture, functions, and cellular complexity, providing a physiolocially relevant gut environment for microbes residing in the gut. Incorporating tumorigenic bacteria, enterotoxigenic Bacteroides fragilis (ETBF), into the GMoC enable the observation of pathogenic behaviors of ETBF, leading to µGut disruption and pro-tumorigenic signaling activations. Pre-treating the µGut with a beneficial gut microbe Lactobacillus spp., effectively prevent ETBF-mediated gut pathogenesis, preserving the healthy state of the µGut through competition-mediated colonization resistance. The GMoC holds potential as a valuable tool for exploring unknown roles of gut microbes in microbe-induced pathogenesis and microbe-based therapeutic development.

With genetic information gained from next-generation sequencing (NGS) and genome-wide association studies (GWAS), it is now possible to select for genes that encode reporter molecules that may be used to detect abnormalities such as alcohol-related liver disease (ARLD), cancer, cognitive impairment, multiple sclerosis (MS), diabesity, and ischemic stroke (IS). This, however, requires a thorough understanding of the gut-brain axis (GBA), the effect diets have on the selection of gut microbiota, conditions that influence the expression of microbial genes, and human physiology. Bacterial metabolites such as short-chain fatty acids (SCFAs) play a major role in gut homeostasis, maintain intestinal epithelial cells (IECs), and regulate the immune system, neurological, and endocrine functions. Changes in butyrate levels may serve as an early warning of colon cancer. Other cancer-reporting molecules are colibactin, a genotoxin produced by polyketide synthetase-positive Escherichia coli strains, and spermine oxidase (SMO). Increased butyrate levels are also associated with inflammation and impaired cognition. Dysbiosis may lead to increased production of oxidized low-density lipoproteins (OX-LDLs), known to restrict blood vessels and cause hypertension. Sudden changes in SCFA levels may also serve as a warning of IS. Early signs of ARLD may be detected by an increase in regenerating islet-derived 3 gamma (REG3G), which is associated with changes in the secretion of mucin-2 (Muc2). Pro-inflammatory molecules such as cytokines, interferons, and TNF may serve as early reporters of MS. Other examples of microbial enzymes and metabolites that may be used as reporters in the early detection of life-threatening diseases are reviewed.

Colorectal cancer (CRC) is a substantial source of global morbidity and mortality in dire need of improved prevention and treatment strategies. As our understanding of CRC grows, it is becoming increasingly evident that the gut microbiota, consisting of trillions of microorganisms in direct interface with the colon, plays a substantial role in CRC development and progression. Understanding the roles that individual microorganisms and complex microbial communities play in CRC pathogenesis, along with their attendant mechanisms, will help yield novel preventive and therapeutic interventions for CRC. In this Review, we discuss recent evidence concerning global perturbations of the gut microbiota in CRC, associations of specific microorganisms with CRC, the underlying mechanisms by which microorganisms potentially drive CRC development and the roles of complex microbial communities in CRC pathogenesis. While our understanding of the relationship between the microbiota and CRC has improved in recent years, our findings highlight substantial gaps in current research that need to be filled before this knowledge can be used to the benefit of patients.

The role of gut microbe-derived metabolites in the development of metabolic syndrome (MetS) remains unclear. This study aimed to evaluate the associations of gut microbe-derived metabolites and MetS traits in the cross-sectional Metabolic Syndrome In Men (METSIM) study. The sample included 10,194 randomly related men (age 57.65 ± 7.12 years) from Eastern Finland. Levels of 35 metabolites were tested for associations with 13 MetS traits using lasso and stepwise regression. Significant associations were observed between multiple MetS traits and 32 metabolites, three of which exhibited particularly robust associations. N-acetyltryptophan was positively associated with Homeostatic Model Assessment for Insulin Resistant (HOMA-IR) (β = 0.02, p = 0.033), body mass index (BMI) (β = 0.025, p = 1.3 × 10-16), low-density lipoprotein cholesterol (LDL-C) (β = 0.034, p = 5.8 × 10-10), triglyceride (0.087, p = 1.3 × 10-16), systolic (β = 0.012, p = 2.5 × 10-6) and diastolic blood pressure (β = 0.011, p = 3.4 × 10-6). In addition, 3-(4-hydroxyphenyl) lactate yielded the strongest positive associations among all metabolites, for example, with HOMA-IR (β = 0.23, p = 4.4 × 10-33), and BMI (β = 0.097, p = 5.1 × 10-52). By comparison, 3-aminoisobutyrate was inversely associated with HOMA-IR (β = -0.19, p = 3.8 × 10-51) and triglycerides (β = -0.12, p = 5.9 × 10-36). Mendelian randomization analyses did not provide evidence that the observed associations with these three metabolites represented causal relationships. We identified significant associations between several gut microbiota-derived metabolites and MetS traits, consistent with the notion that gut microbes influence metabolic homeostasis, beyond traditional risk factors.

