Enhancing Human Superorganism Ecosystem Resilience by Holistically ‘Managing Our Microbes’

Round 1

Reviewer 1 Report

This paper is very interesting. This manuscript was performed by scientific methods.

Author Response

Thank you for reviewing our paper. We hope you also enjoy reading our revised manuscript.

Reviewer 2 Report

I’ve read the manuscript by Coleman et al. with some interest. After reading it, it is unclear to me what this manuscript tries to accomplish. We know that we can manage our microbes to some extent. The paper then goes on to pick 3 cases, to go in-depth. At least one of the cases is not one I’d have picked, since certainly the management of Pneumococci is way better understood than the gut-brain axis. Management of Pseudomonas in COPD would probably also be more important, and recently there has been some literature about hospital pathogens in connection with the cleaning policies (e.g. less harsh cleaning might be better, since it doesn’t destroy the natural environemntal microbiota, which might prevent hospital pathogens from colonizing the surrounding).

The authors then go on to describe various instances where microbes have been managed. They seem to ignore nutrition (besides for the breast milk example) and phage therapy entirely, where the former is probably relevant to the gut-brain axis, and the latter to the Cdif management. They also go way more in-depth into the Staph case than the 2 others. In the Cdif case there is also more than enough data to actually describe the controlled consortia (example given in the points), which is fully ignored here, and for the gut-brain axis the authors have not cited recent mouse studies about hunger and anger management (there were multiple within the last year in Nature/Science, I think).

The also perceive the writing style of the authors as too complicated, especially in the introduction.

Overall, this manuscript reads as if someone tried to string together 4 incoherent shallow reviews and make one manuscript out of it. The authors need to seriously clarify what they want to do here, and need to adjust the writing accordingly.

- I do like the graphical abstract, but the lower hand might need some “evil” microbes

- I’m missing the authors and affiliations in the PDF itself

- Citations which are definitely missing are the papers for MetaHit, the Human Microbiome Project, and the van Nood paper about FMT https://pubmed.ncbi.nlm.nih.gov/23323867/

- Line 210+: There is work going on about this, which probably should be cited, like https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6809015/ or the stuff from Seres

- the death of a patient after FMT should probably also be cited, since this is a good example how you should (not) manage your FMT samples

- I am unsure about the whole evidence map. Isn’t it obvious that I need to weigh the evidence? This whole section could be scrapped without any impact on the manuscript

Author Response

Reviewer 2: Comments and Suggestions for Authors

I’ve read the manuscript by Coleman et al. with some interest. After reading it, it is unclear to me what this manuscript tries to accomplish.

Thank you for this comment. We agree that our original submission did not articulate the aim and motivations of our work.

We prepared a major revision that includes clarifying text to nearly every section of the manuscript (Abstract; Introduction/Background; Case Studies, except Staph A; and Future for Managing our Microbes) and reorganized the fourth case study to include both the breastmilk evidence from Section 5 and information on policies on donor breastmilk and formula from Section 6.

The following is text in the final paragraph of Section 1.2, just above Section 2. Case Study 1.

The aim of our work is to facilitate advancement of targeted -omics research for future applications using formal methods of benefit-risk analysis. Incorporating -omics research is essential, from our perspective, to minimize oversimplifications and confirmation biases that otherwise limit effective medical and societal decision-making in ‘managing our microbes’ as superorganisms.

We know that we can manage our microbes to some extent. The paper then goes on to pick 3 cases, to go in-depth. At least one of the cases is not one I’d have picked, since certainly the management of Pneumococci is way better understood than the gut-brain axis. Management of Pseudomonas in COPD would probably also be more important, and recently there has been some literature about hospital pathogens in connection with the cleaning policies (e.g. less harsh cleaning might be better, since it doesn’t destroy the natural environemntal microbiota, which might prevent hospital pathogens from colonizing the surrounding).

