scholarly journals Correlation between Disease Severity and the Intestinal Microbiome in Mycobacterium tuberculosis-Infected Rhesus Macaques

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Sivaranjani Namasivayam ◽  
Keith D. Kauffman ◽  
John A. McCulloch ◽  
Wuxing Yuan ◽  
Vishal Thovarai ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Host Resistance ◽  
Rhesus Macaques ◽  
Severe Disease ◽  
Predictive Biomarker ◽  
Host Susceptibility ◽  
Intestinal Microbiome ◽  
Metagenomic Sequencing ◽  
Content Type ◽  
The Impact

ABSTRACT The factors that determine host susceptibility to tuberculosis (TB) are poorly defined. The microbiota has been identified as a key influence on the nutritional, metabolic, and immunological status of the host, although its role in the pathogenesis of TB is currently unclear. Here, we investigated the influence of Mycobacterium tuberculosis exposure on the microbiome and conversely the impact of the intestinal microbiome on the outcome of M. tuberculosis exposure in a rhesus macaque model of tuberculosis. Animals were infected with different strains and doses of M. tuberculosis in three independent experiments, resulting in a range of disease severities. The compositions of the microbiotas were then assessed using a combination of 16S rRNA and metagenomic sequencing in fecal samples collected pre- and postinfection. Clustering analyses of the microbiota compositions revealed that alterations in the microbiome after M. tuberculosis infection were of much lower magnitude than the variability seen between individual monkeys. However, the microbiomes of macaques that developed severe disease were noticeably distinct from those of the animals with less severe disease as well as from each other. In particular, the bacterial families Lachnospiraceae and Clostridiaceae were enriched in monkeys that were more susceptible to infection, while numbers of Streptococcaceae were decreased. These findings in infected nonhuman primates reveal that certain baseline microbiome communities may strongly associate with the development of severe tuberculosis following infection and can be more important disease correlates than alterations to the microbiota following M. tuberculosis infection itself. IMPORTANCE Why some but not all individuals infected with Mycobacterium tuberculosis develop disease is poorly understood. Previous studies have revealed an important influence of the microbiota on host resistance to infection with a number of different disease agents. Here, we investigated the possible role of the individual’s microbiome in impacting the outcome of M. tuberculosis infection in rhesus monkeys experimentally exposed to this important human pathogen. Although M. tuberculosis infection itself caused only minor alterations in the composition of the gut microbiota in these animals, we observed a significant correlation between an individual monkey’s microbiome and the severity of pulmonary disease. More importantly, this correlation between microbiota structure and disease outcome was evident even prior to infection. Taken together, our findings suggest that the composition of the microbiome may be a useful predictor of tuberculosis progression in infected individuals either directly because of the microbiome’s direct influence on host resistance or indirectly because of its association with other host factors that have this influence. This calls for exploration of the potential of the microbiota composition as a predictive biomarker through carefully designed prospective studies.

scholarly journals The Impact of Leadered and Leaderless Gene Structures on Translation Efficiency, Transcript Stability, and Predicted Transcription Rates in Mycobacterium smegmatis

2020 ◽  
Vol 202 (9) ◽  
Author(s):  
Tien G. Nguyen ◽  
Diego A. Vargas-Blanco ◽  
Louis A. Roberts ◽  
Scarlet S. Shell
Keyword(s):  
Gene Expression ◽  
Mycobacterium Tuberculosis ◽  
Mycobacterium Smegmatis ◽  
Half Life ◽  
Untranslated Regions ◽  
Translation Efficiency ◽  
Production Rates ◽  
Content Type ◽  
The Impact ◽  
Mrna Half Life

