2'-Fucosyllactose (2'-FL), a predominant human milk oligosaccharide, plays a crucial role in the development of the infant gut microbiota and immune system. However, the microbiota of infants with atopic dermatitis (AD) often has difficulty utilizing 2'-FL. Here, we found that strains from human milk, Bifidobacterium bifidum FN120 and Bifidobacterium longum subsp. longum FN103, utilized 2'-FL for growth by cross-feeding. Through an ex vivo continuous fermentation system, we found that 2'-FL and cross-feeding bifidobacteria synergistically enhanced the production of short-chain fatty acids (SCFAs), particularly acetate and propionate, while reshaping the gut microbiota in infants with AD. The reshaped microbiota was then transplanted into oxazolone-induced mice. We observed that AD symptoms in mice were effectively prevented, with significant changes in the ileum microbiota and increased intestinal SCFA levels. RNA sequencing analysis of Peyer's patches in the small intestine revealed activation of the retinol metabolic pathway. Nontargeted metabolomics analysis revealed a significant increase in plasma retinoate levels, which correlated markedly with AD-related markers. Collectively, our study demonstrated that supplementation with cross-feeding bifidobacteria and 2'-FL reshaped the gut microbiota, activated retinol metabolic pathways, promoted immune tolerance, and thereby prevented AD. Our findings provide novel insights into the therapeutic potential of combining prebiotics and probiotics to modulate the gut - skin axis and support immune tolerance in early life, offering a promising strategy for infantile AD management and prevention.

The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance, which could be influenced by differences in microbiota, and yet no study design has capitalized upon this natural variation. We leveraged natural behavioral variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained sustained antinociception. Mice that did not develop tolerance maintained a higher capacity for production of the short-chain fatty acid (SCFA) butyrate known to bolster intestinal barriers and promote neuronal homeostasis. Both fecal microbial transplantation (FMT) from donor mice that did not develop tolerance and dietary butyrate supplementation significantly reduced the development of tolerance independently of suppression of systemic inflammation. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.

The gut microbiota-derived metabolite indole-3-propionic acid (IPA) plays an important role in maintaining intestinal mucosal homeostasis, while the molecular mechanisms underlying IPA regulation on mucosal CD4+ T cell functions in inflammatory bowel disease (IBD) remain elusive. Here we investigated the roles of IPA in modulating mucosal CD4+ T cells and its therapeutic potential in treatment of human IBD. Leveraging metabolomics and microbial community analyses, we observed that the levels of IPA-producing microbiota (e.g. Peptostreptococcus, Clostridium, and Fournierella) and IPA were decreased, while the IPA-consuming microbiota (e.g. Parabacteroides, Erysipelatoclostridium, and Lachnoclostridium) were increased in the feces of IBD patients than those in healthy donors. Dextran sulfate sodium (DSS)-induced acute colitis and CD45RBhighCD4+ T cell transfer-induced chronic colitis models were then established in mice and treated orally with IPA to study its role in intestinal mucosal inflammation in vivo. We found that oral administration of IPA attenuated mucosal inflammation in both acute and chronic colitis models in mice, as characterized by increased body weight, and reduced levels of pro-inflammatory cytokines (e.g. TNF-α, IFN-γ, and IL-17A) and histological scores in the colon. We further utilized RNA sequencing, molecular docking simulations, and surface plasmon resonance analyses and identified that IPA exerts its biological effects by interacting with heat shock protein 70 (HSP70), leading to inducing Th1/Th17 cell apoptosis. Consistently, ectopic expression of HSP70 in CD4+ T cells conferred resistance to IPA-induced Th1/Th17 cell apoptosis. Therefore, these findings identify a previously unrecognized pathway by which IPA modulates intestinal inflammation and provide a promising avenue for the treatment of IBD.

Tryptophan-derived indoles produced by the gut microbiota, particularly indole-3-propionate (IPA), are key compounds associated with gastrointestinal balance and overall health. Reduced levels of IPA have been associated with inflammatory bowel disease, type 2 diabetes, and colorectal cancer. Since fiber-rich diets have been shown to promote IPA, we aimed to decipher fiber-specific effects and identify associated IPA-producing taxa in a range of healthy individuals. We cultured fecal microbiota from 16 adults with tryptophan and eight different dietary fibers and monitored community shifts by 16S rRNA gene amplicon sequencing and tryptophan-derived indoles using targeted liquid chromatography with diode array detection. The concentrations and types of indoles produced were donor-specific, with pectin strongly promoting IPA production in certain donors. IPA production was not associated with any known IPA producer but with the pectin-utilizing species Lachnospira eligens, which produced indole-3-lactate (ILA) in vitro, the IPA precursor. Supplementation of ILA in additional fecal microbiota cultures (n = 6) revealed its effective use as a substrate for IPA production. We identified a novel IPA producer, Enterocloster aldenensis, which produced IPA exclusively from ILA but not from tryptophan. Co-culture of L. eligens and E. aldenensis resulted in IPA production, providing new evidence for an ILA cross-feeding mechanism that may contribute to the IPA-promoting effects observed with pectin. Overall, we highlight the potential for targeted dietary interventions to promote beneficial gut taxa and metabolites.

The tumor microenvironment (TME) is a complex ecosystem that plays a crucial role in tumor progression and response to therapy. The metabolic characteristics of the TME are fundamental to its function, influencing not only cancer cell proliferation and survival but also the behavior of immune cells within the tumor. Metabolic reprogramming-where cancer cells adapt their metabolic pathways to support rapid growth and immune evasion-has emerged as a key factor in cancer immunotherapy. Recently, the potential of engineered bacteria in cancer immunotherapy has gained increasing recognition, offering a novel strategy to modulate TME metabolism and enhance antitumor immunity. This review summarizes the metabolic properties and adaptations of tumor and immune cells within the TME and summarizes the strategies by which engineered bacteria regulate tumor metabolism. We discuss how engineered bacteria can overcome the immunosuppressive TME by reprogramming its metabolism to improve antitumor therapy. Furthermore, we examine the advantages, potential challenges, and future clinical translation of engineered bacteria in reshaping TME metabolism.