Thank you for these comments. We selected case studies to represent a range of systems and routes, including two nosocomial infections (C. diff and S. aureus), the gut-brain axis for autism, and breastmilk for NICU infants. While we agree that other case studies are interesting and important, the selected case studies also illustrate differences in the ‘state of the science’ and uncertainties for ‘managing our microbes’, a point we address specifically in the breastmilk case study and the closing section of the revision, Future for Managing our Microbes.

The authors then go on to describe various instances where microbes have been managed. They seem to ignore nutrition (besides for the breast milk example) and phage therapy entirely, where the former is probably relevant to the gut-brain axis, and the latter to the Cdif management.

Thank you for these comments.

As suggested, our revision now cites additional studies on phage therapy for C. diff and on diet and nutrition in the concluding section, Future for Managing our Microbes.

They also go way more in-depth into the Staph case than the 2 others. In the Cdif case there is also more than enough data to actually describe the controlled consortia (example given in the points), which is fully ignored here, and for the gut-brain axis the authors have not cited recent mouse studies about hunger and anger management (there were multiple within the last year in Nature/Science, I think).

Thank you for these comments. We expanded the case studies for C. diff and ASD to provide additional detail that better parallels that of the Staph A case study.

We expanded the C. diff case section and added additional headings and discussion of ongoing clinical trials for the controlled consortia on C. diff from a recent review that included a product from SERES Therapeutics (Khanna, 2021). Also included is a new subsection 2.2. Using the Virome: Phage Therapy, citing 12 additional papers.

We also removed the 4^th level headings in the Staph case study for consistency.

We expanded the autism section to discuss additional studies (e.g., Ho et al., 2020; Agarwala et al., 2021; Freund et al., 2021). However, we did not cite additional mouse studies, except from the perspective of the need for deeper understanding of the mechanisms for benefits and risks in the Introduction/Background and the concluding section, Future for Managing our Microbes.

We re-organized the breastmilk section to better parallel the Staph A case study. We moved discussion of donor milk policy issues from the concluding Section 6 into Section 5, the case study on evidence for breastmilk benefits and risks.

Our major revision now cites 155 papers, including more than 40 additional papers that were not cited in our original submission to provide more balanced depth and context for each case study, as suggested by this Reviewer.

The also perceive the writing style of the authors as too complicated, especially in the introduction.

Overall, this manuscript reads as if someone tried to string together 4 incoherent shallow reviews and make one manuscript out of it. The authors need to seriously clarify what they want to do here, and need to adjust the writing accordingly.

Thank you for these comments. We agree that the submitted manuscript organization and transitions needed major improvements. My co-authors and I took significant time to prepare a major revision that now cites 155 studies, including more than 40 additional papers that were not cited in our original submission, to provide additional depth and clarity for our work. 

The major revision now includes a subsection 1.2. Expanding Traditional Risk Paradigms for the Microbiota that cites milestone work of two co-authors, D. Warner North, a member of the U.S. National Research Council committee that prepared the 1983 report commonly described as the ‘red book’ and M.E. Coleman, second author with H. Marks who prepared microbial risk assessment work published in 1998 in the journal Risk Analysis. We adapted a new Figure 1 from this work and begin each case study from the perspective of risk assessment. This new figure on the traditional microbial risk assessment framework is likely unfamiliar to Applied Microbiology readers. Each case study is then introduced relative to this framework. We also point out the importance of designing experiments to test causality, both to inform future risk analysis and to identify the microbes likely driving health and disease processes.

We revised the section headings and sub-headings throughout the revision, expanded the case study content for C. diff and ASD, and condensed discussions of breastmilk evidence and policy issues into the fourth case study.

We believe that our revision provides clearer transitions and connections to our aims and motivations.

- I do like the graphical abstract, but the lower hand might need some “evil” microbes

Thank you for the comment about the graphical abstract. The lower figure is intended to convey loss of density and diversity of natural microbiota for dysbiosis, not necessarily presence and levels of pathogens. We agree that pathogens may fill niches depopulated in dysbiosis. We considered adding text to describe this verbally rather than modifying the figure to insert bacterial pathogens.

- I’m missing the authors and affiliations in the PDF itself

Apologies that this information was not provided. Our revision includes this material.

