nutrients-logo

Journal Browser

Journal Browser

The Latest Research on Probiotics: Nourishing Health or Pathways to Disease Resolution

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Prebiotics and Probiotics".

Deadline for manuscript submissions: closed (5 September 2024) | Viewed by 27287

Special Issue Editor


E-Mail Website
Guest Editor
Department of Veterinary Medicine, National Chung Hsing University, Taichung 40249, Taiwan
Interests: development of functional food for pets or human; probiotics and lactoferrin related studies; control or treatment of metabolic disorders; control or treatment of urinary tract infection

Special Issue Information

Dear Colleagues,

Probiotics are live microorganisms, mostly bacteria and some yeasts, that are believed to provide health benefits to the host when consumed in sufficient quantities. The primary function of probiotics is to promote a healthy balance of microbiota in the gut or reproductive tract. Recently, new probiotics and featured prebiotics have been identified that are believed to have positive effects on human health. Interestingly, specific paraprobiotics, also known as "non-viable probiotics," have been found to confer certain health benefits on the host in a similar manner to live probiotics. As a result, this Special Issue invites original research submissions or review papers describing recent advancements and challenges in the roles and benefits of probiotics, inactivated probiotics, postbiotics, or prebiotics in human health and disease.

This topic aims to include the latest research related to probiotics, covering multiple aspects from early animal trials to clinical applications. We especially focus on the role of probiotics in human nutrition and their potential impact on the treatment and prevention of diseases. The featured topic will provide a platform for communication, fostering collaboration among scientists, clinical doctors, and nutrition experts, working together to leverage probiotic research in addressing various challenges faced by human health.

Given your good expertise and publication record, I warmly invite you to contribute an article/review paper for possible for this Special Issue “The Latest Research on Probiotics: Nourishing Health or Pathways to Disease Resolution”.

In order to plan the whole project, I kindly ask that you let us know as early as possible if you are interested in making a contribution. We look forward to hearing from you.

Dr. Po-Wen Chen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Nutrients is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • probiotic
  • prebiotic
  • Lactobacillus
  • Bifidobacterium
  • postbiotics
  • disease, health
  • gut microbiota

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (10 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review, Other

13 pages, 934 KiB  
Article
Investigating the Probiotic Potential of Vegan Puree Mixture: Viability during Simulated Digestion and Bioactive Compound Bioaccessibility
by Kübra Küçükgöz, Marcin Kruk, Danuta Kołożyn-Krajewska and Monika Trząskowska
Nutrients 2024, 16(4), 561; https://doi.org/10.3390/nu16040561 - 18 Feb 2024
Cited by 1 | Viewed by 1575
Abstract
This study aimed to develop a fermented puree mixture containing plant-based ingredients and potential probiotic strains Lacticaseibacillus rhamnosusK3 and Lactobacillus johnsonii K4. The survival of potential probiotic strains, changes in sugar and organic acid concentrations, bioaccessibility of polyphenols, and antioxidant capacity after [...] Read more.
This study aimed to develop a fermented puree mixture containing plant-based ingredients and potential probiotic strains Lacticaseibacillus rhamnosusK3 and Lactobacillus johnsonii K4. The survival of potential probiotic strains, changes in sugar and organic acid concentrations, bioaccessibility of polyphenols, and antioxidant capacity after simulated digestion were examined with sensory quality. The mixture of apple puree, chia seeds, and oat bran or oat flakes was fermented. The sensory quality of the puree mixture was assessed by the quantitative descriptive profile (QDP) method. In vitro digestion was simulated using a static gastrointestinal model. Antioxidant capacity and total polyphenol content were analyzed before and after the digestion phases. All samples changed sensory profiles after fermentation. The overall quality was above six out of ten for every product. Fermentation also changed the organic acid composition, with significant increases in lactic, succinic, and acetic acids. After the digestion process, the survival rate remained above 5.8 log10 CFU/g. As a result of fermentation with potential probiotics, the bioaccessibility of the total phenolics and antioxidant activity increased. These results showed that the addition of potential probiotic strains increases nutritional value and could help with healthy nourishment habits. This knowledge can guide the development of consumer-satisfying products in the food industry, expanding the probiotic food market with innovative alternatives. Full article
Show Figures

