Review Reports - Microbial Translocation Disorders: Assigning an Etiology to Idiopathic Illnesses

Round 1

Reviewer 1 Report (Previous Reviewer 2)

The resubmitted version is modified

Author Response

Dear reviewer,

Many thanks for reviewing our manuscript.

Best regards,Dr. Sfera

Reviewer 2 Report (New Reviewer)

In this review, Sfera et al. emphasized the link between microbial translocation (MT) and idiopathic illnesses, particularly those triggered by the immune system as a response to invading microbes. The introduction covered some terms used throughout the manuscript and reviewed some mechanisms of tolerance and microbial translocation (MT). The authors also discuss the role of mast cells, innate lymphoid cells, and Tregs in maintaining gut homeostasis. The historical progression of understanding the etiology of many idiopathic diseases was highlighted and linked to MT. The authors illustrated many idiopathic conditions such as autoimmune, fibroproliferative, neuropsychiatric disorders, and malignancies as MTDs. Furthermore, they explained how specific microbes, either bacteria or viruses, could trigger such conditions directly or indirectly. Finally, they discussed some therapeutic interventions which targeted premature endothelial cell senescence.

Sfera et al. reviewed many previous studies and used relevant references in the field with minimum but necessary self-citation. The conclusion was parallel with the main text. They supported their work by using multiple figures and tables. However, this manuscript should have keywords, so consider adding them. I noticed some formatting issues; the highlighted text and tables and the font size of their references.

Overall, this manuscript shows a comprehensive review and is worth publication.

Author Response

Reviewer 2

It is an interesting review discussing the link between microbial translocation (MT) and development of several disorders including neuropathology, cancers, autoimmune, fibroproliferative, and neuropsychiatric.

The authors discussed the immune response related to MT and they provided tables of several microbes associated with diseases.

In general, it is a comprehensive review, well designed and has a good flow

Some comments

In cancers, especially GIT related cancers. It is important to show that some commensal such as Fusobacterium is present in the oral cavity, when the microbe translocated to colon, and the tumor microenvironment, the bacteria start CRC by different mechanisms. Please discuss this point.

Abed J, Maalouf N, Manson AL, Earl AM, Parhi L, Emgård JEM, Klutstein M, Tayeb S, Almogy G, Atlan KA, Chaushu S, Israeli E, Mandelboim O, Garrett WS, Bachrach G. Colon Cancer-Associated Fusobacterium nucleatum May Originate From the Oral Cavity and Reach Colon Tumors via the Circulatory System. Front Cell Infect Microbiol. 2020 Aug 7;10:400. doi: 10.3389/fcimb.2020.00400.

Aside fom Fusobacterium, Bacteriodes fragilis, especially via its B. fragilis toxin (BFT) can trigger chronic intestinal inflammation, predisposing to CRC.

Cheng WT, Kantilal HK, Davamani F. The Mechanism of Bacteroides fragilis Toxin Contributes to Colon Cancer Formation. Malays J Med Sci. 2020 Jul;27(4):9-21. doi: 10.21315/mjms2020.27.4.2.

Also in cancer, I would the authors cite and describes the studies reporting the changes in gut microbiota in patients with GI cancers compared to healthy and provide the common bacterial families/ species drive the cancer program.

The common microbial strains linked to CRC are Bacteroides fragilis, Escherichia coli, Enterococcus faecalis and Streptococcus gallolyticus. Other species identified in CRC patients’ tumor and fecal samples include Fusobacterium nucleatum, Parvimonas, Peptostreptococcus, Porphyromonas and Prevotella.

Rebersek, M. Gut microbiome and its role in colorectal cancer. BMC Cancer 21, 1325 (2021). https://doi.org/10.1186/s12885-021-09054-2

This paragraph was added

Fusobacterium nucleatum is a common oral microbe which can reach the colon, accelerating the progression of CRC. Fusobacterium nucleatum can cause transient bacteremia triggered by chewing, daily hygiene, or dental procedures, indicating several pathways for contributing to tumorigenesis (274). Aside fom Fusobacterium, Bacteriodes fragilis, especially via its B. fragilis toxin (BFT) can trigger chronic intestinal inflammation, predisposing to CRC (275). The common microbial strains linked to CRC are Bacteroides fragilis, Escherichia coli, Enterococcus faecalis and Streptococcus gallolyticus. Other species identified in CRC patients’ tumor and fecal samples include Fusobacterium nucleatum, Parvimonas, Peptostreptococcus, Porphyromonas and Prevotella (276).