Implying connections with gut microbiome and serum metabolites, idiopathic normal pressure hydrocephalus (INPH) emerges as a prevalent neuropsychiatric condition in the elderly. Our objective was to systematically evaluate the potential causality between gut microbiome, derived metabolites, and INPH through the implementation of Mendelian randomization (MR) methodology.

We utilized summary data from extensive genome-wide association studies, encompassing 196 gut microbiomes from the MiBioGen consortium (n = 18,340), 486 serum metabolites from the KORA and TwinsUK studies (n = 7,824), and individuals with INPH (case = 767, control = 375,610), for MR causal estimates. The leading analysis utilized the inverse-variance weighted (IVW) method, supplemented by weighted mode, MR-Egger, weighted median and simple mode approaches. Sensitivity analyses included MR-Egger intercept, Cochran's Q test, leave-one-out analysis and MR-PRESSO.

Our study primarily relied on the IVW method, confirming a causality between 9 genetically predicted abundance of gut microbiomes and INPH. We found an adverse correlation with genetically predicted abundance of order Clostridiales, genus Eubacteriumeligensgroup, genus Gordonibacter, genus Ruminococcus1 concerning INPH. Conversely, class Melainabacteria, genus Eubacteriumruminantiumgroup, genus Adlercreutzia, genus Dialister, genus RikenellaceaeRC9gutgroup potentially correlated with increased INPH risk. As for derived metabolites, IVW estimates indicated a causal connection between 25 genetically predicted serum metabolites and INPH. Sensitivity analysis underscored the robustness of our findings.

Our MR analysis provides evidence supporting the causality of certain gut microbial taxa and their derived metabolites on INPH. This underscores the potential for interventions targeting specific gut microbiota and derived metabolites in the treatment and prevention of INPH.

The prevalence of childhood metabolic syndrome (MetS) and obesity is rising, with emerging evidence suggesting these conditions negatively affect oral health. However, the underlying molecular determinants are unclear. This study investigated the oral microbiome, inflammatory markers, and metabolites in children with obesity and MetS to explore the interrelationships between systemic disease and oral health. We recruited 76 periodontally healthy, caries-free individuals aged 10 to 17 y into 3 groups: MetS (29), metabolically healthy obesity (MHO) (30), and normal-weight healthy (NWH) controls (17). Unstimulated saliva was collected. Bacterial DNA was isolated, V3-V4 regions amplified, and 16S sequencing performed on the Illumina MiSeq platform. Sequences were annotated against the HOMD database. Multiplex assays quantified adipokines and cytokines, with significance determined by Tukey honestly significant difference. Gas chromatography/mass spectrometry identified metabolite peaks that were annotated against the Small Molecule Pathway Database, with enrichment analysis determining significance. Integrated multiomics analysis was performed using multiblock sparse partial least squares regression discriminant analysis. The MHO and MetS groups demonstrated lower abundances of Streptococcus, Actinomyces, and Schaalia and higher levels of Aggregatibacter, Campylobacter, Alloprevotella, Prevotella, Leptotrichia, and Porphyromonas compared with NWH, despite similar clinical oral status in all cohorts. MetS and MHO also had increased leptin, tumor necrosis factor-α, interleukin (IL)-1β, and IL-15 and decreased adiponectin levels versus NWH. Disease-associated metabolites, including glutamate, cholesterol, isoleucine, tyrosine, phenylalanine, serine, and indoleacetic acid, were significantly enriched in the MetS and MHO groups. Integrated multiomic analysis identified key correlations in the saliva of subjects with metabolic health or disease. Decreases in health-associated species and increases in proinflammatory cytokines and disease-associated metabolites in the saliva of MetS and obese adolescents with clinical oral health indicate an "at-risk" environment, potentially explaining their elevated risk for oral diseases. Increased salivary leptin and decreased adiponectin levels highlight the potential of saliva as a noninvasive biomarker source for childhood MetS.

Our previous study demonstrated that Lactobacillus acidophilus KLDS1.0901 significantly alleviated symptoms of high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and showed a strong association with the gut microbiota; however, the underlying mechanisms remained unclear. In this study, we focused on changes in intestinal metabolic pathways in mice following intervention with Lactobacillus acidophilus KLDS1.0901, using non-targeted metabolomics. Tryptophan metabolism was found to be closely associated with NAFLD alleviation, and indole-3-aldehyde (IAld) was identified as a key target. Animal experiments showed no significant differences in the levels of liver triglycerides, fasting blood glucose, alanine aminotransferase, aspartate aminotransferase, IL-6, IL-1β, TNF-α, and IL-10 between the direct-feeding IAld group and the Lactobacillus acidophilus KLDS1.0901 group. This suggests that the IAId, produced by Lactobacillus acidophilus KLDS1.0901, is the key intermediate mediator responsible for its improvement of NAFLD. The alleviating effect of Lactobacillus acidophilus KLDS1.0901 on NAFLD symptoms was suppressed after the inhibition of the IAld receptor aromatic hydrocarbon receptor (AhR), suggesting that the bacterium relies on the AhR signaling pathway to mediate its effect on NAFLD. Cellular experiments showed that IAld significantly reduced triglyceride content, decreased lipid accumulation, and increased glycogen levels in oleic acid-induced cells. The effects of IAld on gene transcription levels in oleic acid-induced HepG2 cells were further analyzed using high-throughput sequencing. Transcriptomic analysis revealed that IAld regulates key pathways, including the NF-κB, chemokine and AGE-RAGE signaling pathways. Our study identified the ameliorative effects of tryptophan metabolites, particularly IAld, on NAFLD, along with the underlying mechanisms, offering new insights into potential treatment strategies for NAFLD.

