Health benefits and risks of fermented foods—the PIMENTO initiative

Worldwide, fermented foods (FF) are recognized as healthy and safe. Despite the rapid increase of research papers, there is a lack of systematic evaluation of the health benefits and risks of FF. The COST Action CA20128 “Promoting innovation of fermented foods” (PIMENTO) aims to provide a comprehensive assessment on the available evidence by compiling a set of 16 reviews. Seven reviews will cover clinical and biological endpoints associated with major health indicators across several organ systems, including the cardiovascular, gastrointestinal, neurological, immune, and skeletal systems. Nine reviews will address broader biological questions associated with FF including bioactive compounds and vitamin production, nutrient bioavailability and bioaccessibility, the role of FF in healthy diets and personalized nutrition, food safety, regulatory practices, and finally, the health properties of novel and ethnic FF. For each outcome assessed in the reviews, an innovative approach will be adopted based on EFSA’s published guidance for health claim submissions. In particular, each review will be composed of three parts: (1) a systematic review of available human studies; (2) a non-systematic review of the mechanism of action related to the clinical endpoints measured by the human studies identified in part 1; and (3) a non-systematic review of the characterization of the FF investigated in the human studies identified in part 1. The evidence and research gaps derived from the reviews will be summarized and published in the form of a strategic road map that will pave the way for future research on FF.


Review title
Ideally the title should state succinctly the interventions or exposures being reviewed and the associated health or social problems.Where appropriate, the title should use the PI(E)COS structure to contain information on the Participants, Intervention (or Exposure) and Comparison groups, the Outcomes to be measured and Study designs to be included.Provide title.

Anticipated or actual start date
The date of commencement for the systematic review can be defined as any point after completion of a protocol but before formal screening of the identified studies against the eligibility criteria begins.

Stage of review at time of this submission
Indicate the stage of progress of the review by ticking the relevant Started and Completed boxes.Please note: Reviews that have progressed beyond the point of completing data extraction at the time of initial registration are not eligible for inclusion in the study protocol.Should evidence of incorrect status and/or completion date being provided at the time of submission come to light, the content of the study protocol will be removed leaving only the title and named contact details and a statement that inaccuracies in the

Review team members and their organizational affiliations
The review team members listed below have already contributed and plan to further contribute to the review.Those persons will be co-authors of the manuscript, based on their current and future contribution to each of the following three tasks.The table will be adapted as the work progress.
1. Planning and contribution to one or several components (conception, design, conduct, analysis, or interpretation) of the work which led to the paper or interpreting at least a portion of the results; 2. Writing a draft of the article or revising it for intellectual content; and 3. Final approval of the version to be published.

Funding sources/sponsors
Details of the individuals, organizations, groups or other legal entities who take responsibility for initiating, managing, sponsoring and/or financing the review.
This review is part of the COST Action CA20128 -Promoting Innovation of Fermented Foods (PIMENTO).

Conflicts of interest
The conflicts of interest listed cover the review team as a whole, as well as individuals in the team: Write either "The authors declare no conflict of interest" or describe the conflict(s) of interest.

Collaborators
All contributors to the review are listed under point 7.

Review question
Review-specific text: Text.

Search strategy
The generic search strings developed by the Library of the University of Zurich (Alisa Berger) for PIMENTO will be used by each of the 16 reviews (PIMENTO search strings).These strings encompass terms for the search of a broad scope of fermented foods across all food groups, of all types of human studies, as well as of dietary intake.The generic search string will be published as Supplementary file in the position paper by Todorovic et al. to which is study protocol is linked.
The complete search (strings) for each Project will be published as Supplementary file of the review.
In addition to the PIMENTO search strings, review-specific strings covering the search for the functional part of the review (e.g., clinical indication, biological activity) will be defined as specified below.Reviewspecific changes from the PIMENTO search strings will be presented and justified in the manuscript.
Specify the functional part of the review (e.g., clinical indication, biological activity): Text.
Present and justify review-specific changes from the PIMENTO search strings: Provide information or write "No review-specific changes".

Condition or domain being studied
Give a short description of the disease, condition, or healthcare domain being studied: Text.
Of note the manuscript of the reviews will contain a description of the condition being studied based on Section 3 "Characterization of the claimed effect" of the EFSA guidance (EFSA Panel on Dietetic Products, 2021b).

Participants/population
Summary criteria for the participants or populations being studied by the review.The preferred format includes details of both inclusion and exclusion criteria.Example: Inclusion: Adults with schizophrenia (as diagnosed using any recognised diagnostic criteria).Exclusion: Adolescents (under 18 years of age) and elderly people (over 70).
Adults are considered from the age of 18 and above.

