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Probiotics, Gut Microbiota, and Metabolic Health: From Mechanisms to Therapeutics

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A Special Issue of Nutrients (ISSN 2072-6643) belonging to the section "Prebiotics, Probiotics and Postbiotics".

Deadline for manuscript submissions: 15 December 2026 | Viewed by 7224

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Editors

Dr. Dandan Han

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Guest Editor

State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
Interests: gut microbiota; animal nutrition; fermentation; prebiotics; probiotics; fiber; inflammatory bowel disease; mucosal immunity
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Dr. Xiaolong Gu

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Guest Editor

College of Veterinary Medicine, Yunnan Agricultural University, Kunming 650201, China
Interests: toxicology; metabolism; molecular mechanism; signaling pathway; food toxicity and chemical
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The gut microbiota stands as a critical interface between our internal milieu and the external environment, playing an indispensable role in maintaining host nutritional metabolism and systemic health. Dysbiosis of the gut microbial ecosystem is increasingly recognized as a pivotal contributor to a wide spectrum of metabolic disorders.

While the association between gut microbiota and metabolic health is well established, the underlying mechanisms remain incompletely understood. It is crucial to understand how nutrition and diet shape microbial community structure and function, and how these changes are transduced into host signals that modulate immune responses, energy homeostasis, and organ function. The molecular links—including microbial metabolites, endocrine signals, and neural pathways—that connect gut microbes to improved host metabolic phenotypes are under intense investigation.

This Special Issue aims to bridge the gap between fundamental mechanistic insights and therapeutic applications. We welcome submissions of original research articles and comprehensive reviews that explore the tripartite relationship among probiotics, gut microbiota, and metabolic health. We are particularly interested in studies that unravel the causal mechanisms and demonstrate translational potential.

Topics of interest include, but are not limited to:

Mechanisms of Action by which gut microbiota affects metabolism and Key Microbial Metabolites.
Cross-Talk of Probiotics and Host Systems.
The Gut–Organ Axis in Metabolism.
Clinical and Pre-clinical Evidence about gut microbiota and metabolic health.
Next-Generation Probiotics.

Dr. Dandan Han
Dr. Xiaolong Gu
Guest Editors

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Keywords

prebiotics
probiotics
dietary fiber
metabolic
gut microbiota
inflammation

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Published Papers (6 papers)

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22 pages, 8654 KB

Open AccessArticle

Early-Life Compound Probiotic Intervention Programs Intestinal Barrier Maturation Through Indole-3-Lactic Acid in a Porcine Model

by Mingzhi Yang, Huan He, Jie Fu, Zhixin Yu, Wentao Li, Lixia Kai, Caihong Hu, Jie Feng, Tizhong Shan, Yizhen Wang, Mingliang Jin and Zeqing Lu

Nutrients 2026, 18(17), 2776; https://doi.org/10.3390/nu18172776 - 25 Aug 2026

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Abstract

Background: The early-life gut microbiota plays a critical role in programming intestinal barrier function and immune homeostasis, with profound implications for long-term host health. However, the effects of early-life compound probiotic intervention on the maturation of intestinal barrier function and the underlying molecular mechanisms remain incompletely understood, particularly in large-animal models relevant to human physiology. Methods: In this preclinical study, 3627 neonatal piglets—a well-established translational model for human infant gut development—were orally administered a novel compound probiotic formulation comprising Bifidobacterium longum subsp. infantis BZ, Lactobacillus plantarum LZ, and Pediococcus acidilactici PZ during early life. A total of 1512 fecal samples collected at seven time points from birth to day 180 were analyzed by 16S rRNA sequencing, and 525 samples from three developmental windows (days 10, 25, and 70) were subjected to LC-MS-based metabolomics. The candidate metabolite indole-3-lactic acid (ILA) was further mechanistically validated in a DSS-induced colitis mouse model and in IPEC-J2 cells. Results: Early-life probiotic intervention significantly enhanced intestinal barrier integrity, as evidenced by improved intestinal morphology and upregulated expression of tight junction proteins—zonula occludens-1 (ZO-1), occludin (OCLN), and Claudin-1 (CLDN1)—in the jejunum (p < 0.05). Notably, intervention at birth was more effective than post-weaning administration, and two administrations (birth + weaning) yielded superior outcomes compared with a single administration (p < 0.05). Microbiome analysis revealed enhanced microbial diversity and enrichment of beneficial genera during the juvenile-to-adult transition (p < 0.05). Metabolomic profiling identified ILA as a signature metabolite consistently elevated by probiotic supplementation. Conclusions: These findings provide evidence that early-life compound probiotic intervention is associated with improved intestinal barrier maturation, with ILA identified as a key candidate metabolite that may mediate this effect, as supported by functional validation in murine and cellular models. This provides a mechanistic rationale for probiotic-based strategies to support intestinal health in human infants during critical developmental windows. Full article

