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Jang SB, Kim Y, Yeo HC, Kang GH, An BC, Ryu Y, Chung MJ, Cho SG. Probiotic-Derived P8 Protein: Promoting Proliferation and Migration in Stem Cells and Keratinocytes. Int J Stem Cells 2025; 18:87-98. [PMID: 39491493 PMCID: PMC11867908 DOI: 10.15283/ijsc24107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/07/2024] [Accepted: 10/11/2024] [Indexed: 11/05/2024] Open
Abstract
Probiotics exert various effects on the body and provide different health benefits. Previous reports have demonstrated that the P8 protein (P8), isolated from Lactobacillus rhamnosus, has anticancer properties. However, its efficacy in stem cells and normal cells has not been reported. In this study, the effect of P8 on cell proliferation and wound healing was evaluated, investigating its underlying mechanism. Based on scratch assay results, we demonstrated that P8 treatment significantly increases wound healing by activating the cell cycle and promoting stem cell stemness. Cellular mechanisms were further investigated by culturing stem cells in a medium containing Lactobacillus-derived P8 protein, revealing its promotion of cell proliferation and migration. Also, it is found that P8 enhances the expression of stemness markers, such as OCT4 and SOX2, along with activation of the mitogen-activated protein kinase (MAPK) signaling and Hippo pathways. These results indicate that P8 can promote cell growth by increasing stem cell proliferation, migration, and stemness in a manner associated with MAPK and Hippo signaling, which could contribute to the increased wound healing after P8 treatment. Furthermore, P8 could promote wound healing in keratinocytes by activating the MAPK signaling pathways. These results suggest that P8 might be a promising candidate to enhance stem cell culture efficiency by activating cell proliferation, and enhance therapeutic effects in skin diseases.
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Affiliation(s)
- Soo Bin Jang
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, Seoul, Korea
| | - Yoojung Kim
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, Seoul, Korea
| | - Han Cheol Yeo
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, Seoul, Korea
| | | | | | - Yongku Ryu
- R&D Center, Cell Biotech Co., Ltd., Gimpo, Korea
| | | | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, Seoul, Korea
- R&D Team, StemExOne Co., Ltd., Seoul, Korea
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2
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Sang G, Wang B, Xie Y, Chen Y, Yang F. Engineered Probiotic-Based Biomaterials for Inflammatory Bowel Disease Treatment. Theranostics 2025; 15:3289-3315. [PMID: 40093907 PMCID: PMC11905135 DOI: 10.7150/thno.103983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 12/09/2024] [Indexed: 03/19/2025] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic condition affecting the intestines, marked by immune-mediated inflammation. This disease is known for its recurrent nature and the challenges it presents in treatment. Recently, probiotic have gained attention as a promising alternative to traditional small molecular drugs and monoclonal antibody chemotherapies for IBD. Probiotic, recognized as a "living" therapeutic agent, offers targeted treatment with minimal side effects and the flexibility for biological modifications, making them highly effective for IBD management. This comprehensive review presents the latest advancements in engineering probiotic-based materials, ranging from basic treatment mechanisms to the modification techniques used in IBD management. It delves deep into how probiotic produces therapeutic effects in the intestinal environment and discusses various strategies to enhance probiotic's efficacy, including genetic modifications and formulation improvements. Additionally, the review addresses the challenges, practical application conditions, and future research directions of probiotic-based therapies in IBD treatment, providing insights into their feasibility and potential clinical implications.
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Affiliation(s)
- Guangze Sang
- Department of Inorganic Chemistry, School of Pharmacy, Naval Medical University, Shanghai, 200433, P. R. China
| | - Bingkai Wang
- Department of Inorganic Chemistry, School of Pharmacy, Naval Medical University, Shanghai, 200433, P. R. China
| | - Yujie Xie
- School of Medicine, Shanghai University, Shanghai, 200444, P. R. China
| | - Yu Chen
- Materdicine lab, School of Life Sciences, Shanghai University, Shanghai, 200444, P. R. China
| | - Feng Yang
- Department of Inorganic Chemistry, School of Pharmacy, Naval Medical University, Shanghai, 200433, P. R. China
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3
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Vidya Bernhardt G, Shivappa P, R Pinto J, Ks R, Ramakrishna Pillai J, Kumar Srinivasamurthy S, Paul Samuel V. Probiotics-role in alleviating the impact of alcohol liver disease and alcohol deaddiction: a systematic review. Front Nutr 2024; 11:1372755. [PMID: 39290562 PMCID: PMC11406471 DOI: 10.3389/fnut.2024.1372755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 08/05/2024] [Indexed: 09/19/2024] Open
Abstract
Background There are few efficient treatment options for alcohol addiction, which continues to be a serious public health concern. The possible contribution of gut microbiota to the onset and progression of alcohol addiction has been brought to light by recent studies. Probiotics have become a cutting-edge intervention in the treatment of alcohol consumption disorder because of its favorable effects on gut health. The purpose of this systematic review is to assess the body of research on the advantages of probiotics in treating alcoholism and associated neuroinflammatory conditions. Methods To find pertinent research published from January 2012 to 2023, a thorough search of electronic databases, including PubMed, Scopus, Google Scholar and Web of Science, was carried out. Included were studies looking at how probiotics affect neuroinflammation, gut- brain axis regulation, alcohol addiction, and related behaviors. Findings Several investigations have shown how beneficial probiotics are in reducing systemic inflammation and alcoholic liver disease (ALD). Probiotic treatments successfully corrected the imbalance of microbiota, decreased intestinal permeability, and stopped the passage of bacterial constituents such lipopolysaccharides (LPS) into the bloodstream. Additionally, probiotics helped to regulate neurotransmitter pathways, especially those connected to GABA, glutamate, and dopamine, which are intimately linked to behaviors related to addiction. Furthermore, it was shown that probiotics altered the expression of neurotransmitter signaling and dopamine receptors. Conclusion There is strong evidence from this systematic study that probiotics have potential advantages in treating alcohol addiction. The potential of probiotic therapies is demonstrated by the way they modulate important neurotransmitter pathways implicated in addiction, decrease neuroinflammation, and restore the balance of gut flora. To fully investigate the therapeutic potential of probiotics in treating alcohol addiction and enhancing the general wellbeing of those afflicted by this condition, more research is necessary.