The purpose of the study was to calculate the relative intake of animal source energy (animal source energy percentage, ASEP) and examine its utility in nutrition and metabolic research with a special attention on children. In addition, the capacity of ASEP to identify potential metabolic biomarkers of plant-forward diets was tested. Four-day food records and 7-day dietary screeners of 51 Finnish children aged 1-7 years, consuming a vegan (n = 7), pesco-/lacto-/ovo-vegetarian (n = 11) or omnivorous diet (n = 33), were used for assessing general performance of ASEP as diet measure. Blood samples of 40 children (six vegans, eight vegetarians, 26 omnivores) were analyzed for plasma LDL cholesterol, erythrocyte folate concentration and serum untargeted MS-metabolomics. Estimated ASEPs varied between 0% and 52%. Vegetarians and omnivores showed overlapping ASEPs. ASEP had a strong positive correlation with saturated fatty acid (percent of energy, E%; r = 0.785) and cholesterol intake (r = 0.715) and a strong negative correlation with fibre (r = - 0.811) and polyunsaturated fatty acid (E%; r = - 0.819) intake. ASEP also correlated with plasma LDL cholesterol (r = 0.699) concentration. Serum indoleacrylic acid (IAA) is suggested to be further investigated as a possible biomarker of plant-forward diet. ASEP provides a useful tool for objective and quantitative assessment of diet characteristics in research.

This study evaluates the efficacy of the postbiotic Probio-Eco in alleviating constipation in humans and mice. A randomized, double-blind, placebo-controlled crossover trial involving 110 adults with chronic constipation (Rome IV criteria) demonstrates that a 3-week Probio-Eco intervention significantly improves constipation symptoms, stool straining, and worry scores. Gut microbiota and metabolomic analyses reveal modulations in specific gut microbiota, succinate, tryptophan derivatives, deoxycholate, propionate, butyrate, and cortisol, correlating with symptom relief. A loperamide-induced mouse model confirms that Probio-Eco and its bioactive components (succinate, 3-indoleacrylic acid, and 5-hydroxytryptophan) alleviate constipation by stimulating mucin-2 secretion, regulating intestinal transport hormones, and promoting anti-inflammatory responses. Multi-omics integration identifies key pathways, including succinate-short-chain fatty acid, tryptophan-5-hydroxytryptophan-serotonin, and tryptophan-3-indoleacrylic acid, driving intestinal homeostasis and motility. These findings highlight the comprehensive efficacy of Probio-Eco and provide robust evidence for its clinical application in constipation management. This study was registered at Chinese Clinical Trial Registry (ChiCTR2100054376).

It is argued that commensal bacteria in the upper respiratory tract (URT) protect against pathogen colonization and infection, including respiratory viruses. Given that the microbiome can mediate immune modulation, a link between the URT microbiome (URTM) and COVID-19 susceptibility and severity is expected. This 16S metagenomics cross-sectional study assessed URTM composition, metabolic prediction, and association with laboratory biomarkers in non-COVID-19 pneumonia (NO-CoV), moderate (M-CoV), severe (S-CoV) COVID-19 patients, as well as COVID-19-negative, asymptomatic (NC) patients. The S-CoV group exhibited reduced URTM diversity, primarily due to a decreased abundance of eubiotic taxa. Some of these taxa (e.g., Haemophilus sp., Neisseria sp.) were also associated with inflammatory biomarkers. Multiple metabolic pathways (e.g., short-chain fatty acids, vitamin B12) linked to immune response, antiviral activity, and host susceptibility showed decreased abundance in S-CoV. These pathways could suggest potential alternatives for the therapeutic arsenal against COVID-19, providing reassurance about the progress in understanding and treating this disease.

Derivation of Qingchang Huashi formula, named Qingchang Huashi Jianpi Bushen (QCHS_JPBS) formula, has shown significant therapeutic effect on patients with ulcerative colitis (UC). In this study, the potential mechanism of QCHS_JPBS formula in repairing mucosal damage was explored from the perspective of intestinal stem cell (ISCs) differentiation, and potential targets of the QCHS_JPBS formula to improve UC were predicted using network pharmacology analysis.

The therapeutic efficacy of QCHS_JPBS formula was evaluated in a mouse model of 2.5% dextran sulfate sodium (DSS) induced colitis. The effect of this formula on the ISC differentiation was evaluated using tissue transmission electron microscopy, immunofluorescence, and RT-qPCR. The cecal contents were subjected to 16s RNA sequencing analysis and non-target metabolomics analysis using LC-MS/MS. The fecal microbiota transplantation method verified the essential role of gut microbiota in promoting ISC differentiation and repairing mucosal damage.

The results indicated that QCHS_JPBS formula suppressed the inflammatory response and repaired the damaged intestinal epithelial barrier in DSS-induced colitis mice. QCHS_JPBS formula promoted ISC differentiation, particularly in the direction of goblet cells. QCHS_JPBS formula restored gut dysbiosis and regulated metabolic disorders in DSS-induced colitis mice. And then, the results of fecal microbiota transplantation indicated that QCHS_JPBS formula promoted differentiation of intestinal stem cells to repair mucosal damage through gut microbiota. Finally, a total of 79 active ingredients of QCHS_JPBS formula were identified based on LC-MS analysis and EGFR, STAT3, SRC, AKT1, and HSP90AA1 were considered as potential therapeutic UC targets of QCHS_JPBS formula based on network pharmacology analysis.

The present study demonstrated that QCHS_JPBS formula promoted the differentiation of ISCs through gut microbiota to repair the damaged intestinal epithelial barrier in UC mice.

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the intestine, frequently complicated by intestinal fibrosis. As fibrosis progresses, it can result in luminal stricture and compromised intestinal function, significantly diminishing patients' quality of life. Emerging evidence suggests that gut microbiota and their metabolites contribute to the pathogenesis of IBD-associated intestinal fibrosis by influencing inflammation and modulating immune responses. This review systematically explores the mechanistic link between gut microbiota and intestinal fibrosis in IBD and evaluates the therapeutic potential of traditional Chinese medicine (TCM) interventions. Relevant studies were retrieved from PubMed, Web of Science, Embase, Scopus, CNKI, Wanfang, and VIP databases. Findings indicate that TCM, including Chinese herbal prescriptions and bioactive constituents, can modulate gut microbiota composition and microbial metabolites, ultimately alleviating intestinal fibrosis through anti-inflammatory, immunemodulatory, and anti-fibrotic mechanisms. These insights highlight the potential of TCM as a promising strategy for targeting gut microbiota in the management of IBD-associated fibrosis.

