Lin Shi

Obesity poses a major global health challenge, necessitating safe and effective therapeutic strategies. Using high-throughput genomic screening for bile salt hydrolase (BSH)-producing strains, we identified Ligilactobacillus salivarius (L. salivarius) XA1416, a strain isolated from the feces of healthy individuals, which exhibits high BSH activity, strong acid resistance, and efficient colonization in the gastrointestinal tract. Oral administration of L. salivarius XA1416 counteracted high-fat diet-induced weight gain in mice, improved glucose homeostasis, and enhanced GLP-1 secretion. The strain modulated the gut microbiota, enriching taxa such as Bacteroides, Alistipes, and Faecalibaculum, and altered bile acid profiles, notably increasing ursodeoxycholic acid (UDCA). Mendelian randomization analysis leveraging large-scale human GWAS data and two cross-sectional cohorts' data, complemented by in vitro fecal microbiota fermentation experiments, collectively supports a key role of UDCA in weight control. The oral administration of UDCA recapitulated the anti-obesity effects and metabolic benefits of XA1416, functioning as an intestinal Farnesoid X receptor antagonist and Takeda G-protein-coupled receptor 5 agonist to stimulate GLP-1 secretion. This mechanism likely involves modulation of the hepatic FXR/SHP/SREBP-1c pathway and concurrent activation of the GLP-1 receptor, contributing to improved metabolic homeostasis. Additionally, we gavaged the mice fed with normal chow or a high-fat diet with GR-7, a specific inhibitor of microbial BSHs, leading to a reduction in UDCA level and GLP-1 production. Using HepG2 cell models and molecular dynamics simulations, we further demonstrated that UDCA directly activates the GLP-1 receptor. Taken together, our findings position L. salivarius XA1416 as a promising anti-obesity probiotic, with UDCA serving as a key microbial metabolite that mediates its beneficial metabolic effects.

This study provides a comprehensive evaluation of the physicochemical properties, volatile profiles, metabolomic characteristics, and health benefits of pasteurized kiwifruit juice fermented with Lactiplantibacillus plantarum , Lactobacillus gasseri , and their mixed culture (COM). Kiwifruit juice proved to be a suitable fermentation matrix for these strains, supported by increased colony counts, lactic acid and total phenolic content, while decreasing pH and total soluble solids. Sensory evaluation and gas chromatography-ion mobility spectrometry revealed distinct, strain-specific volatile flavor profiles. Samples fermented by COM for 24 h exhibited the most preferred sensory attributes, characterized by elevated 1-hexanol, 3-methyl-1-butanol, isobutanol, and tert-butanol, collectively contributing to a mellower overall fragrance. Additionally, COM-fermented juice maintained superior flavor quality and antioxidant capacity throughout storage compared to the unfermented juice, highlighting its commercial potential. Furthermore, COM fermentation enriched 132 metabolites involved in glutathione, purine, and arginine metabolism pathways. Network pharmacology identified 66 compounds enriched by COM fermentation such as barbatic acid, epicatechin and isoliquiritigenin, may exert its nutritional functions through multiple pathways such as neuroactive ligand–receptor interaction, lipid and atherosclerosis, insulin resistance, and peroxisome proliferator-activated receptor signaling pathway. These findings underscore the potential of fermentation using probiotic strains in producing high-quality and shelf-stable kiwifruit juice with improved flavor and health-promoting functionality. Graphical Abstract

Postbiotics demonstrate superior stability and safety compared to probiotics. We found that wheat bran arabinoxylan (WBAX) served as an effective substrate for the tryptophan-metabolizing probiotic Limosilactobacillus reuteri WX-94, enhancing its tryptophan metabolism to produce indole-3-acetic and indole-lactic acids in vitro. Oral administration of WBAX-L. reuteri postbiotic alleviated colitis and hepatic disorders, outperforming strains cultured with glucose- or xylo-oligosaccharide. Multiomics analysis showed that WBAX-L. reuteri restored metabolic homeostasis and activated hepatic FXR/SHP/PPAR signaling, improving bile acid and lipid metabolism. Key microbial contributors included Faecalibacterium, Burkholderiales, Christensenellaceae_R-7_group, Muribaculum. Mendelian randomization suggested causal relationship between WBAX-L. reuteri-enhanced bacteria and bile-acid-metabolizing enzymes, while molecular docking confirmed bile acid-protein interactions. Additionally, WBAX-L. reuteri's lipid-modulating effects were confirmed in HepG2 cells within the safe toxicity range. Our findings highlight WBAX's role in enhancing therapeutic potential of postbiotic L. reuteri, offering postbiotic strategies for improving colon health and associated metabolic functions via a gut-liver axis.