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Affiliation(s)
- Grisilda Vidya Bernhardt
- Department of Biochemistry, RAKCOMS, Ras Al-Khaimah Medical and Health Sciences University, Ras Al-Khaimah, United Arab Emirates
| | - Pooja Shivappa
- Department of Biochemistry, RAKCOMS, Ras Al-Khaimah Medical and Health Sciences University, Ras Al-Khaimah, United Arab Emirates
| | - Janita R Pinto
- Department of Biomedical Sciences, Gulf Medical University, Ajman, United Arab Emirates
| | - Rashmi Ks
- Department of Physiology, Kasturba Medical College Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Jayachithra Ramakrishna Pillai
- Department of Pharmaceutical Chemistry, RAKCOPS, Ras Al-Khaimah Medical and Health Sciences University, Ras Al-Khaimah, United Arab Emirates
| | - Suresh Kumar Srinivasamurthy
- Department of Pharmacology, RAKCOMS, Ras Al-Khaimah Medical and Health Sciences University, Ras Al-Khaimah, United Arab Emirates
| | - Vijay Paul Samuel
- Department of Anatomy, RAKCOMS, Ras Al-Khaimah Medical and Health Sciences University, Ras Al-Khaimah, United Arab Emirates
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Stastna M. The Role of Proteomics in Identification of Key Proteins of Bacterial Cells with Focus on Probiotic Bacteria. Int J Mol Sci 2024; 25:8564. [PMID: 39201251 PMCID: PMC11354107 DOI: 10.3390/ijms25168564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 09/02/2024] Open
Abstract
Probiotics can affect human health, keep the balance between beneficial and pathogenic bacteria, and their colonizing abilities enable the enhancement of the epithelial barrier, preventing the invasion of pathogens. Health benefits of probiotics were related to allergy, depression, eczema, cancer, obesity, inflammatory diseases, viral infections, and immune regulation. Probiotic bacterial cells contain various proteins that function as effector molecules, and explaining their roles in probiotic actions is a key to developing efficient and targeted treatments for various disorders. Systematic proteomic studies of probiotic proteins (probioproteomics) can provide information about the type of proteins involved, their expression levels, and the pathological changes. Advanced proteomic methods with mass spectrometry instrumentation and bioinformatics can point out potential candidates of next-generation probiotics that are regulated under pharmaceutical frameworks. In addition, the application of proteomics with other omics methods creates a powerful tool that can expand our understanding about diverse probiotic functionality. In this review, proteomic strategies for identification/quantitation of the proteins in probiotic bacteria were overviewed. The types of probiotic proteins investigated by proteomics were described, such as intracellular proteins, surface proteins, secreted proteins, and the proteins of extracellular vesicles. Examples of pathological conditions in which probiotic bacteria played crucial roles were discussed.
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Affiliation(s)
- Miroslava Stastna
- Institute of Analytical Chemistry of the Czech Academy of Sciences, Veveri 97, 602 00 Brno, Czech Republic
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Masheghati F, Asgharzadeh MR, Jafari A, Masoudi N, Maleki-Kakelar H. The role of gut microbiota and probiotics in preventing, treating, and boosting the immune system in colorectal cancer. Life Sci 2024; 344:122529. [PMID: 38490297 DOI: 10.1016/j.lfs.2024.122529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 12/03/2023] [Accepted: 02/21/2024] [Indexed: 03/17/2024]
Abstract
The gut microbiome plays a significant role in developing colorectal cancer (CRC). The gut microbiome usually acts as a protective barrier against harmful pathogens and infections in the intestine, while also regulating inflammation by affecting the human immune system. The gut microbiota and probiotics play a role not only in intestinal inflammation associated with tumor formation but also in regulating anti-cancer immune response. As a result, they associated with tumor progression and the effectiveness of anti-cancer therapies. Research indicates that gut microbiota and probiotics can be used as biomarkers to predict the impact of immunotherapy and enhance its efficacy in treating CRC by regulating it. This review examines the importance of gut microbiota and probiotics in the development and progression of CRC, as well as their synergistic impact on anti-cancer treatments.