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder globally. Probiotic supplementation has shown promise in its prevention and treatment. Although Weissella viridescens, a lactic acid bacterium with immunomodulatory effects, has antibacterial and anti-inflammatory activities, there is a lack of direct evidence for its role in alleviating MASLD. This study aimed to investigate the protective effects of W. viridescens strain Wv2365, isolated from healthy human feces, in a high-fat diet (HFD)-induced rat model of MASLD. Methods: Rats were randomly assigned to a normal chow diet (NC), high-fat diet (HFD), and HFD supplemented with W. viridescens Wv2365 (Wv2365) groups. All groups were fed their respective diets for 8 weeks. During this period, the NC and HFD groups received a daily oral gavage of PBS, while the Wv2365 group received a daily oral gavage of Wv2365. Results: Wv2365 supplementation significantly reduced HFD-induced body weight gain, improved NAFLD activity scores, alleviated hepatic injury, and restored lipid metabolism. A liver transcriptomic analysis revealed the downregulation of inflammation-related pathways, along with decreased serum levels of TNF-α, IL-1β, IL-6, MCP-1, and LPS. Wv2365 also activated the Nrf2/HO-1 antioxidant pathway, enhanced hepatic antioxidant enzyme activities and reduced malondialdehyde levels. A gut microbiota analysis showed the enrichment of beneficial genera, including Butyricicoccus, Akkermansia, and Blautia. Serum metabolomic profiling revealed increased levels of metabolites including indole-3-propionic acid, indoleacrylic acid, and glycolithocholic acid. Conclusions: Wv2365 attenuates hepatic injury, oxidative stress, and inflammation in a rat model of high-fat-diet-induced MASLD, supporting its potential as a probiotic candidate for the modulation of MASLD.

Diarrheal diseases remain a major public health concern, particularly in regions with poor sanitation. Polysaccharides extracted from natural gums have been investigated as functional agents for intestinal health, and their fractionation enables the production of oligosaccharides with potential prebiotic activity. This study aimed to produce cashew gum (CG) fractions through Smith degradation (CGD48) and partial hydrolysis (CGD24) and to evaluate their ability to modulate and protect the intestinal microbiota. Balb/c mice were administered CG (1200 mg/kg), CGD24 (800 mg/kg), or CGD48 (800 mg/kg) for 10 and 26 days, followed by infection with Shiga toxin-producing Escherichia coli (STEC) (5 × 1010 CFU/mL) for three days. Characterization assays confirmed the fragmentation of CG. Both CGD24 and CGD48 promoted the growth of beneficial bacteria with and without infection and reduced STEC colonization. Furthermore, they preserved mucin levels in the cecum and large intestine and maintained baseline levels of superoxide dismutase (SOD), suggesting protection of the intestinal mucosa. These findings indicate that CG fractions exhibit microbiota-modulating and protective effects against STEC, highlighting their therapeutic potential and the need for further studies to elucidate the underlying mechanisms.

Tumor is one of the leading causes of death worldwide. The occurrence and development of tumors are related to multiple systems and factors such as the immune system, gut microbiota, and nervous system. The immune system plays a critical role in tumor development. Studies have also found that the gut microbiota can directly or indirectly affect tumorigenesis and tumor development. With increasing attention on the tumor microenvironment in recent years, the nervous system has emerged as a novel regulator of tumor development. Some tumor therapies based on the nervous system have also been tested in clinical trials. However, the nervous system can not only directly interact with tumor cells but also indirectly affect tumor development through the gut microbiota. The nervous system-mediated gut microbiota can regulate tumorigenesis, growth, invasion, and metastasis through the immune system. Here, we mainly explore the potential effects of the nervous system-gut microbiota-immune system axis on tumorigenesis and tumor development. The effects of the nervous system-gut microbiota-immune system axis on tumors involve the nervous system regulating immune cells through the gut microbiota, which can prevent tumor development. Meanwhile, the direct effects of the gut microbiota on tumors and the regulation of the immune system by the nervous system, which can affect tumor development, are also reviewed.

Tryptophan (Trp), an essential amino acid obtained through dietary sources, plays a crucial role in various physiological processes. The metabolism of Trp branches into three principal pathways: the serotonin pathway, the kynurenine pathway, and the indole pathway. The kynurenine and serotonin pathways are host pathways while the indole pathway is solely the result of bacterial metabolism. Trp metabolites extend their influence beyond protein biosynthesis to affect a spectrum of pathophysiological mechanisms including, but not limited to, neuronal function, immune modulation, inflammatory responses, oxidative stress regulation, and maintenance of intestinal health. This review focuses on indole derivatives and their impact on vascular health. Trp-containing dipeptides are highlighted as a targeted nutraceutical approach to modulate Trp metabolism, enhance beneficial metabolite production, and mitigate risk factors for vascular diseases. The importance of optimizing Trp intake and dietary strategies to harness the benefits of Trp-derived metabolites for vascular health is underscored, bringing to light the need for further research to refine these therapeutic approaches.

Fluxapyroxad is the most commonly used succinate dehydrogenase inhibitor fungicide. This work investigated its adverse effects on colitis susceptibility and explored the underlying mechanisms based on a mouse model. After 13 weeks of exposure at the acceptable daily intake (ADI) level, fluxapyroxad exacerbated the susceptibility to colitis, impaired the intestinal barrier, and elevated proinflammatory cytokines and chemokines of the colon in mice. It was found that this toxic effect was caused by the disruption of the gut microbiome. Specifically, the abundance of Lachnospiraceae and Muribaculaceae decreased, while Desulfovibrionaceae and Eggerthellaceae increased. Altered microbiota reduced fecal indole derivatives, including indole-3-lactic acid (ILA), indole-3-acetic acid (IAA), and indole-3-acrylic acid (IArA), inhibiting aryl hydrocarbon receptor (AHR) activation, disrupting immune homeostasis by overactivating Th17 cells and insufficient Treg cell differentiation, and causing mild colonic inflammation. Oral antibiotic-treated mice and fecal transfer experiments validated the pathway. Susceptibility to colitis induced by fluxapyroxad was not detected in the oral antibiotic-treated mice. Fecal transfer of the disordered gut microbiota caused by fluxapyroxad could aggravate the severity of colitis in recipient oral antibiotic-treated mice that did not receive fluxapyroxad exposure. In conclusion, chronic fluxapyroxad exposure at the ADI level exacerbated colitis via a gut microbiota-indole derivatives-Treg/Th17 cell balance axis, offering a new risk assessment perspective of fluxapyroxad.