Figure 1

17 pages, 2136 KiB  
Article
Efficacy of Lactiplantibacillus plantarum PBS067, Bifidobacterium animalis subsp. lactis BL050, and Lacticaseibacillus rhamnosus LRH020 in the Amelioration of Vaginal Microbiota in Post-Menopausal Women: A Prospective Observational Clinical Trial
by Franco Vicariotto, Patrizia Malfa, Elisa Viciani, Federica Dell’Atti, Diletta F. Squarzanti, Andrea Marcante, Andrea Castagnetti, Rosetta Ponchia, Laura Governini and Vincenzo De Leo
Nutrients 2024, 16(3), 402; https://doi.org/10.3390/nu16030402 - 30 Jan 2024
Cited by 3 | Viewed by 3845
Abstract
The menopausal transition marks a significant physiological shift in women. Menopause-related symptoms can significantly affect a woman’s quality of life and probiotics have emerged as a promising avenue. This study aims to investigate the benefits of probiotics in improving vaginal well-being and microbiota [...] Read more.
The menopausal transition marks a significant physiological shift in women. Menopause-related symptoms can significantly affect a woman’s quality of life and probiotics have emerged as a promising avenue. This study aims to investigate the benefits of probiotics in improving vaginal well-being and microbiota composition in post-menopausal women. A prospective observational clinical trial was carried out enrolling 50 post-menopausal healthy women, aged between 45 and 65 years old, taking a supplement containing Lactiplantibacillus plantarum PBS067, Bifidobacterium animalis subsp. lactis BL050, and Lacticaseibacillus rhamnosus LRH020 (3B CFU/day) for 28 days. Vaginal swabs were collected to evaluate microbiota fluctuation and the inflammatory pattern was recorded. A Vaginal Health Index was provided to evaluate vaginal well-being throughout the trial. Clinical outcomes revealed a decrease in menopausal symptoms. Significant improvements were observed across various parameters: a 50% enhancement in the VHI score (p < 0.0001), alongside substantial reductions in inflammatory cytokine levels. An 87.8% decrease in IL-6, 57.6% in IL-1β, and 40.8% in TNF-α was observed (p < 0.05). Moreover, the probiotic intervention facilitated the restoration of vaginal microbiota, evidenced by an increase in lactobacilli abundance. In conclusion, the combination of these specific probiotic strains, previously clinically tested in childbearing-age women, showed to be effective also for post-menopausal women. Full article
Show Figures