(This article belongs to the Special Issue Probiotics, Gut Microbiota, and Metabolic Health: From Mechanisms to Therapeutics)

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16 pages, 2653 KB

Open AccessArticle

Butyrate Ameliorates ISO-Induced Cardiac and Intestinal Injury in Rats via Modulation of Bitter Taste Receptors (Tas2rs) and GPR41/43 to Inhibit NLRP3 Activation

by Tianxing Yu, Anqi Cao, Feng Zhu, Zhongwen Xie, Shanshan Hu and Daxiang Li

Nutrients 2026, 18(10), 1530; https://doi.org/10.3390/nu18101530 - 12 May 2026

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Abstract

Background: The gut microbiota and its metabolite short-chain fatty acids (SCFAs) regulate host physiology, but whether butyrate, a key SCFA, protects against myocardial injury via the gut–heart axis remains unclear. Objectives: This study aimed to investigate the cardioprotective effect of butyrate in a rat model of isoproterenol (ISO)-induced myocardial injury and to explore its underlying gut–heart mechanism. Methods: In this experimental study, male Sprague-Dawley rats received intragastric butyrate pre-treatment followed by ISO injection to induce myocardial injury. Cardiac function, myocardial remodeling, gut–heart homeostasis, intestinal barrier integrity, and the expression of Tas2r, GPR41/43, and NLRP3 pyroptosis pathway components were assessed. Results: Butyrate pre-treatment significantly restored cardiac function (LVEF increased by 19.67 units; 95% CI, 11.17–28.16; p < 0.001) and ameliorated electrophysiological abnormalities (QTc shortened by 63.21 ms; 95% CI, 45.45–80.97; p < 0.0001). Mechanistically, butyrate suppressed aberrant myocardial Tas2r signaling (Tas2r137 reduced by 1.06 units; 95% CI, 0.37–1.74; p < 0.01), upregulated GPR41/43, inhibited NLRP3 inflammasome activation (NLRP3 reduced by 1.23 units; 95% CI, 0.13–2.33; p < 0.05), and repaired intestinal barrier integrity, thereby reducing bacterial translocation and secondary injury. Conclusions: Butyrate ameliorates ISO-induced myocardial injury through a simultaneous gut–heart mechanism, acting on both the cardiac Tas2r137/GPR41/43-NLRP3 pathway and intestinal barrier protection. These findings identify butyrate as a key functional molecule in gut–heart crosstalk and suggest its potential as a therapeutic agent for myocardial injury. Full article

(This article belongs to the Special Issue Probiotics, Gut Microbiota, and Metabolic Health: From Mechanisms to Therapeutics)

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15 pages, 449 KB

Open AccessArticle

Modulation of Glucose Homeostasis, Metabolic Endotoxemia and Circulating Short-Chain Fatty Acids Following Multi-Species Probiotic Supplementation: Findings from a 12-Week Randomised Placebo-Controlled Trial

by George Moschonis, Pauline Dacaya, Thy T. Truong, Angela Amoruso and Marco Pane