There is an escalating need to comprehend the long-term impacts of nuclear radiation exposure since the permeation of ionizing radiation has been frequent in our current societal framework. A system evaluation of the microbes that reside inside a host's colon could meet this knowledge gap since the microbes play major roles in a host's response to stress. Indeed, our past study suggested that these microbes might break their symbiotic association with moribund hosts to form a pro-survival condition exclusive to themselves. In this study, we undertook metagenomics and metabolomics assays regarding the descending colon content (DCC) of adult mice. DCCs were collected 1 month and 6 months after 7 Gy or 7.5 Gy total body irradiation (TBI). The assessment of the metagenomic diversity profile in DCC found a significant sex bias caused by TBI. Six months after 7.5 Gy TBI, decreased Bacteroidetes were replaced by increased Firmicutes in males, and these alterations were reflected in the functional analysis. For instance, a larger number of networks linked to small chain fatty acid (SCFA) synthesis and metabolism were inhibited in males than in females. Additionally, bioenergy networks showed regression dynamics in females at 6 months post-TBI. Increased accumulation of glucose and pyruvate, which are typical precursors of beneficial SCFAs coupled with the activated networks linked to the production of reactive oxygen species, suggest a cross-sex energy-deprived state. Overall, there was a major chronic adverse implication in male mice that supported the previous literature in suggesting females are more radioresistant than males. The sex-biased chronic effects of TBI should be taken into consideration in designing the pertinent therapeutics.

Insulin overdose may cause hypoglycemic encephalopathy. In this study, Mendelian randomization was employed to analyze changes in the serum metabolites of patients with hypoglycemic encephalopathy, and metabolomics analysis was conducted to detect differential metabolites in the serum of a rat model of hypoglycemic encephalopathy induced by insulin overdose. The results indicated an overall upward trend in the tryptophan metabolism pathway in patients with hypoglycemic encephalopathy and rats with hypoglycemic encephalopathy caused by insulin overdose, while serum glutamate levels declined. The metabolic changes in the tryptophan pathway provide new insights into the impact of hypoglycemia on brain function. The related products of the tryptophan metabolism pathway have a certain diagnostic value for hypoglycemic encephalopathy and forensic identification of insulin overdose-induced hypoglycemic encephalopathy death.

Gastric ulcer is a multifaceted ailment of multiple causes and is chronic warranting the discovery of remedies to alleviate its symptoms and severity. Pancratium maritimum L. is recognized for its several health benefits, although its potential against gastric ulcers has yet to be reported.

This study reports on the effects of P. maritimum L. whole plant (PM-EtOH) ethanol extract at a dose of 25, 50, and 100 mg/kg body weight orally for managing ethanol-induced peptic ulcer in rats. The anti-ulceration capacity of PM-EtOH was determined against ethanol (EtOH)-induced rats via biochemical, histological, immunohistochemical, and western blotting assays. The profiling of the bioactive metabolites in P. maritimum extract was based on Ultra-high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-qTOF-MS/MS) analysis. Following PM-EtOH treated group, the gastric glutathione (GSH) level dropped in the ulcer group receiving ethanol was restored to normal levels. Additionally, following PM-EtOH, elevated malondialdehyde (MDA) content in the stomach tissues diminished. PM-EtOH treated group displayed recovery and comparable morphology compared with normal group, concurrent with lower levels of Tumor Necrosis Factor α (TNF-α), MyD88, and NLRP3, along with low expression of Nuclear Factor kappa β (NF-кβ) and high-mobility group box protein 1 (HMGB1) proteins. Immune-histochemicals of caspase-3 and toll-like receptors-4 (TLR-4) showed their normalization. These findings imply that PM-EtOH exerts a protective effect on rat stomach damage that has yet to be further tested in clinical trials for treatment of stomach ulcers. Phytochemical profiling of PM-EtOH via UHPLC-ESI-qTOF-MS/MS led to the identification of 84 metabolites belonging to amino acids, organic acids, phenolic acids, alkaloids, flavonoids, and fatty acids to likely mediate for the observed effects.

These outcomes provided evidence for the potential of PM-EtOH in gastric ulcers management.

The colonic mucus layer acts as a physicochemical barrier to pathogen invasion and as a habitat for mucus-associated microbes. This mucosal microbiome plays a crucial role in moderating mucus production, maintaining barrier integrity, and shaping the host immune response. However, unchecked mucin foraging may render the host vulnerable to disease. To better understand these dynamics in the mucus layer, it is essential to advance fundamental knowledge on how commensals bind to and utilize mucin as well as their interactions with both the host and their microbial neighbors. We present an overview of approaches for surveying mucus-associated bacteria and assessing their mucin-utilizing capacity, alongside a discussion of the limitations of existing methods. Additionally, we highlight how diet and host secretory immunoglobulin A interact with the mucosal bacterial community in the colon. Insights into this subset of the microbial community can guide therapeutic strategies to optimally support and modulate mucosal barrier integrity.

