*2.2. Data Sources and Search Strategy*

The search was carried out on 1 December 2020 using three electronic databases, MED-LINE (via PubMed), ISI Web of Science, and Scopus. Multiple search terms are used including the microbiome, microflora, intestinal microbiota, gu<sup>t</sup> microbiota, titanium dioxide, TiO2, and E171. The search string for each database is described in Table S2. Hand searching of eligible studies was done to find studies that may not have been found in the databases.

## *2.3. Study Selection*

The

The study selection process was independently carried out by two reviewers (P.R.; E.R.). All articles generated from the electronic search were imported into Mendeley© (Elsevier, Amsterdam, The Netherlands), a references managemen<sup>t</sup> software, and duplicates were removed. Titles and abstracts were screened for eligibility based on inclusion criteria. All titles assessed as ineligible were excluded. Differences in judgment during the selection process between the two reviewers were settled by discussion and consensus.

#### *2.4. Data Extraction and Reporting*

After full-text analysis, the following information was extracted from the included articles: title, author information, year of publication, type of study performed, assessed outcome/s, the animal model used, animal gender, age, and weight at baseline, administered dose, length of study, administration route, and main conclusions.

Data was reported using an Excel© (Microsoft Office, Redmond, WA, USA) spreadsheet specifically developed for this study. Each full-text article was retrieved, and any ineligible articles were excluded from the reasoning reported. Differences in judgment between two reviewers (P.R.; E.R.) were settled by discussion and consensus.

## *2.5. Quality Assessment*

The quality of the included studies was assessed following the Animal Research Reporting of In Vivo Experiments (ARRIVE) guidelines [22]. These guidelines consist of the minimum information that animal research studies should include such as the number and specific characteristics of animals, details of housing and husbandry, experimental and statistical methods, reporting and interpretation of the results.

Moreover, SYRCLE's risk of bias tool [23] was used to assess the risk of bias of animal studies. SYRCLE's tool is an adapted version of the Risk of Bias tool provided by the Cochrane Collaboration. It consists of ten entries associated with selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases. Quality assessment was independently performed by two reviewers (P.R. and E.R.) and a consensus should be reached for discrepancies.