The gut microbiome plays a crucial role in various diseases, and its regulation is a potential treatment option for these conditions. However, the relationship between the gut microbiome and venous thromboembolism (VTE) remains poorly explored.

In this study, we collected feces and serum samples from 8 VTE patients and 7 healthy controls. The gut microbiota and serum metabolites were analyzed using 16S rRNA gene sequencing and liquid chromatography-mass spectrometry, respectively. Additionally, a combined analysis of microbiota and metabolome was performed.

The alpha and beta diversity between the VTE and control groups were significantly different. Patients with VTE exhibited an overgrowth of Blautia, Roseburia, Coprococcus, and Ruminococcus. Moreover, serum metabolomics analysis revealed altered levels of choline and lithocholic acid. Pathway enrichment analysis indicated a significant upregulation of bile secretion pathways. In addition, a positive correlation was observed between the levels of serum choline and lithocholic acid and the abundance of gut flora enriched in the VTE group.

This study provided novel insights into the disordered gut microbiota and serum metabolome associated with VTE, suggesting potential common pathological mechanisms between VTE and arterial thrombosis. Targeted modulation of the gut microbiome may hold promise as a preventive and therapeutic approach for VTE.

Although rumen development is crucial, hindgut undertakes a significant role in young ruminants' physiological development. High-starch diet is usually used to accelerate rumen development for young ruminants, but always leading to the enteral starch overload and hindgut dysbiosis. However, the mechanism behind remains unclear. The combination of colonic transcriptome, colonic luminal metabolome, and metagenome together with histological analysis was conducted using a goat model, with the aim to identify the potential molecular mechanisms behind the disrupted hindgut homeostasis by overload starch in young ruminants.

Compared with low enteral starch diet (LES), high enteral starch diet (HES)-fed goats had significantly higher colonic pathology scores, and serum diamine oxidase activity, and meanwhile significantly decreased colonic mucosal Mucin-2 (MUC2) protein expression and fecal scores, evidencing the HES-triggered colonic systemic inflammation. The bacterial taxa Prevotella sp. P4-67, Prevotella sp. PINT, and Bacteroides sp. CAG:927, together with fungal taxa Fusarium vanettenii, Neocallimastix californiae, Fusarium sp. AF-8, Hypoxylon sp. EC38, and Fusarium pseudograminearum, and the involved microbial immune pathways including the "T cell receptor signaling pathway" were higher in the colon of HES goats. The integrated metagenome and host transcriptome analysis revealed that these taxa were associated with enhanced pathogenic ability, antigen processing and presentation, and stimulated T helper 2 cell (TH2)-mediated cytokine secretion functions in the colon of HES goats. Further luminal metabolomics analysis showed increased relative content of chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), and decreased the relative content of hypoxanthine in colonic digesta of HES goats. These altered metabolites contributed to enhancing the expression of TH2-mediated inflammatory-related cytokine secretion including GATA Binding Protein 3 (GATA3), IL-5, and IL-13. Using the linear mixed effect model, the variation of MUC2 biosynthesis explained by the colonic bacteria, bacterial functions, fungi, fungal functions, and metabolites were 21.92, 20.76, 19.43, 12.08, and 44.22%, respectively. The variation of pathology scores explained by the colonic bacterial functions, fungal functions, and metabolites were 15.35, 17.61, and 57.06%.

Our findings revealed that enteral starch overload can trigger interrupted hindgut host-microbiome homeostasis that led to impaired mucosal, destroyed colonic water absorption, and TH2-mediated inflammatory process. Except for the colonic metabolites mostly contribute to the impaired mucosa, the nonnegligible contribution from fungi deserves more future studies focused on the fungal functions in hindgut dysbiosis of young ruminants. Video Abstract.

Many of the health-associated impacts of the microbiome are mediated by its chemical activity, producing and modifying small molecules (metabolites). Thus, microbiome metabolite quantification has a central role in efforts to elucidate and measure microbiome function. In this review, we cover general considerations when designing experiments to quantify microbiome metabolites, including sample preparation, data acquisition and data processing, since these are critical to downstream data quality. We then discuss data analysis and experimental steps to demonstrate that a given metabolite feature is of microbial origin. We further discuss techniques used to quantify common microbial metabolites, including short-chain fatty acids (SCFA), secondary bile acids (BAs), tryptophan derivatives, N-acyl amides and trimethylamine N-oxide (TMAO). Lastly, we conclude with challenges and future directions for the field.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and severe fibrosis for which effective treatment options are currently lacking. In this study, we explored the potential of beta-lapachone (βL) as a drug candidate for PSC therapy.

We employed an animal model fed a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to assess the preventive and therapeutic effects of βL. The beneficial effects of βL on PSC pathogenic characteristics, including blood biomarkers, inflammation, and fibrosis, were determined by assessing relevant parameters. Differential gene expression between each group was analyzed by RNA sequencing of liver tissues. Mdr2-/- mice were utilized to explore the involvement of Abcb4 in the βL-induced improvement of PSC pathogenesis.