Figure 1

14 pages, 4197 KiB  
Article
Novel Multi-Strain E3 Probiotic Formulation Improved Mental Health Symptoms and Sleep Quality in Hong Kong Chinese
by Helen Hoi Yin Chan, Pui Ling Kella Siu, Chi Tung Choy, Un Kei Chan, Junwei Zhou, Chi Ho Wong, Yuk Wai Lee, Ho Wang Chan, Joseph Chi Ching Tsui, Steven King Fan Loo and Stephen Kwok Wing Tsui
Nutrients 2023, 15(24), 5037; https://doi.org/10.3390/nu15245037 - 8 Dec 2023
Cited by 3 | Viewed by 3282
Abstract
Mental health issues have emerged as a significant concern in public health, given their association with physical and psychological comorbidities and the resultant socioeconomic burdens. Recent studies have highlighted the interplay between gut microbes and brain functions through the gut–brain axis. To investigate [...] Read more.
Mental health issues have emerged as a significant concern in public health, given their association with physical and psychological comorbidities and the resultant socioeconomic burdens. Recent studies have highlighted the interplay between gut microbes and brain functions through the gut–brain axis. To investigate this further, we conducted a targeted 16S rRNA sequencing and comprehensive bioinformatic analysis among Southern Chinese individuals to explore the role of the gut microbiome in depression, anxiety, and sleep disturbance. We analyzed the differences in the gut microbiome profile of 68 participants with sleep disturbance and mood symptoms before and after an 8-week course of a novel oral E3 multi-strain probiotics formula. The results revealed a significant improvement in subjective sleep quality (PSQI: mean 8.79 at baseline vs. 7.10 at week 8, p < 0.001), depressive symptoms (PHQ9: mean 6.17 at baseline vs. 4.76 at week 8, p < 0.001), and anxious symptoms (GAD7: mean 4.90 at baseline vs. 3.76 at week 8, p < 0.001). Additionally, there were notable differences in beta diversity (weighted UniFrac; p = 0.045) and increased Firmicutes/Bacteroidetes (F/B) ratio (p = 4 × 10−4) were observed in the gut microbiome analysis. Furthermore, the relative abundance of Bifidobacterium bifidum (p < 0.001), Lactobacillus acidophilus (p < 0.001), Lactobacillus helveticus (p < 0.001) and Lactobacillus plantarum (p < 0.001) were significantly increased after the 8-week probiotic supplementation. Our study suggests that the gut microbial landscape varies between responders and non-responders at multiple levels, including genera, species, functional, and network interaction. Notably, the use of probiotics in populations with depressive or anxious symptoms and poor sleeping quality remodeled the gut microbiome and demonstrated improved mood and sleep quality. Full article
Show Figures

Figure 1

17 pages, 3607 KiB  
Article
Lactiplantibacillus plantarum OLL2712 Induces Autophagy via MYD88 and Strengthens Tight Junction Integrity to Promote the Barrier Function in Intestinal Epithelial Cells
by Yumiko Watanabe-Yasuoka, Ayako Gotou, Shigeomi Shimizu and Toshihiro Sashihara
Nutrients 2023, 15(12), 2655; https://doi.org/10.3390/nu15122655 - 7 Jun 2023
Cited by 1 | Viewed by 2182
Abstract
Autophagy is an important system conserved in eukaryotes that maintains homeostasis by degrading abnormal proteins. Autophagy incompetence in intestinal epithelial cells causes the abnormal function of intestinal stem cells and other cells and damages intestinal barrier function. The disruption of the intestinal barrier [...] Read more.
Autophagy is an important system conserved in eukaryotes that maintains homeostasis by degrading abnormal proteins. Autophagy incompetence in intestinal epithelial cells causes the abnormal function of intestinal stem cells and other cells and damages intestinal barrier function. The disruption of the intestinal barrier causes chronic inflammation throughout the body, followed by impaired glucose and lipid metabolism. Lactiplantibacillus plantarum OLL2712 (OLL2712) is a lactic acid bacterium that induces interleukin-10 production from immune cells, alleviates chronic inflammation, and improves glucose and lipid metabolism. In this study, we hypothesized that OLL2712 exerts anti-inflammatory effects by inducing autophagy and ameliorating intestinal barrier dysfunction, and we investigated its autophagy-inducing activities and functions. Caco-2 cells stimulated with OLL2712 for 24 h showed an increased number of autolysosomes per cell, compared with unstimulated cells. Therefore, the permeability of fluorescein isothiocyanate dextran 4000 (FD-4) was suppressed by inducing autophagy. In contrast, mucin secretion in HT-29-MTX-E12 cells was also increased by OLL2712 but not via autophagy induction. Finally, the signaling pathway involved in autophagy induction by OLL2712 was found to be mediated by myeloid differentiation factor 88 (MYD88). In conclusion, our findings suggest that OLL2712 induces autophagy in intestinal epithelial cells via MYD88, and that mucosal barrier function is strengthened by inducing autophagy. Full article
Show Figures