ABSTRACT Regulation of gene expression is critical for Mycobacterium tuberculosis to tolerate stressors encountered during infection and for nonpathogenic mycobacteria such as Mycobacterium smegmatis to survive environmental stressors. Unlike better-studied models, mycobacteria express ∼14% of their genes as leaderless transcripts. However, the impacts of leaderless transcript structures on mRNA half-life and translation efficiency in mycobacteria have not been directly tested. For leadered transcripts, the contributions of 5′ untranslated regions (UTRs) to mRNA half-life and translation efficiency are similarly unknown. In M. tuberculosis and M. smegmatis, the essential sigma factor, SigA, is encoded by a transcript with a relatively short half-life. We hypothesized that the long 5′ UTR of sigA causes this instability. To test this, we constructed fluorescence reporters and measured protein abundance, mRNA abundance, and mRNA half-life and calculated relative transcript production rates. The sigA 5′ UTR conferred an increased transcript production rate, shorter mRNA half-life, and decreased apparent translation rate compared to a synthetic 5′ UTR commonly used in mycobacterial expression plasmids. Leaderless transcripts appeared to be translated with similar efficiency as those with the sigA 5′ UTR but had lower predicted transcript production rates. A global comparison of M. tuberculosis mRNA and protein abundances failed to reveal systematic differences in protein/mRNA ratios for leadered and leaderless transcripts, suggesting that variability in translation efficiency is largely driven by factors other than leader status. Our data are also discussed in light of an alternative model that leads to different conclusions and suggests leaderless transcripts may indeed be translated less efficiently. IMPORTANCE Tuberculosis, caused by Mycobacterium tuberculosis, is a major public health problem killing 1.5 million people globally each year. During infection, M. tuberculosis must alter its gene expression patterns to adapt to the stress conditions it encounters. Understanding how M. tuberculosis regulates gene expression may provide clues for ways to interfere with the bacterium’s survival. Gene expression encompasses transcription, mRNA degradation, and translation. Here, we used Mycobacterium smegmatis as a model organism to study how 5′ untranslated regions affect these three facets of gene expression in multiple ways. We furthermore provide insight into the expression of leaderless mRNAs, which lack 5′ untranslated regions and are unusually prevalent in mycobacteria.

scholarly journals Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

2016 ◽  
Vol 199 (2) ◽  
Author(s):  
Pilar Domenech ◽  
Jason Zou ◽  
Alexandra Averback ◽  
Nishath Syed ◽  
Daniele Curtis ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Treatment Programs ◽  
Nucleotide Polymorphisms ◽  
Content Type ◽  
Fitness Advantage ◽  
Mechanistic Basis ◽  
Dramatic Shift ◽  
Dosr Regulon ◽  
The Impact

ABSTRACT The DosR regulon, a set of 48 genes normally expressed in Mycobacterium tuberculosis under conditions that inhibit aerobic respiration, is controlled via the DosR-DosS/DosT two-component system. While the regulon requires induction in most M. tuberculosis isolates, for members of the Beijing lineage, its expression is uncoupled from the need for signaling. In our attempts to understand the mechanistic basis for this uncoupling in the Beijing background, we previously reported the identification of two synonymous single-nucleotide polymorphisms (SNPs) within the adjacent Rv3134c gene. In the present study, we have interrogated the impact of these SNPs on dosR expression in wild-type strains, as well as a range of dosR-dosS-dosT mutants, for both Beijing and non-Beijing M. tuberculosis backgrounds. In this manner, we have unequivocally determined that the C601T dosR promoter SNP is the sole requirement for the dramatic shift in the pattern of DosR regulon expression seen in this globally important lineage. Interestingly, we also show that DosT is completely nonfunctional within these strains. Thus, a complex series of evolutionary steps has led to the present-day Beijing DosR phenotype that, in turn, potentially confers a fitness advantage in the face of some form of host-associated selective pressure. IMPORTANCE Mycobacterium tuberculosis strains of the Beijing lineage have been described as being of enhanced virulence compared to other lineages, and in certain regions, they are associated with the dramatic spread of multidrug-resistant tuberculosis (TB). In terms of trying to understand the functional basis for these broad epidemiological phenomena, it is interesting that, in contrast to the other major lineages, the Beijing strains all constitutively overexpress members of the DosR regulon. Here, we identify the mutational events that led to the evolution of this unique phenotype. In addition, our work highlights the fact that important phenotypic differences exist between distinct M. tuberculosis lineages, with the potential to impact the efficacy of diagnosis, vaccination, and treatment programs.

scholarly journals Type I Interferons Increase Host Susceptibility to Trypanosoma cruzi Infection