βL effectively inhibited key features of PSC pathogenesis, as demonstrated by reduced blood biomarkers and improved pathogenic characteristics. Treatment with βL significantly mitigated DDC-induced apoptosis, cell proliferation, inflammation, and fibrosis. Analysis of differential gene expression confirmed a new insight that βL could stimulate the expression of genes related to NAD synthesis and Abcb4. Indeed, βL-induced NAD exhibited effective functioning, as evidenced by enhanced sirt1/3 and acetyl-lysine levels, leading to improved mitochondrial stability. The role of Abcb4 in response to βL was confirmed in Mdr2/Abcb4 KO mice, where the beneficial effects of βL were abolished.

This study provided a new concept for PSC treatment, suggesting that pharmacological stimulation of the NAD synthetic pathway and Abcb4 via βL ameliorates PSC pathogenesis.

Evidence from clinical trials and observational studies on the association between thiazide diuretics and colorectal cancer risk is conflicting. We aimed to determine whether thiazide diuretics are associated with an increased colorectal cancer risk compared with dihydropyridine calcium channel blockers (dCCBs). A population-based, new-user cohort was assembled using the UK Clinical Practice Research Datalink. Between 1990-2018, we compared thiazide diuretic initiators with dCCB initiators and estimated hazard ratios (HR) with 95% confidence intervals (CIs) of colorectal cancer using Cox proportional hazard models. Models were weighted using standardized morbidity ratio weights generated from calendar time-specific propensity scores. The cohort included 377,760 thiazide diuretic initiators and 364,300 dCCB initiators, generating 3,619,883 person-years of follow-up. Compared with dCCBs, thiazide diuretics were not associated with colorectal cancer (weighted HR = 0.97, 95% CI: 0.90, 1.04). Secondary analyses yielded similar results, although an increased risk was observed among patients with inflammatory bowel disease (weighted HR = 2.45, 95% CI: 1.13, 5.35) and potentially polyps (weighted HR = 1.46, 95% CI: 0.93, 2.30). Compared with dCCBs, thiazide diuretics were not associated with an overall increased colorectal cancer risk. While these findings provide some reassurance, research is needed to corroborate the elevated risks observed among patients with inflammatory bowel disease and history of polyps.

Sterols can be metabolized by gut microbiota. The cholesterol metabolites have been proposed as promoters of colorectal cancer (CRC), while the effect of plant sterol metabolites is unknown. This study aimed to evaluate the cytotoxicity of metabolites from cholesterol (coprostanol, cholestanol, coprostanone and cholestenone) and β-sitosterol (ethylcoprostanol) on human colon tumor (Caco-2) and non-tumor (CCD-18Co) cells at physiological concentrations (9-300 μM) and exposure time (24 h). Ethylcoprostanol reduced the tumor cell proliferation (MTT), showing in flow cytometry assays induction of apoptosis via production of reactive oxygen species (ROS) and ceramide. Transcriptomic analysis (qPCR) showed activation of the intrinsic apoptosis pathway (BAX/BCL2 ratio and CASP9 increased), accompanied by downregulation of the p21 gene. Cholesterol metabolites, mainly the most hydrophobic, induced apoptosis and G0/G1 phase arrest in non-tumor cells through overproduction of ROS. Both the intrinsic and extrinsic (CASP8 increased) apoptosis pathways occurred. In turn, a reduction in the expression of the cyclin E1 gene confirmed the cell cycle arrest. In addition, ethylcoprostanol protected non-tumor cells from the most cytotoxic cholesterol metabolite (cholestenone). In conclusion, ethylcoprostanol is a promising candidate as a therapeutic adjuvant in CRC, while cholesterol metabolites could act as CRC promoters through their cytotoxicity.

Deoxycholic acid (DCA) has been authorized by the Federal Drug Agency for cosmetic reduction of redundant submental fat. The hydroxylated product (6β-OH DCA) was developed to improve the solubility and pharmaceutic properties of DCA for further applications. Herein, a combinatorial catalytic strategy was applied to construct a powerful Cytochrome P450 biocatalyst (CYP107D1, OleP) to convert DCA to 6β-OH DCA. Firstly, the weak expression of OleP was significantly improved using pRSFDuet-1 plasmid in the E. coli C41 (DE3) strain. Next, the supply of heme was enhanced by the moderate overexpression of crucial genes in the heme biosynthetic pathway. In addition, a new biosensor was developed to select the appropriate redox partner. Furthermore, a cost-effective whole-cell catalytic system was constructed, resulting in the highest reported conversion rate of 6β-OH DCA (from 4.8% to 99.1%). The combinatorial catalytic strategies applied in this study provide an efficient method to synthesize high-value-added hydroxylated compounds by P450s.