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Affiliation(s)
- Forough Masheghati
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Abbas Jafari
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Naser Masoudi
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of General Surgery, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Hadi Maleki-Kakelar
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
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Leser T, Baker A. Molecular Mechanisms of Lacticaseibacillus rhamnosus, LGG ® Probiotic Function. Microorganisms 2024; 12:794. [PMID: 38674738 PMCID: PMC11051730 DOI: 10.3390/microorganisms12040794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
To advance probiotic research, a comprehensive understanding of bacterial interactions with human physiology at the molecular and cellular levels is fundamental. Lacticaseibacillus rhamnosus LGG® is a bacterial strain that has long been recognized for its beneficial effects on human health. Probiotic effector molecules derived from LGG®, including secreted proteins, surface-anchored proteins, polysaccharides, and lipoteichoic acids, which interact with host physiological processes have been identified. In vitro and animal studies have revealed that specific LGG® effector molecules stimulate epithelial cell survival, preserve intestinal barrier integrity, reduce oxidative stress, mitigate excessive mucosal inflammation, enhance IgA secretion, and provide long-term protection through epigenetic imprinting. Pili on the cell surface of LGG® promote adhesion to the intestinal mucosa and ensure close contact to host cells. Extracellular vesicles produced by LGG® recapitulate many of these effects through their cargo of effector molecules. Collectively, the effector molecules of LGG® exert a significant influence on both the gut mucosa and immune system, which promotes intestinal homeostasis and immune tolerance.
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Affiliation(s)
- Thomas Leser
- Future Labs, Human Health Biosolutions, Novonesis, Kogle Alle 6, 2970 Hoersholm, Denmark;
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Al-Najjar MAA, Abdulrazzaq SB, Alzaghari LF, Mahmod AI, Omar A, Hasen E, Athamneh T, Talib WH, Chellappan DK, Barakat M. Evaluation of immunomodulatory potential of probiotic conditioned medium on murine macrophages. Sci Rep 2024; 14:7126. [PMID: 38531887 DOI: 10.1038/s41598-024-56622-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 03/08/2024] [Indexed: 03/28/2024] Open
Abstract
Probiotics are a mixture of beneficial live bacteria and/or yeasts that naturally exist in our bodies. Recently, numerous studies have focused on the immunostimulatory effects of single-species or killed multi-species probiotic conditioned mediums on macrophages. This study investigates the immunostimulatory effect of commercially available active, multi-species probiotic conditioned medium (CM) on RAW264.7 murine macrophages. The probiotic CM was prepared by culturing the commercially available probiotic in a cell-culture medium overnight at 37 °C, followed by centrifugation and filter-sterilization to be tested on macrophages. The immunostimulatory effect of different dilution percentages (50%, 75%, 100%) of CM was examined using the MTT assay, proinflammatory cytokine (tumor necrosis factor TNF-alpha) production in macrophages, migration, and phagocytosis assays. For all the examined CM ratios, the percentages of cell viability were > 80%. Regarding the migration scratch, TNF-alpha and phagocytosis assays, CM demonstrated a concentration-dependent immunostimulatory effect. However, the undiluted CM (100%) showed a significant (p-value < 0.05) stimulatory effect compared to the positive and negative controls. The findings suggest that the secretions and products of probiotics, as measured in the CM, may be closely associated with their immune-boosting effects. Understanding this relationship between probiotic secretions and immune function is crucial for further exploring the potential benefits of probiotics in enhancing overall health and well-being.
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Affiliation(s)
| | | | | | | | - Amin Omar
- Faculty of Pharmacy, Applied Science Private University, 11937, Amman, Jordan
| | - Eliza Hasen
- MEA Research Center, Middle East University, Amman, Jordan
| | - Tamara Athamneh
- Institute of Nanotechnology, Jordan University of Science and Technology, Irbid, Jordan
| | - Wamidh H Talib
- Faculty of Allied Medical Sciences, Applied Science Private University, 11937, Amman, Jordan
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
| | - Muna Barakat
- Faculty of Pharmacy, Applied Science Private University, 11937, Amman, Jordan.