- Citations which are definitely missing are the papers for MetaHit, the Human Microbiome Project, and the van Nood paper about FMT https://pubmed.ncbi.nlm.nih.gov/23323867/

- Line 210+: There is work going on about this, which probably should be cited, like https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6809015/ or the stuff from Seres Therapeutics

We revised the Introduction/Background to include the following studies: MetaHIT reference (Helman and Greenway, 2016); and Human Microbiome Project references (Helman and Greenway, 2016; NIH, 2019; iHMP Research Network Consortium, 2019; Ducarmon et al., 2021).

We considered the suggested abstract (Bobilev et al., 2019) but prefer to cite fully peer-reviewed studies in our revision. We also considered the study of Van Nood et al. (2013), but focused our revision on more recent work. The review by Khanna (2021) summarized recent clinical trials with defined probiotic consortia, including the VE303 trial described in the abstract and products from Seres Therapeutics, that were derived from human stool as alternatives to undefined FMT. We cited the papers noted above as well as more than 40 additional papers that were not cited in our original submission.

- the death of a patient after FMT should probably also be cited, since this is a good example how you should (not) manage your FMT samples

We cited a recent study on FMT adverse effects (Yadav and Khanna, 2021) about recent disease transmissions and deaths in some immunocompromised recipients, as well as other context for benefits and risks of FMT in the discussion of the Future for Managing our Microbes, as this information is relevant to C. diff and autism case studies and other potential preventative or therapeutic interventions.

- I am unsure about the whole evidence map. Isn’t it obvious that I need to weigh the evidence? This whole section could be scrapped without any impact on the manuscript

Thank you for commenting about uncertainties on the relevance of the breastmilk evidence map. We agree with the Reviewer that the need to weigh benefits is obvious; however, we are unaware of applications of benefit-risk methodology for evaluating evidence on ‘managing our microbes’.

We addressed this concern of the Reviewer by: i) introducing a modification of a figure on microbial risk assessment from one of our 1998 papers; and ii) provided transitions linking each case study to a need for future applications of benefit-risk methodology. The final section now emphasizes diet more strongly and closes with advantages of evidence mapping to inform research designs to fill knowledge gaps for risk analysis and decision support.

Our revision now cites 155 studies, with more than 40 additional papers that were not cited in our original submission. Further, we expanded our description of the motivation and development of the breastmilk evidence map to point out the need for consideration of both benefits and risks of potential therapeutic interventions to ‘manage our microbes’.

We revised the Abstract and added text in the Introduction and in the breastmilk evidence map sections to clarify the motivation and relevance of this case study that references a recently accepted manuscript in this special collection.

We see the value of this paper as a basis for future deliberations of the bodies of evidence for managing our microbes, not just with microbiologists, but with stakeholders in decisions, including public health professionals and perhaps consumers who may be confused by conflicting and ambiguous information and marketing for commercial products, be they pharmaceuticals or microbial products like probiotics, prebiotics, and synbiotics.

Thank you for your suggestions that were very helpful in preparing a major revision of our manuscript. We revised material in nearly every section of our initial submission: Abstract; Introduction/Background; each Case Study except Staph A; and Future for Managing our Microbes. We added three new figures and text that ties the content of the sections together in a more coherent form. We will acknowledge the helpful input of this Reviewer in the Acknowledgements section as appropriate.

