The Effect of Probiotic Supplementation on the Gut–Brain Axis in Psychiatric Patients

The present review summarized the effect of probiotic supplementation on the gut microbiota and the metabolic potential in psychiatric patients. The review is overall comprehensive and well written. Some minor points are listed as below:

Thank you for your time reviewing our manuscript.

1. Are there promising probiotics that have been in the clinical trials for psychiatric diseases?

For addressing this point, I can say that till the moment, we cannot confirm the implementation of prebiotics in the realm of psychiatric disorders. However, some trials have been launched to use probiotic in fecal transplantation to deal with autism.

2. Are there potential adverse effects in the application of probiotic supplementation?

It is not 100% yes or no. the idea is related mainly to the concentration and type of the bacteria added. Thus, some probiotic supplementations when taken at higher doses may disrupt the balance in the gut biota resulting in dysbiosis.

In this review, Sabit et al. discuss the effect of probiotic supplementation on gut microbiota and their metabolic potential in psychiatric patients. The manuscript is well-written and very interesting. I have only minor comments that can improve this review:

-   I suggest the Authors to discuss a recent research paper (PMID: 36400332), in which the authors found a dysbiosis in trauma-exposed susceptible mice. This dysbiosis promotes the production of abundant levels of the L-tyrosine-derived metabolite p-cresol, which in turn affects the central dopaminergic system in a brain region-dependent manner. These results may be relevant in the context of stress-related disorders such as PTSD.

Thank you for your time reviewing our manuscript and for your nice words.

For the article you mention, we inserted it to the suitable place in the manuscript. And it is highlighted in yellow for the ease of tracking.

Reduce the text of all chapters to Chapter 10. 

Expand the paragraph on gut microbioma and psychiatric disorder. It is suggested to use tables and figures to better compare the common characteristics and diversity of the different papers cited.

Both considerations serve to make the work easy to read and focus on the topic microbiome and psychiatric disorder.

In addition, a more organic reworking of the various papers mentioned is needed. Using tables to summarize the similarities and differences of different papers is an easy way to compare literature

Thank you for your efforts reviewing our manuscript.

Indeed, we designed 6 original figures to illustrate different mechanisms we discussed within the manuscript. In a previous version of this work, we tabulated some data for comparisons, but it was not informative enough, so we decided to replace it with figures.

For the reduction of text until chapter 10, we think that this length is mainly to cover all aspects of the manuscript. We beg your pardon in this point.

For expanding the part of gut microbiota, I can say that this is the expanded part in the entire manuscript, so we don’t find it needs further data seeking the concise manner of the manuscript and for the readers not to be overwhelmed with more details.  

The review paper from H. Sabit et al. aims at describing the relationships between probiotic supplementation, bacteria of the gut microbiota and their metabolites (focusing essentially on species providing probiotics strains) and psychiatric diseases. It examines the potential of the effects of such probiotic supplementation on these diseases and provides some tracks towards the potential medicinal applications.

The review of about 23 pages includes 136 literature references between 2005 and 2022 (with most between 2018-2022) and is illustrated by six figures. It provides an updated synthetic overview of the different aspects of the relationships between the gut microbiota and the brain axis with a focus on probiotic bacteria and psychiatric diseases. It presents successively i) the probiotics (definition, main sources, possible health issues, clinical usages, roles in immune modulation), ii) the gut microbiota, the gut-brain axis and its modulation by probiotics, and iii) the relationships between the gut microbiota and psychiatric disorders (mainly depressive disorders and schizophrenia).

The aim of the review is interesting and distinguishes from the numerous other reviews previously published on probiotics over years by its main focus on psychiatric disorders. The paper is globally written in a good English.

A number of points detailed below have to be taken into account.

Many thanks for your efforts and kind comments.

Specific comments

1-    The abstract and the title of the review are not fully in accordance: the title focuses on “The Effect of Probiotic Supplementation on Gut Microbiota and their Metabolic Potential in Psychiatric Patients”, but the abstract does not mention in any way neither the probiotics nor the effects of probiotics supplementation. It only describes the relationships between the gut microbiota, the microbiota-gut-brain axis and the mental health and disorders. The title and abstract have to communicate the aim and content of the review and should merge. They have thus to be modified appropriately.

Thank you for this positive comment. The title has been modified.