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Jastrząb R, Tomecki R, Jurkiewicz A, Graczyk D, Szczepankowska AK, Mytych J, Wolman D, Siedlecki P. The strain-dependent cytostatic activity of Lactococcus lactis on CRC cell lines is mediated through the release of arginine deiminase. Microb Cell Fact 2024; 23:82. [PMID: 38481270 PMCID: PMC10938756 DOI: 10.1186/s12934-024-02345-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/20/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, posing a serious public health challenge that necessitates the development of new therapeutics, therapies, and prevention methods. Among the various therapeutic approaches, interventions involving lactic acid bacteria (LAB) as probiotics and postbiotics have emerged as promising candidates for treating and preventing CRC. While human-isolated LAB strains are considered highly favorable, those sourced from environmental reservoirs such as dairy and fermented foods are also being recognized as potential sources for future therapeutics. RESULTS In this study, we present a novel and therapeutically promising strain, Lactococcus lactis ssp. lactis Lc4, isolated from dairy sources. Lc4 demonstrated the ability to release the cytostatic agent - arginine deiminase (ADI) - into the post-cultivation supernatant when cultured under conditions mimicking the human gut environment. Released arginine deiminase was able to significantly reduce the growth of HT-29 and HCT116 cells due to the depletion of arginine, which led to decreased levels of c-Myc, reduced phosphorylation of p70-S6 kinase, and cell cycle arrest. The ADI release and cytostatic properties were strain-dependent, as was evident from comparison to other L. lactis ssp. lactis strains. CONCLUSION For the first time, we unveil the anti-proliferative properties of the L. lactis cell-free supernatant (CFS), which are independent of bacteriocins or other small molecules. We demonstrate that ADI, derived from a dairy-Generally Recognized As Safe (GRAS) strain of L. lactis, exhibits anti-proliferative activity on cell lines with different levels of argininosuccinate synthetase 1 (ASS1) expression. A unique feature of the Lc4 strain is also its capability to release ADI into the extracellular space. Taken together, we showcase L. lactis ADI and the Lc4 strain as promising, potential therapeutic agents with broad applicability.
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Affiliation(s)
- Rafał Jastrząb
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland
- Olimp Laboratories, Pustynia 84F, Debica, 39-200, Poland
| | - Rafał Tomecki
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland
- Faculty of Biology, University of Warsaw, Miecznikowa 1, Warsaw, 02-089, Poland
| | - Aneta Jurkiewicz
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland
| | - Damian Graczyk
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland
| | - Agnieszka K Szczepankowska
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland
| | | | - Damian Wolman
- Olimp Laboratories, Pustynia 84F, Debica, 39-200, Poland
| | - Pawel Siedlecki
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland.
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Mantel M, Durand T, Bessard A, Pernet S, Beaudeau J, Guimaraes-Laguna J, Maillard MB, Guédon E, Neunlist M, Le Loir Y, Jan G, Rolli-Derkinderen M. Propionibacterium freudenreichii CIRM-BIA 129 mitigates colitis through S layer protein B-dependent epithelial strengthening. Am J Physiol Gastrointest Liver Physiol 2024; 326:G163-G175. [PMID: 37988603 DOI: 10.1152/ajpgi.00198.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/10/2023] [Accepted: 11/20/2023] [Indexed: 11/23/2023]
Abstract
The growing incidence of human diseases involving inflammation and increased gut permeability makes the quest for protective functional foods more crucial than ever. Propionibacterium freudenreichii (P. freudenreichii) is a beneficial bacterium used in the dairy and probiotic industries. Selected strains exert anti-inflammatory effects, and the present work addresses whether the P. freudenreichii CIRM-BIA129, consumed daily in a preventive way, could protect mice from acute colitis induced by dextran sodium sulfate (DSS), and more precisely, whether it could protect from intestinal epithelial breakdown induced by inflammation. P. freudenreichii CIRM-BIA129 mitigated colitis severity and inhibited DSS-induced permeability. It limited crypt length reduction and promoted the expression of zonula occludens-1 (ZO-1), without reducing interleukin-1β mRNA (il-1β) expression. In vitro, P. freudenreichii CIRM-BIA129 prevented the disruption of a Caco-2 monolayer induced by proinflammatory cytokines. It increased transepithelial electrical resistance (TEER) and inhibited permeability induced by inflammation, along with an increased ZO-1 expression. Extracellular vesicles (EVs) from P. freudenreichii CIRM-BIA129, carrying the surface layer protein (SlpB), reproduced the protective effect of P. freudenreichii CIRM-BIA129. A mutant strain deleted for slpB (ΔslpB), or EVs from this mutant strain, had lost their protective effects and worsened both DSS-induced colitis and inflammation in vivo. These results shown that P. freudenreichii CIRM-BIA129 daily consumption has the potential to greatly alleviate colitis symptoms and, particularly, to counter intestinal epithelial permeability induced by inflammation by restoring ZO-1 expression through mechanisms involving S-layer protein B. They open new avenues for the use of probiotic dairy propionibacteria and/or postbiotic fractions thereof, in the context of gut permeability.NEW & NOTEWORTHY Propionibacterium freudenreichii reduces dextran sodium sulfate (DSS)-induced intestinal permeability in vivo. P. freudenreichii does not inhibit inflammation but damages linked to inflammation. P. freudenreichii inhibits intestinal epithelial breakdown through S-layer protein B. The protective effects of P. freudenreichii depend on S-layer protein B. Extracellular vesicles from P. freudenreichii CB 129 mimic the protective effect of the probiotic.
