A systematically biosynthetic investigation of lactic acid bacteria reveals diverse antagonistic bacteriocins that potentially shape the human microbiome
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Abstract
Background: Lactic acid bacteria (LAB) produce various bioactive secondary metabolites (SMs), which endow LAB with a protective role for the host. However, the biosynthetic potentials of LAB-derived SMs remain elusive, particularly in their diversity, abundance, and distribution in the human microbiome. Thus, it is still unknown to what extent LAB-derived SMs are involved in microbiome homeostasis. Results: Here, we systematically investigate the biosynthetic potential of LAB from 31,977 LAB genomes, identifying 130,051 secondary metabolite biosynthetic gene clusters (BGCs) of 2,849 gene cluster families (GCFs). Most of these GCFs are species-specific or even strain-specific and uncharacterized yet. Analyzing 748 human-associated metagenomes, we gain an insight into the profile of LAB BGCs, which are highly diverse and niche-specific in the human microbiome. We discover that most LAB BGCs may encode bacteriocins with pervasive antagonistic activities predicted by machine learning models, potentially playing protective roles in the human microbiome. Class II bacteriocins, one of the most abundant and diverse LAB SMs, are particularly enriched and predominant in the vaginal microbiome. We utilized metagenomic and metatranscriptomic analyses to guide our discovery of functional class II bacteriocins. Our findings suggest that these antibacterial bacteriocins have the potential to regulate microbial communities in the vagina, thereby contributing to the maintenance of microbiome homeostasis. Conclusions: Our study systematically investigates LAB biosynthetic potential and their profiles in the human microbiome, linking them to the antagonistic contributions to microbiome homeostasis via omics analysis. These discoveries of the diverse and prevalent antagonistic SMs are expected to stimulate the mechanism study of LAB’s protective roles for the microbiome and host, highlighting the potential of LAB and their bacteriocins as therapeutic alternatives.
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Four fundamental regions in the genome of L. plantarum 55A were identified to produce bacteriocins and secondary metabolites including cyclic-lactone autoinducer, RiPP-like molecules, T3PKS, and terpenes.
“Four fundamental regions in the genome of L. plantarum 55A were identified to produce bacteriocins and secondary metabolites including cyclic-lactone autoinducer”
From Genomic Characterization of Lactiplantibacillus plantarum Strains: Potential Probiotics from Ethiopian Traditional Fermented Cottage Cheese (2024) · cites this paper as [48]
The Results sections on LAB biosynthetic potential and BGC diversity identify bacteriocin-associated RiPP-like clusters, T3PKS, and terpene clusters across lactic acid bacteria. They do not identify four regions in the genome of L. plantarum 55A or mention a cyclic-lactone autoinducer; searches for “55A” and “cyclic lactone autoinducer” found no supporting passage. The indexed passages have no page numbers. (LLM, conf=0.81)
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Small intestinal microbiota: from taxonomic composition to metabolism
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Lactic acid bacteria: Nature, characterization, mode of action, products and applications
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“By addressing these challenges, microbial nutraceuticals are poised to become a cornerstone of the functional food and dietary supplement industries, aligning with the growing consumer demand for sustainable, health-promoting products.”
Lactobacilli biology, applications and host interactions
Mejía-Caballero, A., & Marco, M. L. (2025) · Nature Reviews Microbiology · doi:10.1038/s41579-025-01205-7 · Cited by 60 · see citing works
“Lactobacilli synthesize diverse antimicrobial peptides known as bacteriocins 62 included along with other specialized metabolites in biosynthetic gene clusters 63 .”
Uhegwu, C. C., & Anumudu, C. K. (2025) · Microorganisms · doi:10.3390/microorganisms13112521 · Cited by 50 · see citing works
“Another study by Zhang et al. [118] analyzed 31,977 LAB genomes and identified over 130,000 secondary metabolite biosynthetic gene clusters (BGCs) using machine learning models to predict their antimicrobial potential.”