Reviewer 3 Report (New Reviewer)

The manuscript presents “Microbial translocation disorders: assigning an etiology to idiopathic illnesses”. The author explained the MTDs in every aspect. I found a few minor typos mistake that should be removed by the author.

I will suggest a few suggestions as mentioned below.

· The first paragraph of the introduction: What is meant by the “outside world”? Please use an appropriate word.

· In 3^rd paragraph of the introduction, the definition of “Translocation” is given without reference. Please give an appropriate reference.

· In 4^th paragraph of the introduction, please be clear about M-cells, either mast cells or others.

· In the 9^th paragraph of the introduction: the author said as “increased immune tolerance promotes MT and give an example of IBD. Not clear. Please recheck this.

· In the last paragraph of the introduction, “Transcellular MT, a process of microbial passage through the IECs or M cells, …………………. to achieve for gut barrier repair than each modality applied individually” is given without reference. Please give an appropriate reference.

· In “Autoimmune disease as MTD phenomenon”, MTD is not defined prior to using an acronym.

· Table 1: please improve this by adjusting space and others. Also, write down the name of the bacteria in italic.

· There is no need to highlight the text. Please remove it.

· Table 2: No need to use “Bold text”. I will suggest removing it if possible and modifying this accordingly.

Author Response

I will suggest a few suggestions as mentioned below.

The first paragraph of the introduction: What is meant by the “outside world”? Please use an appropriate word.

Each other was used instead(highlighted in the text)

In 3rd paragraph of the introduction, the definition of “Translocation” is given without reference. Please give an appropriate reference.

References 4 and 5 added

In 4th paragraph of the introduction, please be clear about M-cells, either mast cells or others.

Membranous was added

In the 9th paragraph of the introduction: the author said as “increased immune tolerance promotes MT and give an example of IBD. Not clear. Please recheck this.

Chron’s disease and ulcerative colitis were added as examples of IBD.

In the last paragraph of the introduction, “Transcellular MT, a process of microbial passage through the IECs or M cells, …………………. to achieve for gut barrier repair than each modality applied individually” is given without reference. Please give an appropriate reference.

Reference 41 was added

In “Autoimmune disease as MTD phenomenon”, MTD is not defined prior to using an acronym.

Microbial translocation disorders added

Table 1: please improve this by adjusting space and others. Also, write down the name of the bacteria in italic.

Both tables were adjusted.

There is no need to highlight the text. Please remove it.

Removed

Table 2: No need to use “Bold text”. I will suggest removing it if possible and modifying this accordingly.

Adjusted

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The authors have made serious efforts to study the recent literature looking for possible links between a range of different disease entities and microbial translocation. Unfortunately, they build hypotheses on hypotheses, which gets them to link just anything to anything. It seems a bit odd to classify cancer as an idiopathic illness. There are issues with definitions: microbial translocation in their view includes toxins (line 37), but which toxins? It is unclear how the entire paragraph which ends on line 216 can be linked to microbial translocation. Some general statements are not supported by sufficient scientific evidence.

Reviewer 2 Report

The authors discussed the immune response related to MT and they provided tables of several microbes associated with diseases.

In general, it is a comprehensive review , well designed and has a good flow

Some comments

1- In cancers, especially GIT related cancers. It is important to show that some commensal such as Fusobacterium is present in the oral cavity, when the microbe translocated to colon, and the tumor microenvironment, the bacteria start CRC by different mechanisms. Please discuss this point.

Not only Fusobacterium, but also Bacteriodes fragilis

2- Also in cancer, I would the authors cite and describes the studies reporting the changes in gut microbiota in patients with GI cancers compared to healthy and provide the common bacterial families/ species drive the cancer program