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Affiliation(s)
- Marine Mantel
- The Enteric Nervous System In Gut And Brain Disorders, IMAD, Institut National de la Santé et de la Recherche Médicale, Nantes Université, Nantes, France
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Unité Mixte de Recherche, L'Institut Agro, Rennes, France
| | - Tony Durand
- The Enteric Nervous System In Gut And Brain Disorders, IMAD, Institut National de la Santé et de la Recherche Médicale, Nantes Université, Nantes, France
| | - Anne Bessard
- The Enteric Nervous System In Gut And Brain Disorders, IMAD, Institut National de la Santé et de la Recherche Médicale, Nantes Université, Nantes, France
| | - Ségolène Pernet
- The Enteric Nervous System In Gut And Brain Disorders, IMAD, Institut National de la Santé et de la Recherche Médicale, Nantes Université, Nantes, France
| | - Julie Beaudeau
- The Enteric Nervous System In Gut And Brain Disorders, IMAD, Institut National de la Santé et de la Recherche Médicale, Nantes Université, Nantes, France
- Centres de Recherche en Nutrition Humaine-Ouest, Nantes, France
| | - Juliana Guimaraes-Laguna
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Unité Mixte de Recherche, L'Institut Agro, Rennes, France
| | - Marie-Bernadette Maillard
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Unité Mixte de Recherche, L'Institut Agro, Rennes, France
| | - Eric Guédon
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Unité Mixte de Recherche, L'Institut Agro, Rennes, France
| | - Michel Neunlist
- The Enteric Nervous System In Gut And Brain Disorders, IMAD, Institut National de la Santé et de la Recherche Médicale, Nantes Université, Nantes, France
| | - Yves Le Loir
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Unité Mixte de Recherche, L'Institut Agro, Rennes, France
| | - Gwénaël Jan
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Unité Mixte de Recherche, L'Institut Agro, Rennes, France
| | - Malvyne Rolli-Derkinderen
- The Enteric Nervous System In Gut And Brain Disorders, IMAD, Institut National de la Santé et de la Recherche Médicale, Nantes Université, Nantes, France
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Domínguez-Díaz C, Avila-Arrezola KE, Rodríguez JA, del-Toro-Arreola S, Delgado-Rizo V, Fafutis-Morris M. Recombinant p40 Protein Promotes Expression of Occludin in HaCaT Keratinocytes: A Brief Communication. Microorganisms 2023; 11:2913. [PMID: 38138057 PMCID: PMC10745755 DOI: 10.3390/microorganisms11122913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 11/27/2023] [Accepted: 11/30/2023] [Indexed: 12/24/2023] Open
Abstract
The ability of epithelial barriers to perform as the first defense line against external damage derives from tight junctions, protein complexes that block microorganisms through the paracellular space. Indeed, disturbances of barrier permeability caused by bacterial metabolites and other inflammatory stimuli are the consequence of changes in protein expression in these complexes. Postbiotics, molecules derived from bacteria with beneficial effects on the host, improve barrier function through the activation of survival pathways in epithelial cells. Lacticaseibacillus rhamnosus GG secretes the muramidase p40, which protects intestinal barriers through an EGFR-dependent pathway. In this work, we cloned, expressed, and purified the recombinant p40 protein from L. rhamnosus GR-1 to evaluate its effect on cell viability, cell cytotoxicity, TEER, and protein levels of tight junctions, as well as EGFR activation via Western blot on HaCaT keratinocytes subjected to LPS. We found a novel mutation at residue 368 that does not change the structure of p40. Our protein also reduces the LPS-induced increase in cell cytotoxicity when it is added prior to this stimulus. Furthermore, although LPS did not cause changes in barrier function, p40 increased TEER and occludin expression in HaCaT, but unlike previous work with p40 from LGG, we found that recombinant p40 did not activate EGFR. This suggests that recombinant p40 enhances epithelial barrier function through distinct signaling pathways.
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Affiliation(s)
- Carolina Domínguez-Díaz
- Doctoral Program in Biomedical Sciences, Physiology Department, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico;
- Immunology and Dermatology Research Center (CIINDE), Zapopan 45190, Mexico;
| | | | - Jorge A. Rodríguez
- Department of Industrial Biotechnology, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Zapopan 45019, Mexico;
| | - Susana del-Toro-Arreola
- Physiology Department, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (S.d.-T.-A.); (V.D.-R.)
| | - Vidal Delgado-Rizo
- Physiology Department, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (S.d.-T.-A.); (V.D.-R.)
| | - Mary Fafutis-Morris
- Immunology and Dermatology Research Center (CIINDE), Zapopan 45190, Mexico;
- Physiology Department, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (S.d.-T.-A.); (V.D.-R.)