Submission Date: 10 August 2021

Date of this review: 26 Aug 2021 14:56:42

Date of this response: 27 Sep 2021

SOME ADDITIONAL REFERENCES CITED IN REVISION

1. Adriaenssens EM. Phage Diversity in the Human Gut Microbiome: a Taxonomist's Perspective. mSystems. 2021;6(4):e0079921. doi:10.1128/mSystems.00799-21.
2. Agarwala, S., Naik, B., & Ramachandra, N. B. (2021). Mucosa-associated specific bacterial species disrupt the intestinal epithelial barrier in the autism phenome. Brain, Behavior, & Immunity-Health, 15, 100269.
3. Alcock J, Maley CC, Aktipis CA. Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. Bioessays. 2014 Oct;36(10):940-9. doi: 10.1002/bies.201400071. Epub 2014 Aug 8. PMID: 25103109; PMCID: PMC4270213.
4. Barber TM, Valsamakis G, Mastorakos G, Hanson P, Kyrou I, Randeva HS, Weickert MO. Dietary Influences on the Microbiota-Gut-Brain Axis. Int J Mol Sci. 2021 Mar 28;22(7):3502. doi: 10.3390/ijms22073502.
5. Beam A, Clinger E, Hao L. Effect of Diet and Dietary Components on the Composition of the Gut Microbiota. Nutrients. 2021 Aug 15;13(8):2795. doi: 10.3390/nu13082795.
6. Bienenstock J, Kunze WA, Forsythe P. Disruptive physiology: olfaction and the microbiome-gut-brain axis. Biol Rev Camb Philos Soc. 2018 Feb;93(1):390-403. doi: 10.1111/brv.12348..
7. Dietert RR, Dietert JM. Microbiome First Approaches in Pain Prevention and Management. Amer J Biomed Sci Res in press
8. Ducarmon, Q. R., Kuijper, E. J., & Olle, B. (2021). Opportunities and challenges in development of live biotherapeutic products to fight infections. The Journal of Infectious Diseases, 223(Supplement_3), S283-S289.
9. Esberg, A.; Haworth, S.; Hasslöf, P.; Lif Holgerson, P.; Johansson, I. Oral Microbiota Profile Associates with Sugar Intake and Taste Preference Genes. Nutrients 2020, 12, 681. https://doi.org/10.3390/nu12030681
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Author Response File: Author Response.pdf

Reviewer 3 Report

The authors have submitted a manuscript of illustrating a current overview regarding a possible beneficial relationship between microbes and humans for their healthy symbiosis. The authors searched a range of eligible literature, from well-known classical, and latest research regarding an association of microbiota with human diseases to current knowledge of management of microbes, resulting in reliable conclusions and perspective. This issue is of interest, and impact of their review is strong. My overall concern with the review describing the current available data regarding beneficial relationship between microbes and humans is that information provided may offer something substantial that helps advance our understanding of an innovative idea which draws beneficial living with microbes. The reference list may be useful for readers who are interested in this issue. A graphical abstract will serve as a take-home message for readers who wish to better understand the authors’ perspective.

To strengthen authors’ conclusion, The authors are strongly recommended to add what we should go beyond the results of “dysbiotic human superorganism”. The opposite, toxicological effects of expected outcomes, if known, may influence largely the authors’ perspective.

Author Response

Reviewer 3: Comments and Suggestions for Authors

The authors have submitted a manuscript of illustrating a current overview regarding a possible beneficial relationship between microbes and humans for their healthy symbiosis. The authors searched a range of eligible literature, from well-known classical, and latest research regarding an association of microbiota with human diseases to current knowledge of management of microbes, resulting in reliable conclusions and perspective. This issue is of interest, and impact of their review is strong.

Thank you for these comments.

My overall concern with the review describing the current available data regarding beneficial relationship between microbes and humans is that information provided may offer something substantial that helps advance our understanding of an innovative idea which draws beneficial living with microbes.

Thank you for noting this concern. We interpret your concern as your perception that we present an overly optimistic view of the state of the science and uncertainties as sufficient for managing our microbes for each case study.

We expanded the content of our case studies and introduced more risk analysis work in preparing a major revision. The revision provides additional detail and cited more than 40 additional references. We added a figure and context for risk analysis in the Introduction/Background section. We revised nearly every section in this major revision (Abstract, Introduction, three of four Case Studies, Future for Managing our Microbes).

The reference list may be useful for readers who are interested in this issue. A graphical abstract will serve as a take-home message for readers who wish to better understand the authors’ perspective.

Thank you for these comments. We are uncertain if the reviewer was noting that we need to provide the references in the journal format or additional references. The revision includes both: the appropriate reference format; and more than 40 additional studies that were not cited in our original submission.