Figure 1

Review

Jump to: Research, Other

16 pages, 725 KiB  
Review
The Influence of Intestinal Microbiota on BDNF Levels
by Marta Molska, Kinga Mruczyk, Angelika Cisek-Woźniak, Wojciech Prokopowicz, Patrycja Szydełko, Zuzanna Jakuszewska, Karolina Marzec and Martyna Trocholepsza
Nutrients 2024, 16(17), 2891; https://doi.org/10.3390/nu16172891 - 29 Aug 2024
Viewed by 1751
Abstract
The regulation of neurogenesis, the complex process of producing and differentiating new brain tissue cells, is influenced by a complex interaction of internal and external factors. Over the past decade, extensive research has been conducted on neurotrophins and their key role in adult [...] Read more.
The regulation of neurogenesis, the complex process of producing and differentiating new brain tissue cells, is influenced by a complex interaction of internal and external factors. Over the past decade, extensive research has been conducted on neurotrophins and their key role in adult neurogenesis, as well as their impact on diseases such as depression. Among neurotrophins, the brain-derived neurotrophic factor (BDNF) has been the subject of comprehensive studies on adult neurogenesis, and scientific evidence supports its necessity for neurogenesis in the subventricular zone of the hippocampus. A novel area of research is the emerging role of gut microbiota as a significant contributor to neurogenesis and neurotrophin production. Studies have shown that reduced BDNF levels can lead to mood disorders, which are observed in intestinal dysbiosis, characterized by an imbalance in the composition and quantity of the intestinal microbiota. There is evidence in the literature that there is a link between brain function and gut microbiota. Physical activity, and especially the regularity and intensity of exercise, is important in relation to the level of BDNF and the intestinal microbiota. Probiotics, prebiotics and physical activity may have a positive effect on the intestinal microbiota, and therefore also on the level of the brain-derived neurotrophic factor. Full article
Show Figures

Figure 1

14 pages, 657 KiB  
Review
Exploration of the Muribaculaceae Family in the Gut Microbiota: Diversity, Metabolism, and Function
by Yiqing Zhu, Borui Chen, Xinyu Zhang, Muhammad Toheed Akbar, Tong Wu, Yiyun Zhang, Li Zhi and Qun Shen
Nutrients 2024, 16(16), 2660; https://doi.org/10.3390/nu16162660 - 12 Aug 2024
Cited by 5 | Viewed by 3358
Abstract
The gut microbiota are mainly composed of Bacteroidetes and Firmicutes and are crucial for metabolism and immunity. Muribaculaceae are a family of bacteria within the order Bacteroidetes. Muribaculaceae produce short-chain fatty acids via endogenous (mucin glycans) and exogenous polysaccharides (dietary fibres). The [...] Read more.
The gut microbiota are mainly composed of Bacteroidetes and Firmicutes and are crucial for metabolism and immunity. Muribaculaceae are a family of bacteria within the order Bacteroidetes. Muribaculaceae produce short-chain fatty acids via endogenous (mucin glycans) and exogenous polysaccharides (dietary fibres). The family exhibits a cross-feeding relationship with probiotics, such as Bifidobacterium and Lactobacillus. The alleviating effects of a plant-based diet on inflammatory bowel disease, obesity, and type 2 diabetes are associated with an increased abundance of Muribaculaceae, a potential probiotic bacterial family. This study reviews the current findings related to Muribaculaceae and systematically introduces their diversity, metabolism, and function. Additionally, the mechanisms of Muribaculaceae in the alleviation of chronic diseases and the limitations in this field of research are introduced. Full article
Show Figures