2011 ◽  
Vol 79 (5) ◽  
pp. 2112-2119 ◽  
Author(s):  
Anne-Danielle C. Chessler ◽  
Kacey L. Caradonna ◽  
Akram Da'dara ◽  
Barbara A. Burleigh
Keyword(s):  
Trypanosoma Cruzi ◽  
Parasite Burden ◽  
Host Susceptibility ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Content Type ◽  
Type I Ifns ◽  
Ifn Γ ◽  
The Impact

ABSTRACTTrypanosoma cruzi, the protozoan parasite that causes human Chagas' disease, induces a type I interferon (IFN) (IFN-α/β) response during acute experimental infection in mice and in isolated primary cell types. To examine the potential impact of the type I IFN response in shaping outcomes in experimentalT. cruziinfection, groups of wild-type (WT) and type I IFN receptor-deficient (IFNAR−/−) 129sv/ev mice were infected with two differentT. cruzistrains under lethal and sublethal conditions and several parameters were measured during the acute stage of infection. The results demonstrate that type I IFNs are not required for early host protection againstT. cruzi. In contrast, under conditions of lethalT. cruzichallenge, WT mice succumbed to infection whereas IFNAR−/−mice were ultimately able to control parasite growth and survive.T. cruziclearance in and survival of IFNAR−/−mice were accompanied by higher levels of IFN-γ production by isolated splenocytes in response to parasite antigen. The suppression of IFN-γ in splenocytes from WT mice was independent of IL-10 levels. While the impact of type I IFNs on the production of IFN-γ and other cytokines/chemokines remains to be fully determined in the context ofT. cruziinfection, our data suggest that, under conditions of high parasite burden, type I IFNs negatively impact IFN-γ production, initiating a detrimental cycle that contributes to the ultimate failure to control infection. These findings are consistent with a growing theme in the microbial pathogenesis field in which type I IFNs can be detrimental to the host in a variety of nonviral pathogen infection models.

scholarly journals Impact of Currently Marketed Tampons and Menstrual Cups onStaphylococcus aureusGrowth and Toxic Shock Syndrome Toxin 1 ProductionIn Vitro

2018 ◽  
Vol 84 (12) ◽  
pp. e00351-18 ◽  
Author(s):  
Louis Nonfoux ◽  
Myriam Chiaruzzi ◽  
Cédric Badiou ◽  
Jessica Baude ◽  
Anne Tristan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Toxic Shock Syndrome ◽  
Severe Disease ◽  
Toxin Production ◽  
Toxic Shock ◽  
Content Type ◽  
Physiological Conditions ◽  
Simple Protocol ◽  
Toxic Shock Syndrome Toxin ◽  
The Impact

ABSTRACTFifteen currently marketed intravaginal protection products (11 types of tampon and 4 types of menstrual cup) were tested by the modified tampon sac method to determine their effect onStaphylococcus aureusgrowth and toxic shock syndrome toxin 1 (TSST-1) production. Most tampons reducedS. aureusgrowth and TSST-1 production, with differences based on brand and composition, and the level ofS. aureusgrowth was higher in destructured than in unaltered tampons. We observed higher levels ofS. aureusgrowth and toxin production in menstrual cups than in tampons, potentially due to the additional air introduced into the bag by cups, with differences based on cup composition and size.IMPORTANCEMenstrual toxic shock syndrome is a rare but severe disease. It occurs in healthy women vaginally colonized byStaphylococcus aureusproducing toxic shock syndrome toxin 1 using intravaginal protection, such as tampons or menstrual cups. Intravaginal protection induces TSS by the collection of catamenial products, which act as a growth medium forS. aureus. Previous studies evaluated the impact of tampon composition onS. aureusproducing toxic shock syndrome toxin 1, but they are not recent and did not include menstrual cups. This study demonstrates that highly reproducible results forS. aureusgrowth and TSST-1 production can be obtained by using a simple protocol that reproduces the physiological conditions of tampon and cup usage as closely as possible, providing recommendations for tampon or cup use to both manufacturers and consumers. Notably, our results do not show that menstrual cups are safer than tampons and suggest that they require similar precautions.

scholarly journals Developing New Drugs for Mycobacterium tuberculosis Therapy: What Information Do We Get from Preclinical Animal Models?

