Cysteine dependence of Lactobacillus iners is a potential therapeutic target for vaginal microbiota modulation

Vaginal microbiota composition affects many facets of reproductive health. Lactobacillus iners-dominant microbial communities are associated with poorer outcomes, including higher risk of bacterial vaginosis (BV), compared with vaginal microbiota rich in Lactobacillus crispatus. Unfortunately, standard-of-care metronidazole therapy for BV typically results in dominance of L. iners, likely contributing to post-treatment relapse. Here we generate an L. iners isolate collection comprising 34 previously unreported isolates from 14 South African with and without BV and 4 previously unreported isolates from 3 US women and we report an associated genome catalog comprising 1,218 vaginal Lactobacillus isolate genomes and metagenome-assembled genomes (MAGs) from >300 women across four continents. We show that, unlike L. crispatus, L. iners growth is dependent on L-cysteine in vitro and we trace this phenotype to the absence of canonical cysteine biosynthesis pathways and a restricted repertoire of cysteine-related transport mechanisms. We further show cysteine concentrations in cervicovaginal lavage samples correlate with Lactobacillus abundance in vivo and that cystine uptake inhibitors selectively inhibit L. iners growth in vitro. Combining an inhibitor with metronidazole promotes L. crispatus dominance of defined BV-like communities in vitro by suppressing L. iners growth. Our findings enable a better understanding of L. iners biology and suggest candidate treatments to modulate the vaginal microbiota to improve reproductive health for women globally.

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We look forward to hearing from you soon.This is an excellent study that provides important information for the cervicovaginal microbiome field.The study focusses on characterizing the growth requirements of Lactobacillus iners.This species is highly prevalent in the FGT and is associated with important adverse sexual and reproductive outcomes.However, the functional properties of L. iners and interactions between this species and other microbes that may lead to these outcomes and also explain its prevalence are not well understood.This is largely due to the fact that it is difficult to culture and characterize L. iners in vitro.The study demonstrates that the growth of L. iners isolates was dependent on the availability of Lcysteine, but that L. iners lacked cysteine biosynthesis pathways and key uptake mechanisms that were present in other lactobacilli.The latter was determined through the analysis of >1200 Lactobacillus isolate genomes and metagenome-assembled genomes.The study further showed that Open Access This file is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.In the cases where the authors are anonymous, such as is the case for the reports of anonymous peer reviewers, author attribution should be to 'Anonymous Referee' followed by a clear attribution to the source work.The images or other third party material in this file are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.growth of L. iners was inhibited by cystine uptake inhibitors that did not affect other Lactobacillus species.This study thus provides very useful information about how to isolate and culture L. iners, a further understanding of the functional properties of this species and identifies cystine uptake inhibitors as a possible therapeutic to target L. iners and favor the growth of other lactobacilli following antibiotic treatment for BV.This approach may reduce BV recurrence following treatment, as L. iners dominant communities are highly likely to transition back to BV.The findings are novel and this is a well written and scientifically sound manuscript that requires minor revision prior to publication.
Minor comments: 1.The authors were not able to identify the cystine uptake mechanism utilized by L. iners and that was targeted by the uptake inhibitors utilized in this study.2. It is noted that some experiments included only single or a limited number of L. iners strains, e.g.isotopic tracer experiments.Since major functional differences can exist between strains, can the authors comment on how generalizable these particular findings would be to other strains? 3.Although the use of cystine uptake inhibitors may be a promising strategy to reduce BV recurrence, the authors note that the particular inhibitors used in this study had low potency or potential host toxicity.It would be useful to mention if other uptake inhibitors exist that may be effective and nontoxic in humans.Additionally, it would be useful to comment on the possible impact of uptake inhibitors on host cells and the mucosal barrier -if L-cysteine is considered anti-inflammatory and improves epithelial barrier function, is it possible that treatment with an uptake inhibitor may have a detrimental impact on the mucosal barrier? 4. Page 7, line 142: There is evidence in previous studies showing that the behavior of lactobacilli strains can be modified by switching on or off specific metabolic pathways in response to stress (reviewed by De Angelis et al., 2016).It would be helpful if the authors commented on whether there were any differences in characteristics evaluated in this study between L. iners obtained from BV positive and negative women in this study.5. Page 4, line 73: Clarify in the Abstract that the following work was conducted in vitro: "We demonstrate that cystine uptake inhibitors selectively impede L. iners growth and that combining an inhibitor with metronidazole thus promotes L. crispatus dominance of defined BV-like communities.6. Page 5, line 85: In reference to the following statement "One notable exception is Lactobacillus iners-dominant communities, which are associated with many of the same unfavorable outcomes as BV", please clarify whether L. iners is associated with the same risk of unfavourable outcomes as BV, or is risk relatively lower?7. Page 6, line 106: Define "MRS" 8. Page 8: U.S. and US used interchangeably 9. Page 18, line 374: Is it possible that L-cysteine concentration in the FGT is not directly associated with the microbiota, but is rather associated with inflammation?Please comment.
