The gut microbiome plays a pivotal role in maintaining the health of the hosts; however, there is accumulating evidence that certain bacteria in the host, termed pathobionts, play roles in the progression of diseases. Although antibiotics can be used to eradicate unwanted bacteria, the side effects of antibiotic treatment lead to a great need for more targeted antimicrobial agents as tools to modulate the microbiome more precisely. Herein, we reviewed narrow-spectrum antibiotics naturally made by plants and microorganisms, followed by more targeted antibiotic agents including synthetic peptides, phage, and targeted drug delivery systems, from the perspective of using them as potential tools for modulating the gut microbiome for favorable effects on the health of the host. Given the emerging discoveries on pathobionts and the increasing knowledge on targeted antimicrobial agents reviewed in this article, we anticipate targeted antimicrobial agents will emerge as a new generation of a drug to treat microbiome-involved diseases.

This study investigated the relationship between vaginal microbiota and women’s health conditions in 95 Chinese pregnant women in their third trimester. We conducted vaginal metagenomic analysis, examining species, functional pathways, and genes, and utilized correlation and LEfSe analyses to link microbiota to health conditions. Results revealed that healthy participants exhibited higher levels of Lactobacillus iners, with its abundance associated with tetrahydrofolate biosynthesis pathways. They also possessed more glycosyltransferase and ErmB antibiotic resistance genes compared to women with diagnosed conditions. Comparative genomics demonstrated that L. iners strains linked to bacterial vaginosis (BV) possessed more genes encoding biofilm-associated YhgE/Pip domain-containing proteins than healthy-associated strains. Notably, three BV-associated L. iners strains exhibited stronger biofilm formation abilities than four healthy-associated strains isolated in this study. Also, four out of seven L. iners strains inhibited the growth of Gardnerella vaginalis. Overall, L. iners may help maintain vaginal ecosystem stability in Chinese pregnant women.

Gut microbiome plays a pivotal role in combating diseases and facilitating healthy aging, and natural products derived from biosynthetic gene clusters (BGCs) of the human microbiome exhibit significant biological activities. However, the natural products of the gut microbiome in long-lived populations remain poorly understood. Here, we integrated six cohorts of long-lived populations, encompassing a total of 1029 fecal metagenomic samples, and employed the metagenomic single sample assembled BGCs (MSSA-BGCs) analysis pipeline to investigate the natural products and their associated species. Our findings reveal that the BGC composition of the extremely long-lived group differed significantly from that of younger elderly and young individuals across five cohorts. Terpene and Type I PKS BGCs were enriched in the extremely long-lived, whereas cyclic-lactone-autoinducer BGCs were more prevalent in the young. Association analysis indicated that terpene BGCs were strongly associated with the abundance of Akkermansia muciniphila, which was also more abundant in the long-lived elderly across at least three cohorts. We assembled 18 A. muciniphila draft genomes using metagenomic data from the extremely long-lived group across six cohorts and discovered that they all harbor two classes of terpene BGCs, which aligns with the 97 complete genomes of A. muciniphila strains retrieved from the NCBI database. The core domains of these two BGC classes are squalene/phytoene synthases involved in the biosynthesis of tri- and tetraterpenes. Furthermore, the abundance of fecal A. muciniphila was significantly associated with eight types of triterpenoids. Targeted terpenoid metabolomic analysis revealed that two triterpenoids, Holstinone C and colubrinic acid, were enriched in the A. muciniphila culture solution compared to the medium, thereby confirming the production of triterpenoids by A. muciniphila. The natural products derived from the gut of long-lived populations provide intriguing indications of their potential beneficial roles in regulating health.

Vibrio species are recognized for their role in food- and water-borne diseases in humans, fish, and aquatic invertebrates. We screened bacterial strains isolated from raw food shrimp for those that are bactericidal to Vibrio strains. Here we identify and characterize Aeromonas dhakensis strain A603 which shows robust bactericidal activity specifically towards Vibrio and related taxa but less potency toward other Gram-negative species. Using the A603 genome and genetic analysis, we show that two antibacterial mechanisms account for its vibriocidal activity -- a highly potent Type Six Secretion System (T6SS) and biosynthesis of a vibriocidal phenazine-like small molecule, named here as Ad-Phen. Further analysis indicates coregulation between Ad-Phen and a pore-forming T6SS effector TseC, which potentiates V. cholerae to killing by Ad-Phen.

Dysbiosis of the gut microbiota is strongly implicated in atherosclerosis (AS), thus prompting microbial modulation to be explored as a therapeutic strategy. However, limited evidence exists for probiotic interventions capable of alleviating AS. Here, we focused on Clostridium butyricum (C. butyricum; CB), a probiotic known for its production of short-chain fatty acids (SCFAs). We found that administration of C. butyricum to high-fat diet (HFD)-fed Apoe deficient (Apoe^−/−) mice reduced plaque area by improving blood lipid profiles, decreasing macrophage infiltration in the aortic roots, and lowering the levels of circulating pro-inflammatory monocytes and macrophages. By non-targeted serum metabolomics analysis, C. butyricum treatment significantly reduced the levels of both linoleic acid and its downstream metabolites. Collectively, these findings establish C. butyricum-mediated amelioration of AS through modulation of linoleic acid metabolism.