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
G. L. Drusano ◽  
Brandon Duncanson ◽  
C. A. Scanga ◽  
S. Kim ◽  
S. Schmidt ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Animal Models ◽  
Scale Up ◽  
New Drugs ◽  
Model Systems ◽  
Infection Model ◽  
New Agents ◽  
Content Type ◽  
Preclinical Animal Models ◽  
The Impact

ABSTRACT Preclinical animal models of infection are employed to develop new agents but also to screen among molecules to rank them. There are often major differences between human pharmacokinetic (PK) profiles and those developed by animal models of infection, and these may lead to substantial differences in efficacy relative to that seen in humans. Linezolid is a repurposed agent employed to great effect for therapy of Mycobacterium tuberculosis. In this study, we used the hollow-fiber infection model (HFIM) to evaluate the impact of different pharmacokinetic profiles of mice and nonhuman primates (NHP) versus humans on bacterial cell kill as well as resistance suppression. We examined both plasma and epithelial lining fluid (ELF) profiles. We examined simulated exposures equivalent to 600 mg and 900 mg daily of linezolid in humans. For both plasma and ELF exposures, the murine PK profile provided estimates of effect that were biased low relative to human and NHP PK profiles. Mathematical modeling identified a linkage between minimum concentrations (Cmin) and bacterial kill and peak concentrations (Cpeak) and resistance suppression, with the latter being supported by a prospective validation study. Finding new agents with novel mechanisms of action against M. tuberculosis is difficult. It would be a tragedy to discard a new agent because of a biased estimate of effect in a preclinical animal system. The HFIM provides a system to benchmark evaluation of new compounds in preclinical animal model systems against human PK effects (species scale-up estimates of PK), to safeguard against unwarranted rejection of promising new agents.

scholarly journals Effects of B Cell Depletion on Early Mycobacterium tuberculosis Infection in Cynomolgus Macaques

2016 ◽  
Vol 84 (5) ◽  
pp. 1301-1311 ◽  
Author(s):  
Jiayao Phuah ◽  
Eileen A. Wong ◽  
Hannah P. Gideon ◽  
Pauline Maiello ◽  
M. Teresa Coleman ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
B Cells ◽  
B Cell ◽  
Humoral Immunity ◽  
Nonhuman Primates ◽  
Acute Infection ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Content Type ◽  
The Impact

Although recent studies in mice have shown that components of B cell and humoral immunity can modulate the immune responses againstMycobacterium tuberculosis, the roles of these components in human and nonhuman primate infections are unknown. The cynomolgus macaque (Macaca fascicularis) model ofM. tuberculosisinfection closely mirrors the infection outcomes and pathology in human tuberculosis (TB). The present study used rituximab, an anti-CD20 antibody, to deplete B cells inM. tuberculosis-infected macaques to examine the contribution of B cells and humoral immunity to the control of TB in nonhuman primates during the acute phase of infection. While there was no difference in the overall pathology, disease profession, and clinical outcome between the rituximab-treated and untreated macaques in acute infection, analyzing individual granulomas revealed that B cell depletion resulted in altered local T cell and cytokine responses, increased bacterial burden, and lower levels of inflammation. There were elevated frequencies of T cells producing interleukin-2 (IL-2), IL-10, and IL-17 and decreased IL-6 and IL-10 levels within granulomas from B cell-depleted animals. The effects of B cell depletion varied among granulomas in an individual animal, as well as among animals, underscoring the previously reported heterogeneity of local immunologic characteristics of tuberculous granulomas in nonhuman primates. Taken together, our data clearly showed that B cells can modulate the local granulomatous response inM. tuberculosis-infected macaques during acute infection. The impact of these alterations on disease progression and outcome in the chronic phase remains to be determined.

scholarly journals The Endothelin System Has a Significant Role in the Pathogenesis and Progression of Mycobacterium tuberculosis Infection

2014 ◽  
Vol 82 (12) ◽  
pp. 5154-5165 ◽  
Author(s):  
Andre F. Correa ◽  
Alexandre M. Bailão ◽  
Izabela M. D. Bastos ◽  
Ian M. Orme ◽  
Célia M. A. Soares ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type ◽  
Host Interactions ◽  
Endothelin System ◽  
Etb Receptor ◽  
The Impact ◽  
The Relationship ◽  
Host Tissues