Nutrients 2026, 18(7), 1025; https://doi.org/10.3390/nu18071025 - 24 Mar 2026

Cited by 1 | Viewed by 1726

Abstract

Background: Altered gut microbiota and gut-derived inflammation impair glucose regulation and promote metabolic endotoxemia, yet evidence on probiotic effects across combined glycaemic, inflammatory and short-chain fatty acid (SCFA) outcomes remains limited. This study investigated the effects of a 12-week multi-species probiotic on glucose homeostasis, incretin hormones, inflammatory biomarkers and circulating SCFAs in adults with subthreshold depression. Methods: In a 12-week double-blind, randomised, placebo-controlled trial, 39 adults with subthreshold depression were allocated to either a probiotic supplement containing Limosilactobacillus fermentum LF16, Lacticaseibacillus rhamnosus LR06, Lactiplantibacillus plantarum LP01 and Bifidobacterium longum 04 (n = 19) or placebo (n = 20). Fasting glucose, insulin, HOMA-IR, glucose-dependent insulinotropic peptide (GIP), high-sensitivity C-reactive protein (hs-CRP), lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14) and SCFAs were evaluated at three time points: baseline, week 6 and week 12. Between-group and treatment × time effects were analysed using general linear models. Results: Probiotic supplementation significantly reduced fasting glucose at 12 weeks compared with placebo (−1.8 vs. 0.1 mmol/L; p = 0.036). In the probiotic group, greater reductions in GIP (p = 0.012; p = 0.037), LBP (p < 0.001), sCD14 (p = 0.002; p = 0.001) and hs-CRP (p = 0.047) were also observed compared with placebo. Plasma SCFA concentrations remained largely unchanged, with no significant treatment × time interactions, except for higher valerate levels at 12 weeks in the probiotic group (p = 0.019). Conclusions: Twelve weeks of multi-species probiotic supplementation improved fasting glucose, reduced incretin and inflammatory biomarkers and attenuated metabolic endotoxemia, without alterations in circulating SCFAs. These findings support beneficial modulation of metabolic–immune pathways and highlight the promising role of probiotics to enhance glucose regulation and systemic inflammatory tone in adults with subthreshold depression. Full article

(This article belongs to the Special Issue Probiotics, Gut Microbiota, and Metabolic Health: From Mechanisms to Therapeutics)

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22 pages, 2478 KB

Open AccessArticle

Bifidobacterium animalis subsp. lactis Ca360 Promotes Oral Iron Repletion, Alters the Gut Microbiota, and Regulates Host Metabolism and Inflammatory Status in a Murine Model of Iron Deficiency Anemia Caused by a Low-Iron Diet

by Peiqing Jiang, Jing Yang, Yuejian Mao, Linjun Wu, Xiaoqiong Li, Xiangyu Bian, Jian Kuang, Jianqiang Li, Fangshu Shi, Xiaoqiang Han, Jinjun Li and Haibiao Sun

Nutrients 2026, 18(6), 900; https://doi.org/10.3390/nu18060900 - 12 Mar 2026

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Abstract

Background/Objectives: Iron deficiency anemia (IDA) is a widespread nutritional disorder characterized by impaired iron absorption, inflammation-associated iron restriction, and disrupted iron homeostasis. Increasing evidence suggests that gut microbiota play an important role in iron metabolism; however, the mechanisms underlying probiotic-assisted iron supplementation remain unclear. Our research group previously conducted in vitro fermentation screening experiments and obtained a bacterial strain, B. lactis Ca360, which possesses iron absorption-enhancing activity. Methods: In this study, an IDA mouse model induced by a low-iron diet was used to investigate whether B. lactis Ca360 could synergistically improve iron metabolism when combined with iron supplementation. Mice were treated with FeSO₄ alone or FeSO₄ combined with B. lactis Ca360, and hematological parameters, organ indices, serum iron-related markers, histopathological changes, duodenal iron metabolism-related gene expression, hepatic inflammatory responses, gut microbiota composition, short-chain fatty acid (SCFA) levels, and correlation networks were analyzed. Results: Iron deficiency induced typical anemia phenotypes, multi-organ dysfunction, intestinal iron absorption dysregulation, hepatic inflammation, and gut microbiota dysbiosis. Compared with FeSO₄ alone, the combined intervention more effectively improved hematological parameters, reduced organ indices, restored liver and spleen histological integrity, normalized intestinal iron metabolism-related gene expression, and alleviated hepatic inflammation. In addition, B. lactis Ca360 markedly reshaped gut microbiota composition, enriching SCFA-producing anaerobic genera, including Ruminococcus, Roseburia, Acetatifactor, Intestinimonas, Eubacterium_coprostanoligenes_group_unclassified, and Oscillibacter, accompanied by increased acetate, propionate, and butyrate levels. Spearman correlation analysis further revealed close associations between gut microbiota remodeling, improved iron metabolism, reduced inflammatory status, and recovery of anemia-related phenotypes. Conclusions: Overall, these findings demonstrate that B. lactis Ca360 enhances the efficacy of iron supplementation by modulating SCFA-producing and anti-inflammatory gut microbiota, thereby coordinately regulating intestinal iron absorption, inflammation, and systemic iron homeostasis, supporting probiotic-assisted iron supplementation as a promising nutritional strategy for IDA management. Full article

(This article belongs to the Special Issue Probiotics, Gut Microbiota, and Metabolic Health: From Mechanisms to Therapeutics)