Reviewer #3 (Remarks to the Author): This manuscript represents a significant advance in our understanding of the dynamics of the microbiome of the female reproductive tract.I particular, it identifies a previously unappreciated mechanism by which Lactobacillus taxa often represent the predominant components of the Open Access This file is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.In the cases where the authors are anonymous, such as is the case for the reports of anonymous peer reviewers, author attribution should be to 'Anonymous Referee' followed by a clear attribution to the source work.The images or other third party material in this file are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.microbiome; i.e., their ability to utilize cystine.Moreover, the manuscript identifies differences in the ability of L. iners and other lactobacillus species to utilize these compounds, namely, the ability to transport these metabolites.The manuscript elegantly combines informatic inferences from genomic sequences with simple in vitro growth and biophysical measures in real samples to validate these hypotheses.The one possible weakness of the manuscript is that it doesn't sufficiently address a major taxon (i.e., Lachnocurva vaginae or BVAB1) associated with bacterial vaginosis and other less favorable outcomes.That said, conditions for culture of this bacterium are not readily available.
In addition to the biological significance of the manuscript, there are also clinical implications.Thus, the comparison of growth efficiency of various taxa in the presence of the most common treatment of bacterial vaginosis (e.g., metranidazole) and Cys transport inhibitors suggests new possible modes of clinical intervention.

Author Rebuttal to Initial comments
This is an excellent study that provides important information for the cervicovaginal microbiome field.The study focusses on characterizing the growth requirements of Lactobacillus iners.This species is highly prevalent in the FGT and is associated with important adverse sexual and reproductive outcomes.However, the functional properties of L. iners and interactions between this species and other microbes that may lead to these outcomes and also explain its prevalence are not well understood.This is largely due to the fact that it is difficult to culture and characterize L. iners in vitro.The study demonstrates that the growth of L. iners isolates was dependent on the availability of L-cysteine, but that L. iners lacked cysteine biosynthesis pathways and key uptake mechanisms that were present in other lactobacilli.The latter was determined through the analysis of >1200 Lactobacillus isolate genomes and metagenomeassembled genomes.The study further showed that growth of L. iners was inhibited by cystine uptake inhibitors that did not affect other Lactobacillus species.This study thus provides very useful information about how to isolate and culture L. iners, a further understanding of the functional properties of this species and identifies cystine uptake inhibitors as a possible therapeutic to target L. iners and favor the growth of other lactobacilli following antibiotic treatment for BV.This approach may reduce BV recurrence following treatment, as L. iners dominant communities are highly likely to transition back to BV.The findings are novel and this is a well written and scientifically sound manuscript that requires minor revision prior to publication.
Minor comments: 1.The authors were not able to identify the cystine uptake mechanism utilized by L. iners and that was targeted by the uptake inhibitors utilized in this study.
Author response: Identification of the relevant cysteine/cystine uptake mechanism(s) in L. iners is an obvious area of future interest and importance.Due to the relatively sparse literature on cysteine-related uptake mechanisms in bacteria more generally, considerable further work may be needed to identify and validate candidate transporters in this species, which is not currently tractable to tools for genetic manipulation.
2. It is noted that some experiments included only single or a limited number of L. iners strains, e.g.isotopic tracer experiments.Since major functional differences can exist between strains, can the authors comment on how generalizable these particular findings would be to other strains?