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Yang J, Li D, Zhang M, Lin G, Hu S, Xu H. From the updated landscape of the emerging biologics for IBDs treatment to the new delivery systems. J Control Release 2023; 361:568-591. [PMID: 37572962 DOI: 10.1016/j.jconrel.2023.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/06/2023] [Accepted: 08/06/2023] [Indexed: 08/14/2023]
Abstract
Inflammatory bowel diseases (IBDs) treatments have shifted from small-molecular therapeutics to the oncoming biologics. The first-line biologics against the moderate-to-severe IBDs are mainly involved in antibodies against integrins, cytokines and cell adhesion molecules. Besides, other biologics including growth factors, antioxidative enzyme, anti-inflammatory peptides, nucleic acids, stem cells and probiotics have also been explored at preclinical or clinical studies. Biologics with variety of origins have their unique potentials in attenuating immune inflammation or gut mucosa healing. Great advances in use of biologics for IBDs treatments have been archived in recent years. But delivering issues for biologic have also been confronted due to their liable nature. In this review, we will focus on biologics for IBDs treatments in the recent publications; summarize the current landscapes of biologics and their promise to control disease progress. Alternatively, the confronted challenges for delivering biologics will also be analyzed. To combat these drawbacks, some new delivering strategies are provided: firstly, designing the functional materials with high affinity toward biologics; secondly, the delivering vehicle systems to encapsulate the liable biologics; thirdly, the topical adhering delivery systems as enema. To our knowledge, this review is the first study to summarize the updated usage of the oncoming biologics for IBDs, their confronted challenges in term of delivery and the potential combating strategies.
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Affiliation(s)
- Jiaojiao Yang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Dingwei Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Mengjiao Zhang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Gaolong Lin
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Sunkuan Hu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China
| | - Helin Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
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12
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Xu J, Chen C, Gan S, Liao Y, Fu R, Hou C, Yang S, Zheng Z, Chen W. The Potential Value of Probiotics after Dental Implant Placement. Microorganisms 2023; 11:1845. [PMID: 37513016 PMCID: PMC10383117 DOI: 10.3390/microorganisms11071845] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/15/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Dental implantation is currently the optimal solution for tooth loss. However, the health and stability of dental implants have emerged as global public health concerns. Dental implant placement, healing of the surgical site, osseointegration, stability of bone tissues, and prevention of peri-implant diseases are challenges faced in achieving the long-term health and stability of implants. These have been ongoing concerns in the field of oral implantation. Probiotics, as beneficial microorganisms, play a significant role in the body by inhibiting pathogens, promoting bone tissue homeostasis, and facilitating tissue regeneration, modulating immune-inflammatory levels. This review explores the potential of probiotics in addressing post-implantation challenges. We summarize the existing research regarding the importance of probiotics in managing dental implant health and advocate for further research into their potential applications.
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Affiliation(s)
- Jia Xu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Chenfeng Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of General Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Shuaiqi Gan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yihan Liao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Ruijie Fu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Chuping Hou
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Shuhan Yang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Zheng Zheng
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Wenchuan Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Oral Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Jinjiang Out-Patient Section, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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Pagnini C, Di Paolo MC, Urgesi R, Pallotta L, Fanello G, Graziani MG, Delle Fave G. Safety and Potential Role of Lactobacillus rhamnosus GG Administration as Monotherapy in Ulcerative Colitis Patients with Mild-Moderate Clinical Activity. Microorganisms 2023; 11:1381. [PMID: 37374884 DOI: 10.3390/microorganisms11061381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 04/30/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
Probiotics are microorganisms that confer benefits to the host, and, for this reason, they have been proposed in several pathologic states. Specifically, probiotic bacteria have been investigated as a therapeutic option in ulcerative colitis (UC) patients, but clinical results are dishomogeneous. In particular, many probiotic species with different therapeutic schemes have been proposed, but no study has investigated probiotics in monotherapy in adequate trials for the induction of remission. Lactobacillus rhamnosus GG (LGG) is the more intensively studied probiotic and it has ideal characteristics for utilization in UC patients. The aim of the present study is to investigate the clinical efficacy and safety of LGG administration in an open trial, delivered in monotherapy at two different doses, in UC patients with mild-moderate disease. The UC patients with mild-moderate disease activity (Partial Mayo score ≥ 2) despite treatment with oral mesalamine were included. The patients stopped oral mesalamine and were followed up for one month, then were randomized to receive LGG supplement at dose of 1.2 or 2.4 × 1010 CFU/day for one month. At the end of the study, the clinical activity was evaluated and compared to that at the study entrance (efficacy). Adverse events were recorded (safety). The primary end-point was clinical improvement (reduction in the Partial Mayo score) and no serious adverse events, while the secondary end-points were the evaluation of different efficacies and safeties between the two doses of LGG. The patients with disease flares dropped out of the study and went back to standard therapy. The efficacy data were analyzed in an intention-to-treat (ITT) and per-protocol (PP) analysis. Out of the 76 patients included in the study, 75 started the probiotic therapy (n = 38 and 37 per group). In the ITT analysis, 32/76 (42%) responded to treatment, 21/76 (28%) remained stable, and 23/76 (30%) had a worsening of their clinical condition; 55 (72%) completed the treatment and were analyzed in a PP analysis: 32/55 (58%) had a clinical response, 21 (38%) remained stable, and 2 (4%) had a light worsening of their clinical condition (p < 0.0001). Overall, 37% of the patients had a disease remission. No severe adverse event was recorded, and only one patient stopped therapy due to obstinate constipation. No difference in the clinical efficacy and safety has been recorded between groups treated with different doses of LGG. The present prospective clinical trial demonstrates, for the first time, that LGG in monotherapy is safe and effective for the induction of remission in UC patients with mild-moderate disease activity (ClinicalTrials.gov identifier: NCT04102852).