Excessive sodium chloride (NaCl) intake is associated with adverse health outcomes, highlighting the urgent need for effective salt reduction strategies. This study investigated the cross-modal interaction between saltiness and numbness induced by a supercritical carbon dioxide extract from Zanthoxylum bungeanum (SCZ) in individuals with varying saltiness sensitivities. Integrating psychophysical evaluations, electroencephalography (EEG), sanshool component analysis, and molecular validation in rat taste bud cells, we demonstrated that moderate SCZ enhances saltiness perception and facilitates NaCl reduction without compromising perceived intensity. This effect involves numbness and modulation of taste and trigeminal pathways, with optimal efficacy at intermediate NaCl concentrations in semisensitive cohorts. We identified hydroxyl-α-sanshool (HαSS) as the key bioactive compound, which binds to T1R1/T1R3 and transient receptor potential vanilloid 1 (TRPV1) to activate downstream taste signaling. In conclusion, SCZ enhances saltiness perception via cross-modal mechanisms, providing a strategy for sodium reduction and original insights into the neurobiological basis of salt taste perception.

Background: The rising global prevalence of obesity presents a major public health concern. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) emerge as promising therapeutic agents, showing substantial efficacy in weight reduction in clinical settings. Methods: This review synthesizes data from 1565 clinical trials (Phases I–IV) sourced from the Trialtrove database (November 2024), covering nine GLP-1RAs: mono-agonists (beinaglutide, liraglutide, semaglutide, orforglipron), dual agonists (tirzepatide, mazdutide, survodutide, cagrilintide), and the triple agonist retatrutide. We analyzed trial phase distributions and updated current evidence on safety and efficacy across populations, emphasizing both therapeutic promise and current limitations, particularly the scarcity of long-term and comparative effectiveness data as well as associated adverse effects. Future research must prioritize comparative effectiveness, long-term safety, and personalized strategies for GLP-1RAs, addressing evidence gaps in special populations and treatment individualization. Conclusion: This review synthesizes current evidence on the safety and effectiveness of GLP-1RAs in weight management and potential cardiovascular protection. Further trials are imperative to clarify long-term outcomes, individual variability, and specific adverse effects across diverse populations.

Intermittent fasting (IF) offers a potential strategy to counteract Alzheimer’s disease (AD) progression. In our 16-week study on AD transgenic mice, IF positively affected cognitive function and reduced amyloid-β (Aβ) accumulation, verifying the IF’s role in modulating neuroinflammation. Multiomics integration revealed strong links between IF-induced hippocampal gene expression, gut microbiota, and serum metabolites beneficial for cognition. Indole-3-propionic acid (IPA) emerged as a pivotal microbial metabolite. Blocking its neuronal receptor, pregnane X receptor (PXR), abolished IF’s effects. Human data paralleled these findings, showing lower IPA levels in patients with mild cognitive impairment and AD than in controls. IPA supplementation and IPA-producing Clostridium sporogenes reproduced IF’s cognitive benefits, whereas PXR blockade in neurons or disruption of IPA synthesis abrogated them. IPA crossed the blood-brain barrier, exhibited potent anti-inflammatory activity, and suppressed Aβ accumulation, essential for neuroprotection. These results underscore microbial metabolites regulated by IF, particularly IPA, as therapeutic candidates for AD, highlighting the critical role of the gut-brain axis in neurodegeneration.

Prior studies have demonstrated therapeutic benefits of intermittent fasting (IF) in experimental autoimmune encephalomyelitis (EAE), yet they have predominantly examined prophylactic protocols or implemented short-term post-induction interventions, leaving the therapeutic window undefined and the underlying mechanisms unelucidated. Here, we systematically evaluate intermittent fasting (IF) initiated at a clinically critical juncture of 10 days post-induction (EAE_postIF), which coincides with early symptom onset, demonstrating significant attenuation of disease progression, reduced neuroinflammation, and preserved myelin integrity. Mechanistically, EAE_postIF activates a TRIB3–PERK–autophagy axis in the spinal cord, evidenced by increased ATF4, CHOP, and TRIB3 expression and suppression of mTOR signaling. In TRIB3-deficient mice, the beneficial effects of IF are partially attenuated, with clinical and histological improvements reduced relative to wild-type controls yet remaining superior to untreated cohorts. These findings establish a well-defined therapeutic window for IF intervention in neuroinflammation and identify TRIB3–PERK–autophagy signaling as a critical mediator, supporting IF as a viable metabolic strategy to complement existing MS therapies.

Probiotics are widely used in the prevention and care of obesity. Despite a large number of studies focusing on exploring benefits, probiotics inevitably encountered unexpected stress and challenges in vitro or in vivo during the practical application, which could substantially influence their viability and biological functions. This study summarized the literature that investigated the keywords of probiotics, obesity, and stress. The most reported probiotics genera related to obesity treatments (i.e., Lactobacillus, Bifidobacterium, yeast, and certain potential next-generation beneficial microorganisms), the key stress factors they encounter (i.e., gastric, cholate, organic acid, and other osmotic pressure stress during in vitro fermentation and in vivo application), and potential mechanisms for stress tolerance of certain probiotics were summarized. The main approaches for probiotics to resist stress are regulating the expression of some critical genes, increasing intracellular ATP, maintaining cell membrane function, and enhancing key metabolic pathways. We made recommendations for further research on the stress resistance mechanism of probiotics. The findings provide insights into the mechanisms of stress tolerance of probiotics and for screening of probiotics and development of novel probiotic foods with enhanced efficacy to combat obesity.