Protective Mechanisms of Vaginal Lactobacilli against Sexually Transmitted Viral Infections
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“Bacteriocins activity may play a role in regulating microbial communities in the vagina, thus helping to maintain microbiome balance [67].”
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Molecular insights fast-tracked: AI in biosynthetic pathway research
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“In recent studies, our research has focused on genomics-guided discovery of RiPP antibiotics, leading to the dis-coveryofthe fi rstlanthipeptidefromarchaeawithantagonisticactivity and narrow-spectrum class II bacteriocins from the human microbiome 21,22 .”
BackgroundSelf-citationAntimicrobial roles of probiotics: Molecular mechanisms and application prospects
Yu, X., Liu, Z., Liu, Y., Li, X., Wang, B., & Yin, J. (2025) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2025.105146 · Cited by 26 · see citing works
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Large-scale biosynthetic analysis of human microbiomes reveals diverse protective ribosomal peptides
Zhang, J., Zhang, D., Xu, Y., Zhang, J., Liu, R., Gao, Y., Shi, Y., Cai, P., Zhong, Z., He, B., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58280-w · Cited by 18 · see citing works
“…to the Author) The study by Zhang and colleagues presents a large-scale bioinformatic analysis of RiPP BGC diversity in the human microbiome genomic and metagenomic data and leverages sequencing data from healthy and disease-associated microbiomes to identify RiPPs with potential health phenotypes.”
Self-citationGizachew, S., & Engidawork, E. (2024) · Genes · doi:10.3390/genes15111389 · Cited by 15 · see citing works
“…biofilm formation as well as enzymes involved in the utilization of different sugars) [47], RiPP-like molecules (exhibit antibacterial activity) [48], T3PKS (produce secondary metabolites with diverse biological activities, including antimicrobials) [49], and terpenes (have antimicrobial,…”
Zhang, R., Mei, S., He, G., Wei, M., Chen, L., Chen, Z., Zhong, Y., BiJun, Z., KaiGong, W., Cheng, Z., et al. (2025) · Microbiome · doi:10.1186/s40168-025-02138-2 · Cited by 16 · see citing works
“Lactobacillus plantarum and Enterococcus faecalis , both belonging to the lactic acid bacteria, have demonstrated significant potential in stabilizing the body’s gut microbiota and inhibiting pathogenic colonization [25–28].”
Gao, Y., Zhong, Z., Zhang, D., Zhang, J., & Li, Y. (2024) · Microbiome · doi:10.1186/s40168-024-01807-y · Cited by 14 · see citing works
Self-citationSystematically investigating and identifying bacteriocins in the human gut microbiome
Zhang, D., Zou, Y., Shi, Y., Zhang, J., Liu, J., Wu, G., Zhang, J., Gao, Y., Chen, M., & Li, Y. (2025) · Cell Genomics · doi:10.1016/j.xgen.2025.100983 · Cited by 17 · see citing works
Self-citationLinking the edible plant microbiome and human gut microbiome
Berg, G., Toledo, G. V., Schierstaedt, J., Hyöty, H., & Wicaksono, W. A. (2025) · Gut Microbes · doi:10.1080/19490976.2025.2551113 · Cited by 13 · see citing works
“153 Bacteriocins have also been identified in plant-associated bacteria beyond the lactic acid bacterial group.”
Pedro, N. A., & Mira, N. P. (2024) · Microbiological Research · doi:10.1016/j.micres.2024.127628 · Cited by 13 · see citing works
Prevention and cure of murine C. difficile infection by a Lachnospiraceae strain
Tejada, J. N., Walters, W. A., Wang, Y., Kordahi, M. C., Chassaing, B., Pickard, J. M., Núñez, G., Ley, R. E., & Gewirtz, A. T. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2392872 · Cited by 13 · see citing works
“29,30 Moreover, this segment of the UBA3401 genome encodes a secreted thiopeptide predicted to have direct antibacterial activity.”
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Self-citationCombinatorial discovery of antibacterials via a feature-fusion based machine learning workflow
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“31 However, obtaining such products under standard laboratory conditions can be challenging.”