“The Effect of Probiotic Supplementation on Gut-Brain Axis in Psychiatric Patients”

2-    The organization and structure of the manuscript are not completely clear nor equilibrated between the different sections and as regard the objective. The main focus is the role of bacteria from the gut microbiota (essentially those recognized as probiotics) and their metabolites on the gut-brain axis and mental disorders. These aspects are described and discussed in sections 8.3. ”Modulation of the gut-brain axis by probiotics”, and in section 10 “Gut microbiota and psychiatric disorders” subdivided itself into two sub-sections 10.1. “Major depressive disorder (MDD)” and 10.2. “Schizophrenia”. The logic of the review is not completely clear and its structuration leads to some redundancies between the sections (for instance paragraphs lines 544-549 and 637-648 concern both tryptophane metabolism and could be combined). The organization of the review should thus be improved, taking in particular into account the following points:

-       The main topic of the paper is contained in section 10 “Gut microbiota and psychiatric disorders” and particularly in 10.2. “Schizophrenia”, which is very interesting, but very long compared to the other sections. In addition, this section “Schizophrenia” is not entirely devoted to schizophrenia, but contains a lot of information on other mental diseases. This important section has to be checked carefully and fully reorganized either in several sections or subdivided into sub-sections.

-       A paragraph on how probiotics can interfere with the relationships described and possibly manipulate and modify them should be added, or it could be included in the conclusion which is very brief.

Thank you for that.  The entire section has been substantially reordered and reconstructed.

Some paragraphs in section 10 have been removed and others has been relocated so that it makes the flow as smooth as we can. We also combined the sections related to MDD in one section and the Schiz part in one section.

The redundant part related tryptophan metabolism was removed.

 We added a paragraph at the conclusion to highlight the point you mentioned.

“The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Increased Enterobacteriaceae family were potentially associated with a higher risk of schizophrenia, thus, keeping these types of bacteria in balance will help alleviating the adverse effects of other pathogenic bacteria that might cause several diseases”

3-    The authors made the choice to totally discard Gram-negative bacteria from the review (sections 2 to 8.2. in particular, where they should be included). Indeed probiotics, and in particular those that are commercialized, are essentially Gram-positive strains. However even if less documented the fact that Gram-negative strains can be valuable probiotics has to be pointed. Especially, E. coli Nissle 1917, which is a non pathogenic strain discovered in 1917 by Alfred Nissle and commercialized against dysentery and other intestinal diseases needs being cited. It is largely described mainly for intestinal diseases, but also other applications, in Scaldaferri 2016 (cited in the review but not about the E. coli probiotic strain and its properties), Behnsen J et al Cold Spring Harb Perspect Med. 2013, 3(3): a010074, and also in more recent reviews such as Zhao Zet al. Food Funct. 2022, 13: 5914-5924 and many others.

 Yes, we agree with this point.

We added a paragraph in the suitable place to highlight this point.

It is highlighted in yellow

4-    The authors describe the possible adverse effects of probiotics (section 5), which is indeed an important point, but they only consider the infection risks and do not take into account other risks such as for instance the production of toxic compounds. Also in this regard, E. coli Nissle 1917 is a very good example, as it is able to synthesize both efficient competition molecules (the siderophore microcins), in addition to the classical compounds found in most probiotics as described in the paper. Siderophore microcins kill pathogens in the gut (Sassone-Corsi M, et al, Nature. 2016;540: 280-283) and are responsible for a large part of the beneficial effects, but also a genotoxin (colibactin). These two aspects are important to be told. It was further shown that the two biosynthetic pathways for the antimicrobial compounds and the genotoxin are linked, and how favoring the good one (Massip C, and Oswald E. Front Cell Infect Microbiol. 2020;1 0:381; Martin et al, IUBMB Life 2017, 69(6):435-441). It is thus an excellent example of pointing both positive and negative effects of a probiotic, alert about the risks, and how circumvent them. Other examples in Gram-positive bacteria should be described too.

This point is very clear to us when we designed the structure of the manuscript. Dealing with only G+ probiotic bacteria was the main concern. Yes, I agree with you that it is important to address some G- bacteria, but it was in this manuscript out of scope.

Production of Siderophore microcins and other bacteriocins is an important aspect that could be tackled in a separate RA. Thus, here we beg your pardon that we chose to focus on the G+ bacteria. However, as I mentioned in the last point of your comments, we mentioned the role of E. coli in serving as probiotic bacteria even though it is G-.