ABSTRACTTuberculosis (TB) remains a major global health problem, and although multiple studies have addressed the relationship betweenMycobacterium tuberculosisand the host on an immunological level, few studies have addressed the impact of host physiological responses. Proteases produced by bacteria have been associated with important alterations in the host tissues, and a limited number of these enzymes have been characterized in mycobacterial species.M. tuberculosisproduces a protease called Zmp1, which appears to be associated with virulence and has a putative action as an endothelin-converting enzyme. Endothelins are a family of vasoactive peptides, of which 3 distinct isoforms exist, and endothelin 1 (ET-1) is the most abundant and the best-characterized isoform. The aim of this work was to characterize the Zmp1 protease and evaluate its role in pathogenicity. Here, we have shown thatM. tuberculosisproduces and secretes an enzyme with ET-1 cleavage activity. These data demonstrate a possible role of Zmp1 for mycobacterium-host interactions and highlights its potential as a drug target. Moreover, the results suggest that endothelin pathways have a role in the pathogenesis ofM. tuberculosisinfections, and ETA or ETB receptor signaling can modulate the host response to the infection. We hypothesize that a balance between Zmp1 control of ET-1 levels and ETA/ETB signaling can allowM. tuberculosisadaptation and survival in the lung tissues.

scholarly journals Mycobacterium tuberculosis Subculture Results in Loss of Potentially Clinically Relevant Heteroresistance

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
John Z. Metcalfe ◽  
Elizabeth Streicher ◽  
Grant Theron ◽  
Rebecca E. Colman ◽  
Renee Penaloza ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Genotypic Resistance ◽  
Content Type ◽  
Multiple Drug Resistant ◽  
Dynamic Loss ◽  
Tb Diagnostics ◽  
The Impact

ABSTRACT Multidrug-resistant tuberculosis (TB) presents a major public health dilemma. Heteroresistance, the coexistence of drug-resistant and drug-susceptible strains or of multiple drug-resistant strains with discrete haplotypes, may affect accurate diagnosis and the institution of effective treatment. Subculture, or passage of cells onto fresh growth medium, is utilized to preserve Mycobacterium tuberculosis cell lines and is universally employed in TB diagnostics. The impact of such passages, typically performed in the absence of drug, on drug-resistant subpopulations is hypothesized to vary according to the competitive costs of genotypic resistance-associated variants. We applied ultradeep next-generation sequencing to 61 phenotypically rifampin-monoresistant (n = 17) and preextensively (n = 41) and extensively (n = 3) drug-resistant isolates with presumptive heteroresistance at two time points in serial subculture. We found significant dynamic loss of minor-variant resistant subpopulations across all analyzed resistance-determining regions, including eight isolates (13%) whose antibiogram data would have transitioned from resistant to susceptible for at least one drug through subculture. Surprisingly, some resistance-associated variants appeared to be selected for in subculture.

scholarly journals DNA Gyrase Inhibition Assays Are Necessary To Demonstrate Fluoroquinolone Resistance Secondary togyrBMutations in Mycobacterium tuberculosis

2011 ◽  
Vol 55 (10) ◽  
pp. 4524-4529 ◽  
Author(s):  
Alix Pantel ◽  
Stéphanie Petrella ◽  
Stéphanie Matrat ◽  
Florence Brossier ◽  
Sylvaine Bastian ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Susceptibility Testing ◽  
Dna Gyrase ◽  
Fluoroquinolone Resistance ◽  
Wild Type ◽  
Content Type ◽  
Clinical Strains ◽  
Highly Active ◽  
The Impact