BackgroundNavale, V. D., Yadav, R., Khilari, A. A., Dharne, M. S., Shanmugam, D., & Vamkudoth, K. R. (2024) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-024-10313-4 · Cited by 12 · see citing works
Илиев, И., Yahubyan, G. T., Apostolova, E., Gozmanova, M., Mollova, D., Iliev, I., Ilieva, L., Marhova, M., Gochev, V., & Baev, V. (2025) · Microorganisms · doi:10.3390/microorganisms13010160 · Cited by 12 · see citing works
“The genome also includes multiple biosynthetic gene clusters that exhibit antibacterial properties.”
Chung, Y., Kang, S. B., Son, D., Lee, J. Y., Chung, M. J., & Lim, S. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1308293 · Cited by 8 · see citing works
“The 45 genome sequences were used to annotate carbohydrate-active enzymes and substrates (CAZymes) using the dbCAN3 standalone version in the HMMER and dbCAN3 CAZyme databases (Zheng et al., 2023).”
MethodDillen, J., Dricot, C. E. M. K., Croatti, V., & Lebeer, S. (2026) · Cell Host & Microbe · doi:10.1016/j.chom.2026.03.015 · Cited by 7 · see citing works
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“The Lactobacillaceae spp. have been reported for shaping microbiomes by inhibiting the proliferation of pathogenic microorganisms in the vagina [18] and gut [19,20] of animals by producing bacteriocins and acidi-fying the microenvironment [11].”
Self-citationTargeting vaginal dysbiosis: prospects for the application of live biotherapeutics products
Zhang, Q., Zhao, X., Chen, Z., Chen, R., Lin, X., Zhang, L., Li, K., Wang, M., Liu, Y., Zhou, H., et al. (2026) · Frontiers in Microbiology · doi:10.3389/fmicb.2026.1749581 · Cited by 5 · see citing works
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“A systematic biosynthetic screening of lactic acid bacteria revealed clusters annotated as RRE-containing, rSAM-modified peptides and others, suggesting that additional clusters falling outside of the current classification are likely present (121).”
InfluentialGuo, X., He, Y., Cheng, Y., Liang, J., Xu, P., He, W., Che, J., Men, J., Yuan, Y., & Yue, T. (2024) · Food & Function · doi:10.1039/d4fo00112e · Cited by 5 · see citing works
Immune-mediated indirect interaction between gut microbiota and bacterial pathogens
Keshavarz, M., Franz, M., Xie, H., Zanchi, C., Mbedi, S., Sparmann, S., & Rolff, J. (2025) · BMC Biology · doi:10.1186/s12915-025-02399-1 · Cited by 4 · see citing works
“Also, the metabolic [11, 12] and immunological environments [13, 14] are key contributors to the pathogenicity of invaders.”
Dietert, R. R., & Dietert, J. M. (2023) · American Journal of Biomedical Science & Research · doi:10.34297/ajbsr.2023.20.002708 · Cited by 3 · see citing works
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“The evaluation criteria for Lactobacillus content were based on the Expert Consensus on Clinical Application of Vaginal Microecological Evaluation 4 .”
Self-citationDuarte, V. D. S., Franklin‐Alming, F. V., Krysmann, A., & Porcellato, D. (2025) · npj Biofilms and Microbiomes · doi:10.1038/s41522-025-00860-1 · Cited by 2 · see citing works
“In addition to antimicrobial resistance, bacterial competition through bacteriocin production also shapes microbial community structure in the mammary gland 53 .”
Luo, C., Dong, X., Song, J., Li, Y., Zhang, Q., Pang, Y., Yue, B., Tao, G. U. O., & Fan, Z. (2025) · BMC Microbiology · doi:10.1186/s12866-025-04552-w · Cited by 2 · see citing works
“T3PKS enzymes, commonly found in acti-nobacteria and vaginal lactobacilli, suggesting potential production of bioactive compounds that can inhibit pathogens by disrupting membrane integrity, interfering with iron metabolism, and modulating reactive oxygen species (ROS) [36, 37].”