Recent research has highlighted the complex relationship between gut microbiota, metabolic pathways, and nonalcoholic fatty liver disease (NAFLD) progression. Gut dysbiosis, commonly observed in NAFLD patients, impairs intestinal permeability, leading to the translocation of bacterial products like lipopolysaccharides, short-chain fatty acids, and ethanol to the liver. These microbiome-associated mechanisms contribute to intestinal and hepatic inflammation, potentially advancing NAFLD to NASH. Dietary habits, particularly those rich in saturated fats and fructose, can modify the microbiome composition, leading to dysbiosis and fatty liver development. Metabolomic approaches have identified unique profiles in NASH patients, with specific metabolites like ethanol linked to disease progression. While bariatric surgery has shown promise in preventing NAFLD progression, the role of gut microbiome and metabolites in this improvement remains to be proven. Understanding these microbiome-related pathways may provide new diagnostic and therapeutic targets for NAFLD and NASH. A comprehensive review of current literature was conducted using multiple medical research databases, including PubMed, Scopus, Web of Science, Embase, Cochrane Library, ClinicalTrials.gov, ScienceDirect, Medline, ProQuest, and Google Scholar. The review focused on studies that examine the relationship between gut microbiota composition, metabolic pathways, and NAFLD progression. Key areas of interest included microbial dysbiosis, endotoxin production, and the influence of diet on gut microbiota. The analysis revealed that gut dysbiosis contributes to NAFLD through several mechanisms, diet significantly influences gut microbiota composition, which in turn affects liver function through the gut-liver axis. High-fat diets can lead to dysbiosis, altering microbial metabolic activities and promoting liver inflammation. Specifically, gut microbiota-mediated generation of saturated fatty acids, such as palmitic acid, can activate liver macrophages and increase TNF-α expression, contributing to NASH development. Different dietary components, including cholesterol, fiber, fat, and carbohydrates, can modulate the gut microbiome and influence NAFLD progression. This gut-liver axis plays a crucial role in maintaining immune homeostasis, with the liver responding to gut-derived bacteria by activating innate and adaptive immune responses. Microbial metabolites, such as bile acids, tryptophan catabolites, and branched-chain amino acids, regulate adipose tissue and intestinal homeostasis, contributing to NASH pathogenesis. Additionally, the microbiome of NASH patients shows an elevated capacity for alcohol production, suggesting similarities between alcoholic steatohepatitis and NASH. These findings indicate that targeting the gut microbiota may be a promising approach for NASH treatment and prevention. Recent research highlights the potential of targeting gut microbiota for managing nonalcoholic fatty liver disease (NAFLD). The gut-liver axis plays a crucial role in NAFLD pathophysiology, with dysbiosis contributing to disease progression. Various therapeutic approaches aimed at modulating gut microbiota have shown promise, including probiotics, prebiotics, synbiotics, fecal microbiota transplantation, and dietary interventions. Probiotics have demonstrated efficacy in human randomized controlled trials, while other interventions require further investigation in clinical settings. These microbiota-targeted therapies may improve NAFLD outcomes through multiple mechanisms, such as reducing inflammation and enhancing metabolic function. Although lifestyle modifications remain the primary recommendation for NAFLD management, microbiota-focused interventions offer a promising alternative for patients struggling to achieve weight loss targets.

Inorganic dietary nanoparticles (IDNPs) are frequently utilized as food additives and in packaging, resulting in their exposure becoming a substantial yet often overlooked concern for patients with inflammatory bowel disease (IBD). Considering that impaired intestinal barrier function plays a central role in the pathogenesis of IBD, this review concentrates on the roles and mechanisms of IDNPs in the intestinal barrier (physical, chemical, biological, and immune barriers) of IBD patients. Previous studies have shown that different types of nanoparticles have varying effects on animals in diverse states. In this context, factors such as the source, size, shape, dosage, and duration of action of the nanoparticles, as well as the species, gender, dietary habits, and age of the animals, significantly influence research outcomes. Future studies should undertake more comprehensive explorations into the effects and mechanisms of IDNPs with diverse sources and properties in IBD patients.

Tourette syndrome (TS) is a common chronic neuropsychiatric disorder with a prevalence of approximately 1% in children and adolescents. TS is characterized by sudden involuntary motor tics along with vocal tics. A pathological study on postmortem patients has reported a 50-60% reduction in striatal gamma-aminobutyric acidergic (GABAergic) interneurons, suggesting a role for GABAergic system imbalances in tic disorder development. However, the effect of exogenous GABA administration on tic alleviation remains unreported.

In this study, we aim to investigate the therapeutic effects of exogenous GABA on TS-like behaviors in Sprague-Dawley rats and explore its potential mechanisms, including gut microbiota regulation, oxidative stress mitigation, and restoration of GABA-glutamate balance, to provide insights into TS pathogenesis and alternative treatment strategies.

A TS model rat was established through intraperitoneal administration of 3,3-Iminodipropionitrile (150 mg/kg/day), followed by GABA (20 mg/kg/day) administration by gavage. 15 minutes of behavioral testing (stereotypical behavior and head twitching behavior) was then conducted. 16S rRNA sequencing identified microbiome changes, and LC-MS assessed striatal metabolite changes.

The results showed that a 4-week GABA treatment alleviated TS-like behavior in rats. GABA treatment led to an increase in Acinetobacter and other beneficial bacteria. GABA also significantly upregulated 15 striatal metabolites compared with TS group. By correlation analysis of striatal metabolites and intestinal bacteria, statistical analysis showed that Clostridium_sensu_stricto_1 was negatively correlated with metabolites on the top 20 differential gut microbiota and metabolites. Moreover, changes in gut microbiota correlated with alterations in striatal metabolites, suggesting a gut-brain axis involvement.

Exogenous GABA alleviated TS-like behavior in rats by reducing harmful gut flora and modulating striatal GABA-glutamate metabolism. Despite challenges like low blood-brain barrier permeability and dose safety in humans, GABA's therapeutic potential may be realized through prodrug development and optimized dosing. These findings are preliminary and require further clinical validation.

The immune system has long been recognized as a key driver in the progression of heart failure (HF). However, clinical trials targeting immune effectors have consistently failed to improve patient outcome across different HF aetiologies. The activation of the immune system in HF is complex, involving a broad network of pro-inflammatory and immune-modulating components, which complicates the identification of specific immune pathways suitable for therapeutic targeting. Increasing attention has been devoted to identifying gut microbial pathways that affect cardiac remodelling and metabolism and, thereby impacting the development of HF. In particular, gut microbiota-derived metabolites, absorbed by the host and transported to the peripheral circulation, can act as signalling molecules, influencing metabolism and immune homeostasis. Recent reports suggest that the gut microbiota plays a crucial role in modulating immune processes involved in HF. Here, we summarize recent advances in understanding the contributory role of gut microbiota in (auto-)immune pathways that critically determine the progression or alleviation of HF. We also thoroughly discuss potential gut microbiota-based intervention strategies to treat or decelerate HF progression.

