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Extracellular vesicles of the Gram-positive gut symbiont Bifidobacterium longum induce immune-modulatory, anti-inflammatory effects.

ABSTRACT: The gut microbiota is now well known to affect the host's immune system. One way of bacterial communication with host cells is via the secretion of vesicles, small membrane structures containing various cargo. Research on vesicles secreted by Gram-positive gut bacteria, their mechanisms of interaction with the host and their immune-modulatory effects are still relatively scarce. Here we characterized the size, protein content, and immune-modulatory effects of extracellular vesicles (EVs) secreted by a newly sequenced Gram-positive human gut symbiont strain - Bifidobacterium longum AO44. We found that B. longum EVs exert anti-inflammatory effects, inducing IL-10 secretion from both splenocytes and dendritic cells (DC)-CD4+ T cells co-cultures. Furthermore, the EVs protein content showed enrichment in ABC transporters, quorum sensing proteins, and extracellular solute-binding proteins, which were previously shown to have a prominent function in the anti-inflammatory effect of other strains of B. longum. This study underlines the importance of bacterial vesicles in facilitating the gut bacterial immune-modulatory effects on the host and sheds light on bacterial vesicles as future therapeutics.

SUBMITTER: Mandelbaum N

PROVIDER: S-EPMC10239484 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Extracellular vesicles of the Gram-positive gut symbiont Bifidobacterium longum induce immune-modulatory, anti-inflammatory effects.

Mandelbaum Noa N Zhang Lihan L Carasso Shaqed S Ziv Tamar T Lifshiz-Simon Sapir S Davidovich Irina I Luz Ishai I Berinstein Elliot E Gefen Tal T Cooks Tomer T Talmon Yeshayahu Y Balskus Emily P EP Geva-Zatorsky Naama N

NPJ biofilms and microbiomes 20230603 1

The gut microbiota is now well known to affect the host's immune system. One way of bacterial communication with host cells is via the secretion of vesicles, small membrane structures containing various cargo. Research on vesicles secreted by Gram-positive gut bacteria, their mechanisms of interaction with the host and their immune-modulatory effects are still relatively scarce. Here we characterized the size, protein content, and immune-modulatory effects of extracellular vesicles (EVs) secrete ...[more]

PMID: 37270554

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Project description:Extracellular proteins are important factors in host-microbe interactions; however, the specific factors that enable bifidobacterial adhesion and survival in the gastrointestinal (GI) tract are not fully characterized. Here, we discovered that Bifidobacterium longum NCC2705 cultured in bacterium-free supernatants of human fecal fermentation broth released a myriad of particles into the extracellular environment. The aim of this study was to characterize the physiological properties of these extracellular particles. The particles, approximately 50 to 80 nm in diameter, had high protein and double-stranded DNA contents, suggesting that they were extracellular vesicles (EVs). A proteomic analysis showed that the EVs primarily consisted of cytoplasmic proteins with crucial functions in essential cellular processes. We identified several mucin-binding proteins by performing a biomolecular interaction analysis of phosphoketolase, GroEL, elongation factor Tu (EF-Tu), phosphoglycerate kinase, transaldolase (Tal), and heat shock protein 20 (Hsp20). The recombinant GroEL and Tal proteins showed high binding affinities to mucin. Furthermore, the immobilization of these proteins on microbeads affected the permanence of the microbeads in the murine GI tract. These results suggest that bifidobacterial exposure conditions that mimic the intestine stimulate B. longum EV production. The resulting EVs exported several cytoplasmic proteins that may have promoted B. longum adhesion. This study improved our understanding of the Bifidobacterium colonization strategy in the intestinal microbiome.IMPORTANCEBifidobacterium is a natural inhabitant of the human gastrointestinal (GI) tract. Morphological observations revealed that extracellular appendages of bifidobacteria in complex microbial communities are important for understanding its adaptations to the GI tract environment. We identified dynamic extracellular vesicle (EV) production by Bifidobacterium longum in bacterium-free fecal fermentation broth that was strongly suggestive of differing bifidobacterial extracellular appendages in the GI tract. In addition, export of the adhesive moonlighting proteins mediated by EVs may promote bifidobacterial colonization. This study provides new insight into the roles of EVs in bifidobacterial colonization processes as these bacteria adapt to the GI environment.

Project description:The aim of this study was to identify a Bifidobacterium strain that improves the performance of Limosilactobacillus reuteri DSM 17938. Initial tests showed that Bifidobacterium longum subsp. longum strains boosted the growth of DSM 17938 during in vivo-like conditions. Further characterization revealed that one of the strains, BG-L47, had better bile and acid tolerance compared to BG-L48, as well as mucus adhesion compared to both BG-L48 and the control strain BB536. BG-L47 also had the capacity to metabolize a broad range of carbohydrates and sugar alcohols. Mapping of glycoside hydrolase (GH) genes of BG-L47 and BB536 revealed many GHs associated with plant-fiber utilization. However, BG-L47 had a broader phenotypic fiber utilization capacity. In addition, B. longum subsp. longum cells boosted the bioactivity of extracellular membrane vesicles (MV) produced by L. reuteri DSM 17938 during co-cultivation. Secreted 5'-nucleotidase (5'NT), an enzyme that converts AMP into the signal molecule adenosine, was increased in MV boosted by BG-L47. The MV exerted an improved antagonistic effect on the pain receptor transient receptor potential vanilloid 1 (TRPV1) and increased the expression of the immune development markers IL-6 and IL-1ß in a peripheral blood mononuclear cell (PBMC) model. Finally, the safety of BG-L47 was evaluated both by genome safety assessment and in a human safety study. Microbiota analysis showed that the treatment did not induce significant changes in the composition. In conclusion, B. longum subsp. longum BG-L47 has favorable physiological properties, can boost the in vitro activity of L. reuteri DSM 17938, and is safe for consumption, making it a candidate for further evaluation in probiotic studies.ImportanceBy using probiotics that contain a combination of strains with synergistic properties, the likelihood of achieving beneficial interactions with the host can increase. In this study, we first performed a broad screening of Bifidobacterium longum subsp. longum strains in terms of synergistic potential and physiological properties. We identified a superior strain, BG-L47, with favorable characteristics and potential to boost the activity of the known probiotic strain Limosilactobacillus reuteri DSM 17938. Furthermore, we demonstrated that BG-L47 is safe for consumption in a human randomized clinical study and by performing a genome safety assessment. This work illustrates that bacteria-bacteria interactions differ at the strain level and further provides a strategy for finding and selecting companion strains of probiotics.