Figure 1

16 pages, 837 KiB  
Review
The Antidiabetic Potential of Probiotics: A Review
by Shiming Li, Zichao Liu, Qi Zhang, Dan Su, Pengjie Wang, Yixuan Li, Wenbiao Shi and Qian Zhang
Nutrients 2024, 16(15), 2494; https://doi.org/10.3390/nu16152494 - 31 Jul 2024
Cited by 1 | Viewed by 2511
Abstract
Diabetes has become one of the most prevalent global epidemics, significantly impacting both the economy and the health of individuals. Diabetes is associated with numerous complications, such as obesity; hyperglycemia; hypercholesterolemia; dyslipidemia; metabolic endotoxemia; intestinal barrier damage; insulin-secretion defects; increased oxidative stress; and [...] Read more.
Diabetes has become one of the most prevalent global epidemics, significantly impacting both the economy and the health of individuals. Diabetes is associated with numerous complications, such as obesity; hyperglycemia; hypercholesterolemia; dyslipidemia; metabolic endotoxemia; intestinal barrier damage; insulin-secretion defects; increased oxidative stress; and low-grade, systemic, and chronic inflammation. Diabetes cannot be completely cured; therefore, current research has focused on developing various methods to control diabetes. A promising strategy is the use of probiotics for diabetes intervention. Probiotics are a class of live, non-toxic microorganisms that can colonize the human intestine and help improve the balance of intestinal microbiota. In this review, we summarize the current clinical studies on using probiotics to control diabetes in humans, along with mechanistic studies conducted in animal models. The primary mechanism by which probiotics regulate diabetes is improved intestinal barrier integrity, alleviated oxidative stress, enhanced immune response, increased short-chain fatty acid production, etc. Therefore, probiotic supplementation holds great potential for the prevention and management of diabetes. Full article
Show Figures

Figure 1

15 pages, 797 KiB  
Review
Nutraceuticals Prepared with Specific Strains of Probiotics for Supplementing Gut Microbiota in Hosts Allergic to Certain Foods or Their Additives
by Divakar Dahiya and Poonam Singh Nigam
Nutrients 2023, 15(13), 2979; https://doi.org/10.3390/nu15132979 - 30 Jun 2023
Cited by 8 | Viewed by 3117
Abstract
Certain nutrients cause discomfort, sensitivity reaction, and an intolerance for certain foods or their ingredients when ingested by some consumers. Food reactions and gut inflammation-related problems are increasing worldwide. The primary form of management would be the avoidance of such foods, followed by [...] Read more.
Certain nutrients cause discomfort, sensitivity reaction, and an intolerance for certain foods or their ingredients when ingested by some consumers. Food reactions and gut inflammation-related problems are increasing worldwide. The primary form of management would be the avoidance of such foods, followed by treatment of their symptoms. Adopting a nutritional–therapeutic approach and establishing practices for the inclusion of functional foods and nutraceuticals in the diet could improve the ecology of gut microbiota and alleviate inflammation in the GIT. For this purpose, specific species of microorganisms characterized as probiotic strains have been studied to produce functional food and fermented beverage products. Commercially sold, such items are labelled as probiotic products, displaying the name/s of strain/s and the viable numbers of them contained in the portion size of the products. The importance of the growth of probiotic functional foods is that they can be consumed as a source of nutrition and their intake helps in the subsistence and recuperation of friendly gut bacteria. Probiotics have been reported for their role in ameliorating the risk of food reactions. Probiotic administration has been implemented for its role as an auxiliary improvement and for the prevention of food sensitivities common among pediatric patients. Probiotic products based on non-dairy substrates have potential as nutraceuticals for lactose intolerant consumers who are allergic to dairy milk products. Therefore, the aim of this article is to review GRAS microbial species characterized as probiotics up to the level of their specific strain’s name and/or number. These have been used to produce nutraceuticals that are sources of beneficial bacteria for easing discomfort and allergic reactions by maintaining an inflammation-free gut. Full article
Show Figures