ABSTRACTThe main mechanism of fluoroquinolone (FQ) resistance inMycobacterium tuberculosisis mutation in DNA gyrase (GyrA2GyrB2), especially ingyrA. However, the discovery of unknown mutations ingyrBwhose implication in FQ resistance is unclear has become more frequent. We investigated the impact on FQ susceptibility of eightgyrBmutations inM. tuberculosisclinical strains, three of which were previously identified in an FQ-resistant strain. We measured FQ MICs and also DNA gyrase inhibition by FQs in order to clarify the role of these mutations in FQ resistance. Wild-type GyrA, wild-type GyrB, and mutant GyrB subunits produced from engineeredgyrBalleles by mutagenesis were overexpressed inEscherichia coli, purified to homogeneity, and used to reconstitute highly active gyrase complexes. MICs and DNA gyrase inhibition were determined for moxifloxacin, gatifloxacin, ofloxacin, levofloxacin, and enoxacin. We demonstrated that the eight substitutions in GyrB (D473N, P478A, R485H, S486F, A506G, A547V, G551R, and G559A), recently identified in FQ-resistant clinical strains or encountered inM. tuberculosisstrains isolated in France, are not implicated in FQ resistance. These results underline that, as opposed to phenotypic FQ susceptibility testing, the DNA gyrase inhibition assay is the only way to prove the role of a DNA gyrase mutation in FQ resistance. Therefore, the use of FQ in the treatment of tuberculosis (TB) patients should not be ruled out only on the basis of the presence of mutations ingyrB.

scholarly journals Probiotic Bifidobacterium lactis V9 Regulates the Secretion of Sex Hormones in Polycystic Ovary Syndrome Patients through the Gut-Brain Axis

mSystems ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Jiachao Zhang ◽  
Zhihong Sun ◽  
Shuaiming Jiang ◽  
Xiaoye Bai ◽  
Chenchen Ma ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Sex Hormones ◽  
Intestinal Microbiota ◽  
Polycystic Ovary ◽  
Intestinal Microbiome ◽  
Ovary Syndrome ◽  
Bifidobacterium Lactis ◽  
Content Type ◽  
Gut Colonization ◽  
The Impact

ABSTRACT Although a few studies have investigated the intestinal microbiota of women with polycystic ovary syndrome (PCOS), the functional and metabolic mechanisms of the microbes associated with PCOS, as well as potential microbial biomarkers, have not yet been identified. To address this gap, we designed a two-phase experiment in which we performed shotgun metagenomic sequencing and monitored the metabolic parameters, gut-brain mediators, and sex hormones of PCOS patients. In the first stage, we identified an imbalance in the intestinal microbiota of the PCOS patients, observing that Faecalibacterium, Bifidobacterium, and Blautia were significantly more abundant in the control group, whereas Parabacteroides and Clostridium were enriched in the PCOS group. In the second stage, we monitored the impact of the probiotic Bifidobacterium lactis V9 on the intestinal microbiome, gut-brain mediators, and sex hormones of 14 PCOS patients. Notably, we observed that the levels of luteinizing hormone (LH) and LH/follicle-stimulating hormone (LH/FSH) decreased significantly in 9 volunteers, whereas the levels of sex hormones and intestinal short-chain fatty acids (SCFAs) increased markedly. In contrast, the changes in the indices mentioned above were indistinct in the remaining 5 volunteers. The results of an analysis of the number of viable Bifidobacterium lactis V9 cells in the two groups were highly consistent with the clinical and SCFA results. Therefore, effective host gut colonization of the probiotic Bifidobacterium lactis V9 was crucial for its ability to function as a probiotic. Finally, we propose a potential mechanism describing how probiotics regulate the levels of sex hormones by manipulating the intestinal microbiome in PCOS patients. IMPORTANCE Polycystic ovary syndrome (PCOS) is a common metabolic disorder among women of reproductive age worldwide. Through a two-phase clinical experiment, we first revealed an imbalance in the intestinal microbiome of PCOS patients. By binning and annotating shotgun metagenomic sequences into metagenomic species (MGS), 61 MGSs were identified as potential PCOS-related microbial biomarkers. In the second stage, we monitored the impact of the probiotic Bifidobacterium lactis V9 on the intestinal microbiota, metabolic parameters, gut-brain mediators, and sex hormones of PCOS patients. Notably, we observed that the PCOS-related clinical indices and the intestinal microbiotas of the participating patients exhibited an inconsistent response to the intake of the B. lactis V9 probiotic. Therefore, effective host gut colonization of the probiotic was crucial for its ability to function as a probiotic. Finally, we propose a potential mechanism by which B. lactis V9 regulates the levels of sex hormones by manipulating the intestinal microbiome in PCOS patients.

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