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The human reproductive tract microbiome: A novel source of live biotherapeutics
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“…and Bifidobacteri-aceae families reinforce the intestinal barrier by upregulating tight junction proteins such as occludin, claudins (e.g., claudin-1, -3), and zonula occludens-1 (ZO-1), and downregulating zonulin, a protein that increases paracellular permeability [188–190] (Figure 3).”
Wayah, S. B., Arakawa, K., & Philip, K. (2026) · Frontiers in Microbiology · doi:10.3389/fmicb.2026.1875597 · Cited by 2 · see citing works
“The use of machine-learning and deep learning in genome mining, structure-function prediction, and data-driven peptide engineering is becoming popular (Ma et al., 2022; Zhang et al., 2023; Hamamsy et al., 2024).”
Agolino, G., Cristofolini, M., Ronsivalle, M. A., Cattivelli, A., Tagliazucchi, D., Caggia, C., Solieri, L., & Randazzo, C. L. (2026) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-025-10810-0 · Cited by 1 · see citing works
A probiotic microemulsion with antioxidant activity to promote wound healing
Shao, Y.-X., Wei, P., Tu, J.-W., Li, B.-J., Li, Y., Xu, N.-L., Xia, G., Liu, C.-J., Li, X., & Zhang, L. (2025) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2025.107534 · Cited by 1 · see citing works
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“According to Zhang et al. (2023), the RiPPs and T3PKS clusters are predominant in most LAB genera, implying their important role in the biosynthesis of secondary metabolites.”
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“In recent studies, our research focused on genomics-guided discovery of RiPP antibiotics, resulting in the discovery of antagonistic lanthipeptide from archaea and narrow-spectrum class II bacteriocins from the human microbiome 18, 19 .”
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Self-citationHarnessing Microbial Peptides for Drug Discovery
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Importance scientifique, sanitaire et sociale du microbiome vaginal
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“The presence of bacteriocin gene clusters substantiated the observed broad-spectrum antimicrobial activity against foodborne pathogens, highlighting its potential to modulate gut microbiota composition and exclude pathogens (Zhang et al. 2023b).”
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Breaking the Resistance Barrier
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AI Technologies for Advancing Probiotic Applications
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Developmental dynamics of crop morphology, microbiota, and mucosal immunity in chickens
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From predicted bacteriocins to ecological function
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Self-citation
- Authors
- Zhang, D., Zhang, J., Kalimuthu, S., Liu, J., Song, Z.-M., He, B.-B., Cai, P., Zhong, Z., Feng, C., Neelakantan, P., & Li, Y.-X.
- Affiliations
- University of Hong Kong (HK)
- Fudan University (CN)
- Corresponding author
- Li, Yong-Xin
- ORCID
- Venue
- Microbiome
- Published
- 2023-04-27
- Volume
- 11
- Issue
- 1
- Pages
- 91-91
- ISSN
- 2049-2618 (ISSN-L)
- PMC
- PMC10134562
- OpenAlex
- W4367174807
- Cited by
- 72
- References
- 87
- Citations by year
- 2026: 28 · 2025: 21 · 2024: 16 · 2023: 7
- FWCI
- 10.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Microbiome (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Shenzhen Basic Research General Programme (JCYJ20210324122211031)
- Hong Kong Research Grants Council General research grants (HKU27107320)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Physical Sciences › Environmental Science › Ecology › Bacteriophages and microbial interactions
- Keywords
- lactic acid bacteria, secondary metabolite gene clusters, bacteriocins, class II bacteriocins, antagonistic activity, human microbiome, vaginal microbiota, microbiome homeostasis, gene cluster families, metagenomics, metatranscriptomics, antibacterial peptides
- MeSH terms
- Anti-Bacterial Agents, Bacteriocins, Female, Humans, Metagenome, Lactobacillales, Microbiota
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