The research aimed to assess the influence of arbuscular mycorrhizal fungi (AMF) inoculation on the growth, tolerance, and phytoremediation capacity of Alocasia calidora (Schott) G.Don used in heavy metal/metalloid-polluted soil under field conditions. Five new, young A. calidora plants were planted in each treatment and control plot (1 m × 1 m). AMF inoculum was supplemented on days 0, 30, 60, and 90 in the treatment plot, and the experiment was conducted for 120 days. Substantial growth was observed in the roots and shoots of AMF-inoculated A. calidora. In the shoots of treated A. calidora, a high accumulation of Cu, As, Ni, Mn, and Pb was observed. The AMF-treated plant exhibited a higher accumulation of Cu, Fe, and Ni in the roots (P < 0.05). The removal efficiencies in the AMF-treated soil were 84.67, 74.82, 81.61, 80.77, 88.21, 92.26, 92.35, and 67.32% for As, Cr, Cu, Fe, Mn, Ni, Pb, and Zn, correspondingly, while, for control, the corresponding values were 61.24, 52.42, 62.95, 33.46, 57.89, 61.45, 71.19, and 54.98%. AMF-treated A. calidora demonstrated an increased tolerance and metal/metalloid accumulation in response to a variety of compounds, including tryptophan, S-(4-nitrobenzyl) glutathione, 5,7,2',3'-tetrahydroxy flavone, 5,2-dihydroxy flavone, indole-acrylic acid, and various tripeptides. A. calidora proliferation, tolerance, and metal/metalloid accumulation were enhanced by the inoculated AMF. Therefore, treating soil contaminated with heavy metals/metalloids can be accomplished by combining AMF with plants.

Despite the increasing recognition of the interplay between depression and cardiovascular disease (CVD), the precise mechanisms by which depression contributes to the pathogenesis of cardiovascular disease remain inadequately understood. The involvement of gut microbiota and their metabolites to health and disease susceptibility has been gaining increasing attention. In this study, it was found that depression exacerbated cardiac injury, impaired cardiac function (EF%: P < 0.01; FS%: P < 0.05), hindered long-term survival (P < 0.01), and intensified adverse cardiac remodeling (WGA: P < 0.01; MASSON: P < 0.0001) after myocardial ischemia/reperfusion (MI/R) in mice. Then we found that mice receiving microbiota transplants from chronic social defeat stress (CSDS) mice exhibited worse cardiac function (EF%: P < 0.01; FS%: P < 0.01) than those receiving microbiota transplants from non-CSDS mice after MI/R injury. Moreover, impaired tryptophan metabolism due to alterations in gut microbiota composition and structure was observed in the CSDS mice. Mechanistically, we analyzed the metabolomics of fecal and serum samples from CSDS mice and identified indole-3-propionic acid (IPA) as a protective agent for cardiomyocytes against ferroptosis after MI/R via NRF2/System xc-/GPX4 axis, played a role in mediating the detrimental influence of depression on MI/R. Our findings provide new insights into the role of the gut microbiota and IPA in depression and CVD, forming the basis of intervention strategies aimed at mitigating the deterioration of cardiac function following MI/R in patients experiencing depression.

Serotonin is one of the most potent gastrointestinal, peripheral, and neuronal signaling molecules and plays a key role in regulating energy metabolism. Accumulating evidence has shown the complex interplay between gut microbiota and host energy metabolism. In this review, we summarize recent findings on the role of gut microbiota in serotonin metabolism and discuss the complicated mechanisms by which serotonin, working in conjunction with the gut microbiota, affects total body energy metabolism in the host. Gut microbiota affects serotonin synthesis, storage, release, transport, and catabolism. In addition, serotonin plays an indispensable role in regulating host energy homeostasis through organ crosstalk and microbe-host communication, particularly with a wide array of serotonergic effects mediated by diverse serotonin receptors with unique tissue specificity. This fresh perspective will help broaden the understanding of serotonergic signaling in modulating energy metabolism, thus shedding light on the design of innovative serotonin-targeting strategies to treat metabolic diseases.

The pathophysiological mechanisms of irritable bowel syndrome (IBS) are intricate, and associated with tryptophan metabolites. This study was designed to investigate the relationship between indole metabolites in the feces and intestinal function in patients with IBS.

In this study, 42 patients with diarrhea-predominant IBS (IBS-D) and 36 healthy controls were recruited. The symptom severity was evaluated using IBS-quality of life (IBS-QOL) and IBS symptom severity system (IBS-SSS). The levels of indole metabolite in fecal samples were determined by means of mass spectrometry. Colon mucosal tissues were collected during colonoscopy procedures. Immunohistochemistry or immunofluorescence techniques were employed to analyze the expressions of the aryl hydrocarbon receptor (AHR), cytochrome P450 1A1 (CYP1A1), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), zonula occludens-1 (Zo-1), occludin, substance P (SP), nerve growth factor (NGF), NOD-like receptor family pyrin domain containing 3 (NLRP3), and nuclear factor kappa B (NF-κB) in the mucosal tissues.

Compared with healthy controls, the concentrations of the main indole metabolites (p = 0.020), and the expressions of CYP1A1 (p < 0.001), and Zo-1 (p = 0.017) were decreased in patients with IBS-D, but the expressions of S100B (p < 0.001), NF-κB (p = 0.006), and NRLP3 (p = 0.041) were increased. Immunofluorescence analysis demonstrated the co-expression of AHR with GFAP or S100B. Moreover, the ratio of S100B/AHR (p = 0.011) was higher in IBS-D patients than in health controls. This ratio was positively correlated with IBS-SSS score (r = 0.47, p = 0.006), as well as with the expression levels of NRLP3 (r = 0.505, p = 0.019), NF-κB (r = 0.548, p = 0.01), and SP (r = 0.832, p < 0.01).