Author response: We thank the review for raising this point.The cost and laborintensive nature of the isotopic tracer experiments precluded extending them to the full diverse range of experimental strains tested in our other experimental assays.However, we believe it is reasonable to make species-level extrapolations from the results of the isotopic tracer experiments because the results are consistent with mechanisms predicted by both genome-based predictions from analysis of large, diverse genome collections and phenotype-based predictions from growth and inhibition studies of a diverse set of experimental isolates that share the same genomic features.We have modified language in the Results describing isotopic tracer experiments to read (key added text is underlined): "To phenotypically test this result, we used isotopic tracing to measure the ability of L. iners and L. crispatus to convert Ser into Cys in vitro.Representative strains were grown in MRSQ broth supplemented with labeled Ser ( 13 C-L-Ser) plus homocysteine or with labeled L-Cys ( 13 C-L-Cys; labeling scheme in Fig. 2a), then cellular amino acid isotopic labeling was analyzed via liquid chromatography-mass spectrometry (LC-MS).Both L. iners and L. crispatus took up labeled Ser but failed to convert it to Cys (Fig. 2c,d), consistent with mechanistic predictions from genomic analysis of the comprehensive species genome collections (Fig. 2a,b and Supplementary Table 4)." Open Access This file is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.In the cases where the authors are anonymous, such as is the case for the reports of anonymous peer reviewers, author attribution should be to 'Anonymous Referee' followed by a clear attribution to the source work.The images or other third party material in this file are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
3. Although the use of cystine uptake inhibitors may be a promising strategy to reduce BV recurrence, the authors note that the particular inhibitors used in this study had low potency or potential host toxicity.It would be useful to mention if other uptake inhibitors exist that may be effective and non-toxic in humans.Additionally, it would be useful to comment on the possible impact of uptake inhibitors on host cells and the mucosal barrier -if L-cysteine is considered anti-inflammatory and improves epithelial barrier function, is it possible that treatment with an uptake inhibitor may have a detrimental impact on the mucosal barrier?
Author Response: We appreciate these relevant points and have modified the text as follows (underlined text is new): "The specific inhibitors identified here have potential limitations for use in humans including low potency (SMC) and possible host toxicity (SDLC), and their effects (if any) on the FGT mucosa remain to be characterized.However, our results demonstrate proof of concept for a novel therapeutic approach and provide a rationale to identify additional inhibitors targeting L. iners through this mechanism."4. Page 7, line 142: There is evidence in previous studies showing that the behavior of lactobacilli strains can be modified by switching on or off specific metabolic pathways in response to stress (reviewed by De Angelis et al., 2016).It would be helpful if the authors commented on whether there were any differences in characteristics evaluated in this study between L. iners obtained from BV positive and negative women in this study.
Author Response: We thank the reviewer for raising this interesting question.We agree that that it is highly likely that some metabolic pathways in FGT Lactobacillus species are modified in response to environmental conditions and stresses, such as those encountered within the microbiome during BV.We therefore placed considerable emphasis on validating our phenotypic and genomic results using strains from both North America and South Africa, as well as from women both with and without BV and with diverse microbiota compositions (Figure 1b, Supplementary Table 3).We also validated inhibitor performance in diverse media growth conditions.In summary, we observed no obvious differences in the genomic and phenotypic features of interest between L. iners strains from women with different geographical origins or BV status.
Open Access This file is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.In the cases where the authors are anonymous, such as is the case for the reports of anonymous peer reviewers, author attribution should be to 'Anonymous Referee' followed by a clear attribution to the source work.The images or other third party material in this file are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Based on the concordance between our genomic and phenotypic results, we therefore believe that the features we identify here are primarily due to underlying, universal genetic characteristics of the species rather than due to modifiable patterns of gene regulation or epigenetic modification.
In order to further emphasize this point, we have modified the Results section in two locations as follows.