It is unclear if the reviewer did not have access to our graphical abstract for this manuscript, or if the reviewer considered it overly simplistic. Note that we did clarify more of the complexity of the human microbiome as depicted in the graphical abstract by acknowledging that pathogens may re-populate niches in dysbiotic people, as per a similar comment from Reviewer 2. Also, we expanded our treatment of the broader context of the complexity of issues around managing our microbes and generalizability of results from small clinical trials to the general population.

To strengthen authors’ conclusion, The authors are strongly recommended to add what we should go beyond the results of “dysbiotic human superorganism”. The opposite, toxicological effects of expected outcomes, if known, may influence largely the authors’ perspective.

Thank you for these comments. We agree that both benefits and risks of interventions, whether pharmaceutical or microbiological, merit consideration in managing our microbes. We assume the Reviewer is requesting that the revision goes beyond considerations of dysbiosis and risk to supporting healthy superorganisms as benefits of ‘managing our microbes’.

In response to these comments and those of Reviewer 2, we undertook a major revision of our initial submission. We clarified the aim and motivation of the paper, and improved the transitions between sections. The revision provides more context for risk analysis and points to the need for future applications of formal methods of benefit risk analysis for multiple audiences: researchers who could design studies to fill knowledge gaps; decision makers who might develop evidence-based policies for ‘managing our microbes’; and consumers who may be confused by the often conflicting and ambiguous evidence from commercial companies, medical care providers, and researchers who promote portions of the full body of evidence.

We addressed this concern of the Reviewer by emphasizing the complexities of ecosystems and knowledge gaps for the case studies by citing more than 40 additional papers that were not cited in our original submission. We revised material in nearly every section of our initial submission: Abstract; Introduction/Background; each Case Study except Staph A; and Future for Managing our Microbes. Further, we expanded our description of the motivation and development of the breastmilk evidence map to point out the need for consideration of both benefits and risks of potential therapeutic interventions to ‘manage our microbes’. We added three new figures and text that tie sections together in a more coherent form.

Thank you for your suggestions that were helpful in preparing a major revision of our manuscript.

Submission Date: 10 August 2021

Date of this review: 07 Sep 2021 07:37:22

Date of this response: 27 Sep 2021

SOME ADDITIONAL REFERENCES CITED IN REVISION

1. Adriaenssens EM. Phage Diversity in the Human Gut Microbiome: a Taxonomist's Perspective. mSystems. 2021;6(4):e0079921. doi:10.1128/mSystems.00799-21.
2. Agarwala, S., Naik, B., & Ramachandra, N. B. (2021). Mucosa-associated specific bacterial species disrupt the intestinal epithelial barrier in the autism phenome. Brain, Behavior, & Immunity-Health, 15, 100269.
3. Alcock J, Maley CC, Aktipis CA. Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. Bioessays. 2014 Oct;36(10):940-9. doi: 10.1002/bies.201400071. Epub 2014 Aug 8. PMID: 25103109; PMCID: PMC4270213.
4. Barber TM, Valsamakis G, Mastorakos G, Hanson P, Kyrou I, Randeva HS, Weickert MO. Dietary Influences on the Microbiota-Gut-Brain Axis. Int J Mol Sci. 2021 Mar 28;22(7):3502. doi: 10.3390/ijms22073502.
5. Beam A, Clinger E, Hao L. Effect of Diet and Dietary Components on the Composition of the Gut Microbiota. Nutrients. 2021 Aug 15;13(8):2795. doi: 10.3390/nu13082795.
6. Bienenstock J, Kunze WA, Forsythe P. Disruptive physiology: olfaction and the microbiome-gut-brain axis. Biol Rev Camb Philos Soc. 2018 Feb;93(1):390-403. doi: 10.1111/brv.12348..
7. Dietert RR, Dietert JM. Microbiome First Approaches in Pain Prevention and Management. Amer J Biomed Sci Res in press
8. Ducarmon, Q. R., Kuijper, E. J., & Olle, B. (2021). Opportunities and challenges in development of live biotherapeutic products to fight infections. The Journal of Infectious Diseases, 223(Supplement_3), S283-S289.
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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

I have read this manuscript again. While I'm still not a fan, I have to say it has improved.