Patients with IBS-D exhibited low-grade inflammation in the colon mucosal tissues, compromised intestinal barrier function, and abnormal visceral sensation. This may be attributed to the decreased levels of tryptophan indole metabolites, the heightened activity of enteric glial cells (EGCs), and the inhibition of AHR/CPY1A1 signaling pathway.

The association between gut microbial metabolites and immunologic non-response among people living with HIV (PLHIV) receiving antiretroviral therapy (ART) has not been well established. We aimed to characterize gut microbial metabolites among HIV-infected men who have sex with men (MSM) with different immunologic responses.

We recruited HIV-infected MSM from Guangzhou Eighth People's Hospital and HIV-uninfected MSM (healthy controls, HC) from a local MSM community-based organization in Guangzhou between June and October 2021. HIV-infected MSM were grouped into good immunological responders (GIR) (CD4 + T cell count ≥ 350 cells/μl) and poor immunological responders (PIR) (CD4 + T cell count < 350 cells/μl) after 24 months of ART treatment. Online questionnaires and stool samples were collected. Microbial metabolites in stool were obtained through ultra-performance liquid chromatography coupled to a tandem mass spectrometry (UPLC-MS/MS) system. Differential metabolites were identified and analyzed using the Kruskal-Wallis test, followed by pairwise comparisons with the Wilcoxon rank-sum test. The least absolute selection and shrinkage operator was used to select potential metabolites biomarkers.

A total of 51 HC, 56 GIR, and 42 PIR were included. No statistically significant differences were observed in the median time since HIV diagnosis and ART duration between GIR and PIR. Among the 174 quantified metabolites, 81 significantly differed among HC, GIR, and PIR (P < 0.05). Among differential metabolites, indole-3-propionic acid significantly decreased from HC (11.39 nmol/g) and GIR (8.16 nmol/g) to PIR (6.50 nmol/g). The pathway analysis showed that tryptophan metabolism differed significantly between GIR and PIR (P < 0.05). Four potential metabolites biomarkers (dimethylglycine, cinnamic acid, 3-hydroxyisovaleric acid, and propionic acid) that distinguish GIR and PIR were identified, and the corresponding area under the curve based on potential biomarkers was 0.773 (95% CI: 0.675-0.871).

This study identified significant differences in gut microbial metabolites among HIV-infected MSM with different immunologic responses. These results indicate the potential of gut microbial metabolites as novel disease progression markers and therapeutic targets.

In the gut, microRNAs (miRNAs) produced by intestinal epithelial cells are secreted into the lumen and can shape the composition and function of the gut microbiome. Crosstalk between gut microbes and the host plays a key role in irritable bowel syndrome (IBS) and inflammatory bowel diseases, yet little is known about how the miRNA-gut microbiome axis contributes to the pathogenesis of these conditions. Here, we investigate the ability of miR-21, a miRNA that we found decreased in fecal samples from IBS patients, to associate with and regulate gut microbiome function. When incubated with the human fecal microbiota, miR-21 revealed a rapid internalization or binding to microbial cells, which varied in extent across different donor samples. Fluorescence-activated cell sorting and sequencing of microbial cells incubated with fluorescently labeled miR-21 identified organisms belonging to the genera Bacteroides, Limosilactobacillus, Ruminococcus, or Coprococcus, which predominantly interacted with miR-21. Surprisingly, these and other genera also interacted with a miRNA scramble control, suggesting that physical interaction and/or uptake of these miRNAs by gut microbiota is not sequence-dependent. Nevertheless, transcriptomic analysis of the gut commensal Bacteroides thetaiotaomicron revealed a miRNA sequence-specific effect on bacterial transcript levels. Supplementation of miR-21, but not of small RNA controls, resulted in significantly altered levels of many cellular transcripts and increased transcription of a biosynthetic operon for indole and L-tryptophan, metabolites known to regulate host inflammation and colonic motility. Our study identifies a novel putative miR-21-dependent pathway of regulation of intestinal function through the gut microbiome with implications for gastrointestinal conditions.

The mammalian gut represents one of the largest and most dynamic host-microbe interfaces. Host-derived microRNAs (miRNAs), released from the gut epithelium into the lumen, have emerged as important contributors to host-microbe crosstalk. Levels of several miRNAs are altered in the stool of patients with irritable bowel syndrome or inflammatory bowel disease. Understanding how miRNAs interact with and shape gut microbiota function is crucial as it may enable the development of new targeted treatments for intestinal diseases. This study provides evidence that the miRNA miR-21 can rapidly associate with diverse microbial cells form the gut and increase levels of transcripts involved in tryptophan synthesis in a ubiquitous gut microbe. Tryptophan catabolites regulate key functions, such as gut immune response or permeability. Therefore, this mechanism represents an unexpected host-microbe interaction and suggests that host-derived miR-21 may help regulate gut function via the gut microbiota.

Maternal high fat diet (MHFD) increased colitis susceptibility in adulthood. However, the mechanism remains unclear. We sought to explore whether novel gut immune receptor leucine-rich repeat C19 (LRRC19) contributed to the impaired mucus barrier of offspring exposed to MHFD via gut immune response and microbiota. The results showed that MHFD significantly impaired the intestinal mucus barrier of offspring, and up-regulated the expression of LRRC19. Lrrc19 deletion alleviated the mucus barrier disruption. Mechanistically, metagenome sequencing revealed that the MHFD-induced gut microbiota alteration was partly restored in Lrrc19-/- offspring. Muc2-associated bacteria were decreased in the MHFD group, such as Akkermansia_muciniphila_CAG_154, which increased in the Lrrc19-deficient offspring. Moreover, Lrrc19-/- offspring had a higher rate of indole-3-acetic acid (IAA)-producing bacterium, such as Lactobacillus reuteri. A targeted metabolomics analysis revealed that IAA emerged as the top candidate that might mediate the protective effects. IAA was found to improve the mucus barrier function by increasing the ratio of interleukin-22 (IL-22)+ ILC3 cells in an aryl hydrocarbon receptor (AhR)-dependent manner. These results suggest that MHFD disrupts the intestinal mucus barrier of offspring through regulating gut immune receptor LRRC19 and inducing an imbalance of gut microbiota and microbiota-derived metabolites.