In the second paragraph of the Results, in which we describe the phenotype of Cysdependent growth, we have modified the final two sentences to read (underlined text is new): "Strains broadly representative of species diversity isolated from South African and US women both with and without BV were selected for further experimental characterization (Fig. 1b and Supplementary Table 3).All selected strains grew in MRSQ broth with L-Cys (representative examples in Fig. 1c), confirming Cys-dependent growth as a species-level phenotype." Additionally, in the Results section describing growth inhibition by cystine uptake inhibitors, we have added text to emphasize the uniformity of the phenotype across strains from diverse clinical contexts and in diverse metabolic culture conditions (Underlined text is new): "SMC caused species-specific, dose-dependent growth inhibition of a diverse collection of L. iners strains at concentrations of 32-64 mM, while SDLC caused selective inhibition at 0.25 mM (Fig. 4d,e and Extended Data Fig. 6b,c).Inhibition occurred for strains from both US and South African women, and from women both with and without BV (Supplementary Table 3)… To confirm that growth inhibition was not an artefact specific to MRS media, we assessed inhibition in NYCIII broth, a serum-containing, nutrient-rich medium that supports growth of diverse fastidious FGT bacteria 49 .Both SMC and SDLC inhibited L. iners growth in NYCIII broth, but not growth of L. crispatus (Fig. 4f)." Open Access This file is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.In the cases where the authors are anonymous, such as is the case for the reports of anonymous peer reviewers, author attribution should be to 'Anonymous Referee' followed by a clear attribution to the source work.The images or other third party material in this file are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
non-Lactobacillus-dominant, BV-associated communities and with L. crispatus-dominant communities.For instance, in our group's prior work examining microbiome-associated HIV risk in the FRESH cohort in South Africa (Gosmann, 2017), we observed no incident HIV infections in women with L. crispatus-dominant (CT1) communities, whereas infections occurred in women with L. iners-dominant communities (CT2), and in women with the two BV-associated cervicotypes, CT3 and CT4 (the relevant figure on acquisition risk from Gosmann, 2017, is copied below).{redacted} Although there was a trend toward higher infection rates in CT4 and CT3 compared to CT2, the analysis in this cohort of 236 individuals was not powered to determine whether HIV risk in CT2 was genuinely lower than in CT3 and CT4.
Similarly, in a recent excellent meta-analysis of the relationship between the FGT microbiota, high-risk human papillomavirus (hrHPV) infection, and cervical neoplasia, Norenhag et al (BJOG, 2020) calculated the odds ratios of presence of hrHPV in women with L. crispatus-dominant communities compared to both L. iners-dominant communities and "Low lactobacilli" communities, as well as calculating the odds ratios between L. iners-dominant communities and "Low lactobacilli" communities.(Presumptively, the "Low lactobacilli" communities predominantly represent diverse, anaerobe-dominant communities associated with BV.) Norenhag et al found that compared to L. crispatus-dominant communities, the association with hrHPV infection was significantly higher for women with L. iners-dominant communities (OR 2.11, 95%CI 1.28-3.46)and women with "Low lactobacilli" communities (OR 2.82, 95%CI 1.69-4.70),with overlapping confidence intervals but a higher point estimate for the OR of "Low lactobacilli" compared to L. iners-dominance.In the direct comparison of L. inersdominant communities to "Low lactobacilli" communities, the association with prevalent hrHPV was non-significantly higher for "Low lactobacilli" communities (OR 1.34, 95%CI 0.96-1.

87). Norenhag et al reported a similar pattern when examining association between microbiota composition and presence of any HPV infection or presence of squamous intraepithelial lesions (SIL). (We are including the associated figure below from Norenhag et al for the reviewer's reference). {redacted}
Open Access This file is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.In the cases where the authors are anonymous, such as is the case for the reports of anonymous peer reviewers, author attribution should be to 'Anonymous Referee' followed by a clear attribution to the source work.The images or other third party material in this file are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
In aggregate, we believe these results suggest a pattern in which risk of various adverse outcomes is highest for women with BV-associated, non-Lactobacillus-dominant communities, somewhat lower for women with L. iners-dominant communities, and substantially lower for women with L. crispatus-dominant communities.However most existing studies lack the statistical power to definitively confirm this impression.Thus, in response to the reviewer's question, we request to leave the highlighted sentence from our manuscript unchanged because modifying it to say that risk is relatively lower with L. iners-dominant communities compared to BV (although likely true) would require an inference that is not directly demonstrated by most existing literature.

Page 6, line 106: Define "MRS"
Author response: In the indicated sentence, we have parenthetically added the names "(de Man, Rogosa, Sharpe)" for which MRS media is named.In this sentence, we have also added a citation to the foundational 1960 publication by these authors that first described this media formulation, leading to the eponymous abbreviation "MRS media".

