Due to the challenges of antibiotic resistance to global health, bacteriocins as antimicrobial compounds have received more and more attention. Bacteriocins are biosynthesized by various microbes and are predominantly used as food preservatives to control foodborne pathogens. Now, increasing researches have focused on bacteriocins as potential clinical antimicrobials or immune‐modulating agents to fight against the global threat to human health. Given the broad‐ or narrow‐spectrum antimicrobial activity, bacteriocins have been reported to inhibit a wide range of clinically pathogenic and multidrug‐resistant bacteria, thus preventing the infections caused by these bacteria in the human body. Otherwise, some bacteriocins also show anticancer, anti‐inflammatory, and immune‐modulatory activities. Because of the safety and being not easy to cause drug resistance, some bacteriocins appear to have better efficacy and application prospects than existing therapeutic agents do. In this review, we highlight the potential therapeutic activities of bacteriocins and suggest opportunities for their application.

The gut microbes interact with each other as well as host, influencing human health and some diseases. Many gut commensals and food originated bacteria produce bacteriocins which can inhibit pathogens and modulate gut microbiota. Bacteriocins have comparable narrow antimicrobial spectrum and are attractive potentials for precision therapy of gut disorders. In this review, the bacteriocins from food and gut microbiomes and their involvement in the interaction between producers and gut ecosystem, along with their characteristics, types, biosynthesis, and functions are described and discussed. Bacteriocins are produced by many intestinal commensals and food microbes among which lactic acid bacteria (many are probiotics) has been paid more attention. Bacteriocin production has been generally regarded as a probiotic trait. They give a competitive advantage to bacteria, enabling their colonization in human gut, and mediating the interaction between the producers and host ecosystem. They fight against unwanted bacteria and pathogens without significant impact on the composition of commensal microbiota. Bacteriocins assist the producers to survive and colonize in the gut microbial populations. There is a great need to evaluate and utilize the potential of bacteriocins for improved therapeutic implications for intestinal health.

Nisin Z is a possible alternative for treating bovine mastitis by inhibiting mastitis-causing pathogens and having anti-inflammatory activity. However, the anti-inflammatory mechanism of nisin Z on mastitis is unknown. Our study aimed to investigate the mechanisms of nisin Z on mastitis. Our results showed that nisin Z inhibited the activation of the ERK1/2 and p38 mitogen-activated protein kinase (MAPK) signaling pathway, decreased the release of pro-inflammatory cytokines (i.e., tumor necrosis factor-α, IL-1β, and IL-6), and increased the anti-inflammatory cytokine (IL-10) in lipopolysaccharide (LPS)-induced MCF10A cells. After intraperitoneal injection, nisin Z significantly decreased inflammatory cell infiltration in the mammary gland, as well as decreased myeloperoxidase and pro-inflammatory cytokines in serum and mammary gland. Western blot analysis revealed that nisin Z also dramatically suppressed the activation of the ERK1/2 and p38 MAPK signaling pathways in LPS-induced mastitis mice. We also found that nisin Z treatment could enhance the blood-milk barrier. In summary, our study demonstrated that nisin Z exerted an anti-inflammatory effect by inhibiting the ERK1/2 and p38 MAPK signaling pathway and promoting the blood-milk barrier on LPS-induced mastitis.

Multiple gastrointestinal disorders are associated with impaired gut microbiota. Probiotic Lacticaseibacillus rhamnosus can improve bowel disorder, however, the action mechanism is poorly understood. We integrated multi-omics data from the gut metagenome, metabolome, and colon transcriptome of constipated mice underlying L. rhamnosus LRJ-1 treatment to provide insights into host-microbial metabolic pathway. We found that oral administration of L. rhamnosus LRJ-1 alleviated constipation in mice accompanied by the increased abundances of fecal γ-aminobutyric acid (GABA) and intestinal commensal Bacteroides, and the activation of host GABAergic synapses. B. uniformis was the most enriched Bacteroides species in constipated mice treated with L. rhamnosus LRJ-1, and contributed to the increased abundance of GABA in the gut. Administration of either B. uniformis ATCC 8492 or GABA alleviated constipation and increased gastrointestinal motility in constipated mice. Knockout of the GABA biosynthetic gad gene in B. uniformis ATCC 8492 decreased GABA production and blocked its beneficial effects on constipation. These results confirm the therapeutic potential of L. rhamnosus LRJ-1 in alleviating constipation through promoting gut commensal Bacteroides-derived GABA production. Targeting the gut microbiome to regulate GABA production may open new insights for efficient constipation treatment.

Histidine kinase (HK) NisK is well known to sense lantibiotic nisin for regulating the biosynthesis of nisin. NisK possesses two trans-membrane segments and a large extracellular region and nisin contains 34 amino acids with five lanthionine rings. Unlike most peptide sensing HK with multi trans-membrane segments, NisK is a representative of a group of rarely reported HK that sense peptide as ligand. To reveal how NisK senses nisin molecule to regulate nisin biosynthesis, we constructed a reporter Lactococcus lactis strain with nisRK constitutively expressed and a reporter gene lacZ expressed under the control of promoter P_nisA. We showed that the extracellular region of NisK was involved in recognizing nisin. Conserved residues in this group of HK were found in the extracellular region of NisK and mutagenesis of these residues in the reporter strain revealed that several hydrophobic residues including two aromatic residues are crucial for NisK sensing nisin and regulating nisin biosynthesis. Substitutions of hydrophobic regions in NisK extracellular domain showed that the first strand that was rich of hydrophobic amino acids was involved in regulating nisin biosynthesis. A negatively charged residue in the first βstrand also contributed to nisin biosynthesis. Protein binding analyses demonstrated that nisin could not interact with key NisK mutants, indicating these site in the extracellular region of NisK was involved in recognizing nisin.

Nisin has been widely used in the food industry as a safe and natural preservative and has the potential to be used as a biomedicine. Improving nisin production is important for its enormous applications. Nisin A is produced in Lactococcus lactis and its biosynthesis is induced through the regulation of the 2-component system NisKR. In this study, alanine-scanning mutagenesis was applied to study the key structure or AA in nisin for inducing the 2-component system NisKR to regulate downstream gene expression. Assay of β-galactosidase activity revealed that either ring A or ring B was necessary for nisin to induce lacZ reporter gene expression. A substituted first ring formed by Thr2 and Cys7 in S3A instead of ring A (formed by Ser3 and Cys7) fully retained nisin induction activity. Mutation of cationic AA and addition of cationic ions hardly affected nisin induction activity. These results demonstrated that the N-terminal ring structures in nisin were involved in activating NisKR to act as an inducing molecule, whereas the electrostatic force might not contribute to this process. In addition, 2 specific residues were revealed to have potential for improving both nisin induction and antimicrobial activity, which might be used for increasing nisin production.