I still do not see the purpose of it, but I think that should be up to the editor to judge if it fits into the current selection or not.

• Please don't call it "case study", since it implies for me that experiments were done.
• Line 590-598: I think this could be summarized simply with that htere are differences. The microbes are too diverse, so that mentioning them doesn't make much sense.
• I feel figure 3 is a bit pointless (could do the same for all other sections, but the summary is that there's a lot)
• The evidence map is now figure 5, not anymore 2

Author Response

Responses to Reviews on Enhancing Human Superorganism Ecosystem Resilience by Holistically ‘Managing our Microbes’ (Oct 5, 2021)

Reviewer 2, Round 2 Comments and Suggestions for Authors

I have read this manuscript again. While I'm still not a fan, I have to say it has improved.

Thank you for reviewing our revision and noting improvement.

I still do not see the purpose of it, but I think that should be up to the editor to judge if it fits into the current selection or not.

Thank you for the comment.

We are examining microbiota effects on health status for human superorganisms and offer specific illustrative examples on the state of the science and uncertainties for managing our microbes to improve health. We list the aim of our work as facilitating advancement of targeted -omics research for future applications using formal methods of benefit-risk analysis. We see our perspectives based on microbiology, risk analysis, decision science, and immunology as relevant to the special issue.

Please don't call it "case study", since it implies for me that experiments were done.

Thank you for raising this point. We did not intend to imply that we were conducting clinical case studies or experiments on the microbiology or the potential for managing microbes for any of the four illustrative examples. We replaced ‘case study’ with ‘example’ throughout the text.

Line 590-598: I think this could be summarized simply with that htere are differences. The microbes are too diverse, so that mentioning them doesn't make much sense.

Thank you for this comment.

We agree with the Reviewer that diverse microbes are mentioned here in Section 4.1 for ASD, and also in the next section, 4.2, for the same example. The point we intended to make is that relatively few microbes (10-15), relative to hundreds or thousands that might be present in the healthy gut microbiota transferred by undefined FMT, are correlated with health and may function as a consortia rather than as individual microbes. Thus, these defined consortia may function as drivers of a healthy gut for ASD children, although effects of single strain probiotics (lactobacilli and bifidobacteria described in one cited review) are variable.

It appears to us that similar benefits for ASD children as demonstrated for undefined FMT could be provided by supplements with defined consortia of microbes. However, clear benefits may not be observed without also providing prebiotics or prebiotic fibers for the consortia, as supplements or in the diet, to favor survival and engraftment of the consortia in the gut. We are unaware of clinical evidence on effects of supplementing ASD children with such defined consortia of microbes along with prebiotics targeting growth and engraftment requirements of these microbes.

We revised the summary in Section 4.3 of this revision to improve clarity about the importance of microbial diversity and the potential for managing microbes for ASD children.

I feel figure 3 is a bit pointless (could do the same for all other sections, but the summary is that there's a lot)

Thank you for this comment.

We emphasized the diversity of the breastmilk microbiota in Figure 3 because some scientists have argued to us that raw milks are nearly sterile with low diversity when microbes are present. The perceptions of some scientists and others may focus on studies conducted with culture-based methods and exclude large bodies of evidence generated using -omic methods.

The visual emphasis of the figure seems to us a more effective communication for readers unfamiliar with recent evidence than to list such information in the text.

We believe that including this figure will be important for communicating about the state of the science and uncertainties with trans-disciplinary audiences and stakeholders for decisions about managing our microbes.

The evidence map is now figure 5, not anymore 2

Thank you for noting this editorial error. We made this correction in the revision.

Submission Date: 10 August 2021

Date of this review: 01 Oct 2021 16:55:21

Date of this response: 05 Oct 2021

Author Response File: Author Response.docx