5-    Throughout the paper, the names of bacteria (genus, species) and other organisms should be in italics as it is required. Similar, inside the figures and in the list of the literature references, italics have to be used for the names of bacteria.

All done

6-    Figure 1 shows the main microorganisms considered as probiotics, classified as Lactobacillus, Bifidobacterium, other LABs and non LABs. Why are the “Bifidobacterium” and “other LABs” panels identical? It is probably a mistake…

You are right. Figure 1 was corrected.

7-    Globally the legends to the figures consist only of titles and are not sufficiently detailed. They have to be completed by information making the figures understandable without the help of the main text and should include the meaning of abbreviations, of colours etc.

Ok. Some elaborations have been added wherever needed.

8-    Especially for Figures 3 and 4: it has to be distinguished between Bifidobacteriumand Bacillus by using the three letter abbreviation code of bacteria; similar for other figures where bacteria have an identical first letter; use italics for names of genera and species; Figure 3 change “haemoxygense to “haem oxygenase”; “Citrobacter rodentiumin” to “Citrobacter rodentium in” (with a space).

Fig 3 All done.

For figure 4, we generated the figure via online software, and it generate the figure once and in non-modifiable format, so we could not access it again. Dory for that. But to solve this problem, we mentioned in the figure ligand what every and each B stands for.

9-    Sentence lines 454-56, which is very important, is unclear: please reformulate to more unambiguously indicate in what individuals the highest SCFA are found. 

The statement was corrected, and the confusing part was removed. The rest section is highlighted in yellow. (Newly lines 530-32)

10- Line 465, please indicate the difference between “active” and “responsive MDD”. But, taking into account the content of the 10.1 paragraph, it is better to define and distinguish since the beginning of this paragraph “major depressive disorder (MDD), active-MDD and responsive-MDD, depression, bipolar depression” to avoid confusion when reading further the paragraph. These definitions and abbreviations could be also provided since the beginning of the review.

The types of MDD is mentioned in the abstract of this article that we cited it.

https://pubmed.ncbi.nlm.nih.gov/25882912/

11- Paragraph page 12, lines 484-485:

-       The Painold paper concerns “bipolar depression during depressive episodes” which differs from “depression”. Please modify.

-       To make the sentence understandable, please change “Actinobacteria genus Faecalibacterium” to “Actinobacteria and the genus Faecalibacterium belonging to Clostridia”. Moreover, in this paper, the authors point also other genera that are important and should be cited too. Furthermore, there are two points of attention in this sentence: i) to my knowledge, Faecalibacterium prausnitzii is the only known bacterium in the genus Faecalibacterium; this should be told and especially as ii) Faecalibacterium prausnitzii is a probiotic which is described as beneficial against inflammatory bowel disease due to anti-inflammatory properties. This aspect should be mentioned and the dual properties beneficial/detrimental should be considered here and discussed.

I clarified the difference.

Actinobacteria and the genus Faecalibacterium:Done.

The section denoting the role of these bacteria as probiotic was added and highlighted in yellow.

Minor points

1-  Page 1 lines 42-45, abbreviations of the cited mental disorders that are given and used further have to be provided since the beginning of the paper, the first time the terms happen.

All done

2-  Page 7, line 313: change “Number of gut microbiota” to “The gut microbiota” or “Description of gut microbiota”

All done

3-  The list of literature references has to be checked carefully:

-       in addition to the italics that should be added to the names of bacteria and other organisms/microorganisms (see also point 5 above), capital letters should be suppressed in the title of reference 87;

-       Please use systematically the conventional abbreviations for the journals and not alternatively the abbreviation and the full name.

-       Reference 43 concerns a chapter in a Book; It has to be said and the references of the book (Editors, ISBN number etc) has to be added

Thank you again. We used EndNote, and the style “Numbered” that has been assigned by the journal is that we used. The generated list is without our intervention.

For the abbreviations, and other issues related to the bibliography, this is the style generated by the software.

Again, for referencing, we used the software and the cited material was grabbed from its original webpages so that the software made it the way mentioned in the manuscript.

4-  Typing/style mistakes:
Page 5, line 233, change “generate” to “induce/favor the production of”; Page 7 Line 302 change acidophilu” to “acidophilus”; Page 8, line 314, change “phrase” to “term”; Page 11: line 436: please suppress “Conclusion:”; line 694, change “millions” to “millions people”

Thank you so much for this valuable comments.

All Done and highlighted in yellow