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Affiliation(s)
- Cristiano Pagnini
- Department of Gastroenterology and Digestive Endoscopy, S. Giovanni Addolorata Hospital, Via dell'Amba Aradam 9, 00184 Rome, Italy
| | - Maria Carla Di Paolo
- Department of Gastroenterology and Digestive Endoscopy, S. Giovanni Addolorata Hospital, Via dell'Amba Aradam 9, 00184 Rome, Italy
| | - Riccardo Urgesi
- Department of Gastroenterology and Digestive Endoscopy, S. Giovanni Addolorata Hospital, Via dell'Amba Aradam 9, 00184 Rome, Italy
| | - Lorella Pallotta
- Department of Gastroenterology and Digestive Endoscopy, S. Giovanni Addolorata Hospital, Via dell'Amba Aradam 9, 00184 Rome, Italy
| | - Gianfranco Fanello
- Department of Gastroenterology and Digestive Endoscopy, S. Giovanni Addolorata Hospital, Via dell'Amba Aradam 9, 00184 Rome, Italy
| | - Maria Giovanna Graziani
- Department of Gastroenterology and Digestive Endoscopy, S. Giovanni Addolorata Hospital, Via dell'Amba Aradam 9, 00184 Rome, Italy
| | - Gianfranco Delle Fave
- Department of Gastroenterology, "Sapienza" University of Rome, 00185 Rome, Italy
- Onlus "S. Andrea", 00199 Rome, Italy
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Bnfaga AA, Lee KW, Than LTL, Amin-Nordin S. Antimicrobial and immunoregulatory effects of Lactobacillus delbrueckii 45E against genitourinary pathogens. J Biomed Sci 2023; 30:19. [PMID: 36959635 PMCID: PMC10037868 DOI: 10.1186/s12929-023-00913-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 03/14/2023] [Indexed: 03/25/2023] Open
Abstract
BACKGROUND Lactobacilli are essential microbiota that maintain a healthy, balanced vaginal environment. Vaginitis is a common infection in women during their reproductive years. Many factors are associated with vaginitis; one of them is the imbalance of microbiota in the vaginal environment. This study aimed to evaluate the antimicrobial properties of Lactobacillus delbrueckii 45E (Ld45E) against several species of bacteria, namely, Group B Streptococcus (GBS), Escherichia coli, Klebsiella spp., and Candida parapsilosis, as well as to determine the concentration of interleukin-17 (IL-17) in the presence of Ld45E. METHODS The probiotic characteristics of Ld45E were evaluated by examining its morphology, pH tolerance, adhesive ability onto HeLa cells, hemolytic activity, antibiotic susceptibility, and autoaggregation ability. Then, the antimicrobial activity of Ld45E was determined using Ld45E culture, cell-free supernatant, and crude bacteriocin solution. Co-aggregation and competition ability assays against various pathogens were conducted. The immunoregulatory effects of Ld45E were analyzed by measuring the proinflammatory cytokine IL-17. A p-value less than 0.05 was considered statistical significance. RESULTS Ld45E is 3-5 mm in diameter and round with a flat-shaped colony. pH 4 and 4.5 were the most favorable range for Ld45E growth within 12 h of incubation. Ld45E showed a strong adhesion ability onto HeLa cells (86%) and negative hemolytic activities. Ld45E was also sensitive to ceftriaxone, cefuroxime, ciprofloxacin, and doxycycline. We found that it had a good autoaggregation ability of 80%. Regarding antagonistic properties, Ld45E culture showed strong antimicrobial activity against GBS, E. coli, and Klebsiella spp. but only a moderate effect on C. parapsilosis. Cell-free supernatant of Ld45E exerted the most potent inhibitory effects at 40 °C against all genital pathogens, whereas bacteriocin showed a robust inhibition at 37 °C and 40 °C. The highest co-aggregation affinity was observed with GBS (81%) and E. coli (40%). Competition ability against the adhesion of GBS (80%), E. coli (76%), Klebsiella (72%), and C. parapsilosis (58%) was found. Ld45E was able to reduce the induction of the proinflammatory protein IL-17. CONCLUSIONS Ld45E possessed antimicrobial and immunoregulatory properties, with better cell-on-cell activity than supernatant activity. Thus, Ld45E is a potential probiotic candidate for adjunct therapy to address vaginal infections.