Intervention(s), exposure(s)
Full and clear descriptions or definitions of the nature of the interventions or the exposures to be reviewed.Report the intervention/exposure in enough detail that others could reproduce it or assess its applicability to their own setting.The preferred format includes details of both inclusion and exclusion criteria.For reviews of qualitative studies give details of the focus of the review.
The intervention/exposure consists of the ingestion of any of the fermented foods contained in the PIMENTO search string for fermented foods across the following food groups: dairy, meat and fish, fruits and vegetables, beverages, legumes, cereals and grains.Alcoholic beverages with an alcohol content of more than 1.25% will be excluded.Unless specified otherwise, no limits are set for duration or dosage of the ingested fermented food(s).Unless specified otherwise, studies investigating application of fermented foods other than for nutritional purpose (e.g., nasal or topical) will be excluded.In addition, studied investigating probiotics will be excluded unless the probiotics is/are added at the beginning of the fermentation process and that there are indications from the literature that the probiotic strain(s) contribute(s) to the fermentation of the food matrix.Interventions including any possible confounders such as prebiotic fibres or added bioactive compounds will not be included.Intervention could be designed as a stand-alone intervention or as a combined intervention if the comparator conditions are adequately controlled for non-fermented interventions.
Present and justify review-specific changes from the above guidance.In particular specify the food groups or foods from the PIMENTO search string if the review restricts the search to a subset of fermented foods or food groups.Provide also supplementary information as needed, in particular to define additional inclusion or exclusion criteria: Provide information or write "No review-specific changes".

Comparator(s)/control
The control could be the absence of consumption, or consumption of a lower amount or lower frequency of the fermented food/diet of interest or the consumption of a corresponding non-fermented food/diet.Any adequate non-fermented placebo or control (such as another medication or treatment) will also be accepted as a valid comparator.
The definition of appropriate controls is an important problem in nutritional science.In order to highlight research gaps on this issue as well as to collect data from all human studies as described in the EFSA guidance (EFSA Panel on Dietetic Products, 2021a, 2021b) human studies will first be selected for evaluation irrespective of the quality of the control.The quality of the control will be evaluated subsequently for all studies meeting the PI(E)O criteria (Population, Intervention/Exposure, Outcome).
Provide information or write "No review-specific supplementary information".

Types of study to be included
All human studies will be searched systematically and included according to article 4.2.1.of the EFSA guidance (EFSA Panel on Dietetic Products, 2021b): • Publications reporting on human intervention (efficacy) studies (e.g., randomised controlled studies, randomised uncontrolled studies, non-randomised controlled studies, other intervention studies) • Publications reporting on human observational studies (e.g., cohort studies, case-control studies, cross-sectional studies, other observational studies) • Available systematic reviews with or without meta-analysis will be used to check for potentially missing studies.
Animal and in vitro studies will be excluded from the systematic reviewing process.
Present and justify review-specific changes from the above guidance.Also, provide supplementary information, as needed, in particular to define additional inclusion or exclusion criteria: Provide information or write "No review-specific changes".

Context
Present, as needed, inclusion/exclusion criteria not described elsewhere: Provide information or write "No additional criteria".

Main outcome(s)
Give the pre-specified primary (most important) outcomes of the review, including details of how the outcome is defined and measured and when these measurements are made, if these are part of the review inclusion criteria.For systematic reviews of qualitative studies give details of what the review aims to achieve: Text.

Additional outcome(s)
List the pre-specified secondary (additional) outcomes of the review, with a similar level of detail to that required for primary outcomes: Provide information or write "No additional outcome".
If available, an evaluation of the contribution of the gut microbiota to the main or additional outcomes will be presented.
In addition, outcomes related to safety (e.g., adverse effects or risk markers) will be recorded as indicated in Appendix B of the EFSA guidance (EFSA Panel on Dietetic Products, 2021b).The data extraction form(s) of the interventional and observational studies will be based on combined information provided in the handbook of the Cochrane interactive learning course "Conducting an Intervention Review" (Higgins et al., 2022), Appendix B "Information to be presented in a full study report for human efficacy studies" of the EFSA guidance (EFSA Panel on Dietetic Products, 2021b) and the STROBE guidelines for reporting observational studies (von Elm et al., 2007), respectively.CADIMA software (Kohl et al., 2018) will be used to select the references.A consistency test will be performed in CADIMA using a subset of the literature dataset and, if needed, the study protocol and/or the literature selection strategy will be adapted to improve the efficacy and systematicity of the reviewing process.Overview of the selection process to identify the relevant studies will be documented with a flow diagram.The references will be screened based on titles, abstracts, and texts.

Risk of bias (quality) assessment
The risk of bias will be conducted based on steps 17 (Evaluate study quality and risk of bias), 21 (Exploration of heterogeneity), and 22 (Check reporting bias) of Muka et al. (2020) using tools, such as ROBINS.
Provide supplementary information, as needed Write either "The review will be narrative.Accordingly, the data synthesis will focus on a description of the clinical indications as well as primary and secondary endpoints and bias will not be evaluated" or "No review-specific supplementary information" or provide review-specific information as needed.

Strategy for data synthesis
Data synthesis will be based on steps 19 (Conduct descriptive synthesis) and 23 (Check the quality of the evidence: the confidence in the results presented) of Muka et al. (2020).
An evaluation of the quality of the evidence derived from the human studies will be conducted according to the Grading of Recommendations Assessment (GRADE) according to Module 7 (Interpreting the

22.
Data extraction (selection and coding)Study selection and data extraction will be conducted based on the following steps of the guidance ofMuka et al.(2020): steps 4 (Define selection criteria), 5 (Design data collection form), 8 (Collection of references and abstracts in a single file), 9 (Elimination of duplicates), 10 (Screening of the titles and abstracts by at least two reviewers), 11 (Collection, comparison, and selection of references for retrieval), 12 (Retrieval of full text and application of selection criteria), 13, if needed (Contact experts), 14 (Search for additional references), 16 (Application of the data collection form), and 18 (Preparation of the database for analysis).