Page 8: U.S. and US used interchangeably
Open Access This file is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.In the cases where the authors are anonymous, such as is the case for the reports of anonymous peer reviewers, author attribution should be to 'Anonymous Referee' followed by a clear attribution to the source work.The images or other third party material in this file are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain directly from the copyright holder.To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.cysteine concentrations in FGT secretions from women with BV-associated mucosal inflammation.We will explore this possible interaction between host inflammation and FGT metabolome composition into our future research.We have modified text in the Discussion as follows to mention the hypothesis (added text is underlined): "Since FGT lactobacilli appear to lack de novo Cys biosynthetic capacity, we hypothesize that the high Cys concentrations in Lactobacillus-dominant states are likely primarily host-derived.Possible mechanisms explaining the correlation could thus include preferential Lactobacillus colonization of hosts with high levels of mucosal Cys secretion, induction of host Cys secretion by lactobacilli, Cys degradation by host cells in setting of BV-associated inflammation 58 , and/or degradation of Cys by BV-associated bacteria 57 as a means to outcompete lactobacilli.Further investigation of FGT microbiome-metabolome relationships will be required to fully assess these possibilities." Reviewer #3 (Remarks to the Author): This manuscript represents a significant advance in our understanding of the dynamics of the microbiome of the female reproductive tract.I particular, it identifies a previously unappreciated mechanism by which Lactobacillus taxa often represent the predominant components of the microbiome; i.e., their ability to utilize cystine.Moreover, the manuscript identifies differences in the ability of L. iners and other lactobacillus species to utilize these compounds, namely, the ability to transport these metabolites.The manuscript elegantly combines informatic inferences from genomic sequences with simple in vitro growth and biophysical measures in real samples to validate these hypotheses.The one possible weakness of the manuscript is that it doesn't sufficiently address a major taxon (i.e., Lachnocurva vaginae or BVAB1) associated with bacterial vaginosis and other less favorable outcomes.That said, conditions for culture of this bacterium are not readily available.
In addition to the biological significance of the manuscript, there are also clinical implications.Thus, the comparison of growth efficiency of various taxa in the presence of the most common treatment of bacterial vaginosis (e.g., metranidazole) and Cys transport inhibitors suggests new possible modes of clinical intervention.
Open Access This file is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.In the cases where the authors are anonymous, such as is the case for the reports of peer reviewers, author attribution should be to 'Anonymous Referee' followed by a clear attribution to the source work.The images or other third party material in this file are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Author response: We thank the reviewer for these thoughtful comments.We share their interest in understanding the biology, metabolism, and health effects of the uncultured provisional species Candidatus Lachnocurva vaginae (BVAB1), which has been recognized as holding important epidemiologic associations since its initial description from culture-independent 16S RNA gene sequencing by Fredricks et al in 2005 (NEJM).To our knowledge, this species remains uncultivated; the recent publication renaming it from BVAB1 to Ca. Lachnocurva vaginae by Holm et al (2020, Front Cell Infect Microbiol) relied on culture-independent metagenome-assembled genomes (MAGs), and it therefore remains a provisional Candidatus species designation due to lack of an isolated type strain.Although not heavily emphasized in our current manuscript, during the bacterial isolation efforts that produced our catalog of Lactobacillus isolates, we also generated primary bacterial isolates of dozens of other genital tract species using a variety of media formulations.These isolation efforts will be described in greater detail in future manuscripts.We had hoped that our work might succeed in isolating Ca.Lachnocurva vaginae, but although we did isolate a number of seemingly novel genital tract species, Ca.Lachnocurva vaginae was not among them.We believe therefore that its growth must depend on additional exogenous nutrients beyond what is required to support the growth of Lactobacillus iners and other fastidious species within the genital tract microbiota.

Decision Letter, first revision:
Dear Doug, Thank you for submitting your revised manuscript "Lactobacillus iners cysteine dependence is a novel therapeutic target to modify the vaginal microbiota" (NMICROBIOL-21061527A).It has now been assessed editorially given the relatively minor concerns raised previously by reviewers and we found that the paper has improved in revision, and therefore we'll be happy in principle to publish it in Nature Microbiology, pending minor revisions to comply with our editorial and formatting guidelines.
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Thank you again for your interest in Nature Microbiology Please do not hesitate to contact me if you have any questions.

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Final Decision Letter:
Dear Doug, I am pleased to accept your Article "Cysteine dependence of Lactobacillus iners is a potential therapeutic target for vaginal microbiota modulation" for publication in Nature Microbiology.Thank you for having chosen to submit your work to us and many congratulations.
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Figure
Figure legends must provide a brief description of the figure and the symbols used, within 350 words, Bacterial vaginosis, vaginal microbiome, Lactobacillus Referee #3: vaginal microbiome, women's health, 'omics Reviewers Comments:Reviewer #1 (Remarks to the Author):