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14 pages, 1099 KB

Open AccessArticle

Distinct Gut Microbiome Profiles Underlying Cardiometabolic Risk Phenotypes in Individuals with Obesity

by Iveta Nedeva, Yavor Assyov, Veselka Duleva, Vera Karamfilova, Zdravko Kamenov, Julian Naydenov, Teodora Handjieva-Darlenska, Venelin Denchev, Alexander Kolevski, Victoria Pencheva and Vlayko Vodenicharov

Nutrients 2026, 18(2), 353; https://doi.org/10.3390/nu18020353 - 22 Jan 2026

Viewed by 1147

Abstract

Background: Obesity-related cardiometabolic disorders have been linked to alterations in selected gut microbiome components, yet clinically relevant microbial signatures remain incompletely defined. Objectives: This study investigated associations between selected gut bacterial taxa and cardiometabolic risk phenotypes in individuals with obesity. Methods: In this cross-sectional study, 100 adults with obesity were stratified according to metabolic syndrome status. Gut microbiome composition was assessed using targeted multiplex real-time PCR of functionally relevant bacterial taxa. Associations with anthropometric and cardiometabolic parameters were examined using correlation analysis, ROC curves, and multivariable logistic regression models. Results: Reduced relative abundance of Lachnospiraceae was associated with metabolic syndrome, lower Faecalibacterium abundance with arterial hypertension, and increased Prevotella abundance with dyslipidemia. ROC analyses identified cohort-specific discriminative thresholds with moderate accuracy. Conclusions: Selected taxon-specific gut microbiome signatures are associated with cardiometabolic risk phenotypes in obesity. These findings are exploratory and require validation in longitudinal and independent cohorts. Full article

(This article belongs to the Special Issue Probiotics, Gut Microbiota, and Metabolic Health: From Mechanisms to Therapeutics)

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21 pages, 702 KB

Open AccessSystematic Review

Efficacy of Probiotic Treatment in Alcoholic Liver Disease: A Systematic Review of Animal Studies

by Konrad Sosnowski, Robert Kucharski and Adam Przybyłkowski

Nutrients 2026, 18(4), 608; https://doi.org/10.3390/nu18040608 - 12 Feb 2026

Cited by 3 | Viewed by 1485

Abstract

Background/Objectives: Alcohol-associated liver disease (ALD) is a major cause of chronic liver injury, in which disruption of the gut–liver axis plays a key pathogenic role. Probiotics have been proposed as a potential therapeutic strategy to mitigate alcohol-induced liver damage; however, the preclinical evidence has not been systematically synthesised. This systematic review aimed to evaluate and summarise the hepatoprotective effects of probiotic supplementation in experimental animal models of ALD. Methods: The review protocol was pre-registered in PROSPERO (CRD420250653666) and followed PRISMA guidelines. A systematic search was conducted across PubMed, EMBASE and AGRICOLA databases using relevant keywords from inception to 30 April 2025. We included preclinical randomised controlled trials evaluating single-strain probiotic interventions against placebo or untreated controls in animal models of ALD. Risk of bias was assessed using SYRCLE’s tool, and the certainty of evidence for critical outcomes was evaluated using the GRADE framework. A narrative synthesis was performed, as a quantitative meta-analysis was precluded by incomplete numerical outcome reporting. Results: From initial 628 records, 36 studies were included in the final synthesis. Probiotic supplementation consistently attenuated alcohol-induced liver injury, as evidenced by marked reductions in serum ALT and AST levels and improved liver histology. Mechanistically, probiotics restored gut barrier integrity, reduced systemic endotoxemia, and suppressed pro-inflammatory pathways. Furthermore, probiotic treatment effectively counteracted alcohol-induced gut dysbiosis by increasing microbial diversity and restoring taxonomic balance, notably by reversing the alcohol-induced expansion of Proteobacteria. Despite these consistent directional effects, the overall certainty of evidence for the critical outcomes was rated as very low. Conclusions: Although the preclinical literature suggests hepatoprotective effects of probiotics in experimental ALD, these findings should be interpreted with caution due to the very low certainty of evidence. The observed benefits are limited by methodological shortcomings, indirectness inherent to animal models, and incomplete outcome reporting. This review provides a structured preclinical framework to inform the design of future translational studies and well-controlled clinical trials evaluating probiotics as potential adjunctive therapies in human ALD. Full article

(This article belongs to the Special Issue Probiotics, Gut Microbiota, and Metabolic Health: From Mechanisms to Therapeutics)

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