Figure 1

17 pages, 822 KiB  
Review
Featured Prebiotic Agent: The Roles and Mechanisms of Direct and Indirect Prebiotic Activities of Lactoferrin and Its Application in Disease Control
by Zhen-Shu Liu and Po-Wen Chen
Nutrients 2023, 15(12), 2759; https://doi.org/10.3390/nu15122759 - 15 Jun 2023
Cited by 3 | Viewed by 2921
Abstract
Lactoferrin (LF) is a glycoprotein found in mammalian milk, and lactoferricin is a peptide derived from LF hydrolysate. Both LF and lactoferricin (LFcin) have diverse functions that could benefit mammals. Bovine LF (BLF) and BLFcin exhibit a wide range of antimicrobial activities, but [...] Read more.
Lactoferrin (LF) is a glycoprotein found in mammalian milk, and lactoferricin is a peptide derived from LF hydrolysate. Both LF and lactoferricin (LFcin) have diverse functions that could benefit mammals. Bovine LF (BLF) and BLFcin exhibit a wide range of antimicrobial activities, but most probiotic strains are relatively resistant to their antibacterial effects. BLF and BLF hydrolysate can promote the growth of specific probiotics depending on the culture conditions, the dose of BLF or BLF-related peptides, and the probiotic strains used. BLF supplementation has been shown to modulate several central molecular pathways or genes in Lacticaseibacillus rhamnosus GG under cold conditions, which may explain the prebiotic roles of BLF. LF alone or in combination with selected probiotics can help control bacterial infections or metabolic disorders, both in animal studies and in human clinical trials. Various LF-expressing probiotics, including those expressing BLF, human LF, or porcine LF, have been developed to facilitate the combination of LFs with specific probiotics. Supplementation with LF-expressing probiotics has positive effects in animal studies. Interestingly, inactivated LF-expressing probiotics significantly improved diet-induced nonalcoholic fatty liver disease (NAFLD) in a mouse model. This review highlights the accumulated evidence supporting the use of LF in combination with selected LF-resistant probiotics or LF-expressing probiotics in the field. Full article
Show Figures

Graphical abstract

Other

Jump to: Research, Review

13 pages, 1598 KiB  
Systematic Review
Effect of Probiotics Supplementation on Cortisol Levels: A Systematic Review and Meta-Analysis
by Manav Jain, Aishwarya Anand, Nisha Sharma, Muhammad Aaqib Shamim and Elena Y. Enioutina
Nutrients 2024, 16(20), 3564; https://doi.org/10.3390/nu16203564 - 21 Oct 2024
Viewed by 1640
Abstract
Background: Several randomized controlled trials (RCTs) have shown conflicting results on cortisol levels following probiotic administration in healthy and diseased populations. Previous analyses were inconclusive due to limited studies, and evidence is lacking on how these effects vary by health status; region; [...] Read more.
Background: Several randomized controlled trials (RCTs) have shown conflicting results on cortisol levels following probiotic administration in healthy and diseased populations. Previous analyses were inconclusive due to limited studies, and evidence is lacking on how these effects vary by health status; region; therapy duration; medications, and use of single or multiple strains. Methods: In this systematic review and meta-analysis (PROSPERO [CRD42024538539]), we searched PubMed, Cochrane Library, Embase, Scopus, Web of Science, CINAHL, ProQuest, and Web of Science Preprints until 13 August 2024, for RCTs on probiotic administration, either alone or combined, across all age groups and without specific medical condition requirements. We applied random-effects meta-analysis, assessed bias using the Cochrane RoB 2 tool, and evaluated evidence certainty with GRADE. Findings: We screened 1739 records and retrieved 46 RCTs (3516 participants). Probiotics supplementation decreased cortisol levels compared to the control arm [46 RCTs; SMD: −0.45; 95% CI: −0.83; −0.07; I2: 92.5%, low certainty]. Among various subgroups; probiotics supplementation decreased the cortisol levels in the subgroups without concomitant medications [37 RCTs; SMD: −0.30; 95% CI [−0.58; −0.03], I2: 88.7%] with a single probiotic strain [30 RCTs; SMD: −0.33; 95% CI: −0.63; −0.028; I2: 88.8%], in a healthy population [35 RCTs; SMD:−0.3; 95% CI: −0.58; −0.03; I2: 88.7] and in the Asia region [21 RCTs; SMD: −0.83; 95% CI: −1.58; −0.07; I2: 95%]. Interpretation: A low level of evidence suggests probiotics might reduce cortisol levels, but more targeted studies are needed to identify variables affecting the response in specific subgroups. Full article
Show Figures

Graphical abstract

Back to TopTop