Project description:This study evaluates the efficacy of Bifidobacterium longum subsp. longum BL21 in mitigating symptoms of polycystic ovarian syndrome (PCOS) in DHT-induced PCOS model mice. It focuses on BL21's role in modulating metabolic dysregulation, inflammation, and neuroprotection via the gut-brain-ovary axis. Employing an 8-week treatment regimen, this research assessed the effects of BL21 on prenatal androgen-induced PCOS in ICR mice. Evaluations included body weight, glucose tolerance tests, serum analyses of BDNF, inflammatory markers, sex hormone levels, and 16S rRNA gene sequencing for gut microbiota diversity and composition. Twenty-four ICR mice with induced PCOS served as subjects to examine the probiotic's impact. Mice were administered a daily oral dose of 1 × 109 CFU of BL21 continuously for a total of 8 weeks. BL21 significantly enhanced sex hormone levels (P < 0.05), particularly those of follicle-stimulating hormone (FSH) and estradiol (E2), indicating improved ovarian function and offering a novel PCOS treatment approach. The intervention notably curbed weight gain and improved glucose tolerance in PCOS mice (P < 0.05). BL21 reduced inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and lipopolysaccharides (LPS), while increasing IL-10, BDNF, FSH, and E2 levels (P < 0.05 for all). It also enriched gut microbiota diversity, enhancing populations of Bifidobacterium and Lactobacillus. Correlation analyses underscored the positive shifts in microbiota linked to beneficial hormonal and inflammatory profiles. BL21 shows promise in alleviating PCOS symptoms through metabolic regulation, inflammation reduction, and neuroprotection, validating its potential in integrated therapeutic strategies.IMPORTANCEPolycystic ovarian syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age, characterized by metabolic irregularities, hormonal imbalances, and chronic inflammation. Existing treatments are often inadequate, addressing symptoms without targeting the underlying etiological factors. The investigation of Bifidobacterium longum subsp. longum BL21 as a probiotic intervention offers a novel approach by potentially regulating the gut-brain-ovary axis. This could lead to innovative therapeutic strategies that not only manage but also potentially reverse the multifaceted symptoms of PCOS, enhancing quality of life and reproductive health.

Project description:BackgroundThe importance of the gut microbiota at the early stage of life and their longitudinal effect on host health have recently been well investigated. In particular, Bifidobacterium longum subsp. longum, a common component of infant gut microbiota, appears in the gut shortly after birth and can be detected there throughout an individual's lifespan. However, it remains unclear whether this species colonizes in the gut over the long term from early infancy. Here, we investigated the long-term colonization of B. longum subsp. longum by comparing the genotypes of isolates obtained at different time points from individual subjects. Strains were isolated over time from the feces of 12 subjects followed from early infancy (the first six months of life) up to childhood (approximately six years of age). We also considered whether the strains were transmitted from their mothers' perinatal samples (prenatal feces and postnatal breast milk).ResultsIntra-species diversity of B. longum subsp. longum was observed in some subjects' fecal samples collected in early infancy and childhood, as well as in the prenatal fecal samples of their mothers. Among the highlighted strains, several were confirmed to colonize and persist in single individuals from as early as 90 days of age for more than six years; these were classified as long-term colonizers. One of the long-term colonizers was also detected from the corresponding mother's postnatal breast milk. Quantitative polymerase chain reaction data suggested that these long-term colonizers persisted in the subjects' gut despite the existence of the other predominant species of Bifidobacterium.ConclusionsOur results showed that several strains belonging to B. longum subsp. longum colonized in the human gut from early infancy through more than six years, confirming the existence of long-term colonizers from this period. Moreover, the results suggested that these strains persisted in the subjects' gut while co-existing with the other predominant bifidobacterial species. Our findings also suggested the importance of microbial-strain colonization in early infancy relative to their succession and showed the possibility that probiotics targeting infants might have longitudinal effects.Trial registrationTRN: ISRCTN25216339 . Date of registration: 11/03/2016. Prospectively registered.

Dataset Information

Extracellular vesicles of the Gram-positive gut symbiont Bifidobacterium longum induce immune-modulatory, anti-inflammatory effects.

Publications

Extracellular vesicles of the Gram-positive gut symbiont Bifidobacterium longum induce immune-modulatory, anti-inflammatory effects.

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