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Affiliation(s)
- Ameda Abdullah Bnfaga
- Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Department of Para-Clinic, Faculty of Medicine, Aden University, Aden, Yemen
| | - Kai Wei Lee
- Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Leslie Thian Lung Than
- Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Syafinaz Amin-Nordin
- Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
- Hospital Sultan Abdul Aziz Shah, Universiti Putra Malaysia, Persiaran MARDI-UPM, 43400, Serdang, Malaysia.
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15
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Transcriptional responses of human intestinal epithelial HT-29 cells to spore-displayed p40 derived from Lacticaseibacillus rhamnosus GG. BMC Microbiol 2022; 22:316. [PMID: 36550414 PMCID: PMC9772600 DOI: 10.1186/s12866-022-02735-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUNDS The aims of this study were to construct spore-displayed p40, a Lacticaseibacillus rhamnosus GG-derived soluble protein, using spore surface display technology and to evaluate transcriptional responses in human intestinal epithelial cells. RESULTS p40 was displayed on the surface of Bacillus subtilis spores using spore coat protein CotG as an anchor protein. Effects of spore-displayed p40 (CotG-p40) on gene expression of intestinal epithelial cell line HT-29 were evaluated by transcriptome analysis using RNA-sequencing. As a result of differentially expressed gene (DEG) analysis, 81 genes were up-regulated and 82 genes were down-regulated in CotG-p40 stimulated cells than in unstimulated cells. Gene ontology enrichment analysis showed that CotG-p40 affected biological processes such as developmental process, metabolic process, cell surface receptor linked signaling pathway, and retinoic acid metabolic process. Gene-gene network analysis suggested that 10 DEGs (EREG, FOXF1, GLI2, PTGS2, SPP1, MMP19, TNFRSF1B, PTGER4, CLDN18, and ALDH1A3) activated by CotG-p40 were associated with probiotic action. CONCLUSIONS This study demonstrates the regulatory effects of CotG-p40 on proliferation and homeostasis of HT-29 cells. This study provided comprehensive insights into the transcriptional response of human intestinal epithelial cells stimulated by CotG-p40.
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Kang SJ, Jun JS, Hong KW. Transcriptome Analysis Reveals Immunomodulatory Effect of Spore-Displayed p75 on Human Intestinal Epithelial Caco-2 Cells. Int J Mol Sci 2022; 23:ijms232314519. [PMID: 36498846 PMCID: PMC9739243 DOI: 10.3390/ijms232314519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/19/2022] [Accepted: 11/20/2022] [Indexed: 11/23/2022] Open
Abstract
Lacticaseibacillus rhamnosus GG (LGG) can promote intestinal health by modulating the immune responses of the gastrointestinal tract. However, knowledge about the immunomodulatory action of LGG-derived soluble factors is limited. In our previous study, we have displayed LGG-derived p75 protein on the spore surface of Bacillus subtilis. The objective of this study was to determine the effect of spore-displayed p75 (CotG-p75) on immune system by investigating transcriptional response of Caco-2 cells stimulated by CotG-p75 through RNA-sequencing (RNA-seq). RNA-seq results showed that CotG-p75 mainly stimulated genes involved in biological processes, such as response to stimulus, immune regulation, and chemotaxis. KEGG pathway analysis suggested that many genes activated by CotG-p75 were involved in NF-ĸB signaling and chemokine signaling pathways. CotG-p75 increased cytokines and chemokines such as CXCL1, CXCL2, CXCL3, CXCL8, CXCL10, CCL20, CCL22, and IL1B essential for the immune system. In particular, CotG-p75 increased the expression levels of NF-ĸB-related genes such as NFKBIA, TNFAIP3, BIRC3, NFKB2, and RELB involved in immune and inflammatory responses. This study provides genes and pathways involved in immune responses influenced by CotG-p75. These comprehensive transcriptome profiling could be used to elucidate the immunomodulatory action of CotG-p75.
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Kvakova M, Kamlarova A, Stofilova J, Benetinova V, Bertkova I. Probiotics and postbiotics in colorectal cancer: Prevention and complementary therapy. World J Gastroenterol 2022; 28:3370-3382. [PMID: 36158273 PMCID: PMC9346452 DOI: 10.3748/wjg.v28.i27.3370] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/22/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of human mortality worldwide. As conventional anticancer therapy not always being effective, there is growing interest in innovative “drug-free” cancer treatments or interventions that improve the efficacy of established therapy. CRC is associated with microbiome alterations, a process known as dysbiosis that involves depletion and/or enrichment of particular gut bacterial species and their metabolic functions. Supplementing patient treatment with traditional probiotics (with or without prebiotics), next-generation probiotics (NGP), or postbiotics represents a potentially effective and accessible complementary anticancer strategy by restoring gut microbiota composition and/or by signaling to the host. In this capacity, restoration of the gut microbiota in cancer patients can stabilize and enhance intestinal barrier function, as well as promote anticarcinogenic, anti-inflammatory, antimutagenic or other biologically important biochemical pathways that show high specificity towards tumor cells. Potential benefits of traditional probiotics, NGP, and postbiotics include modulating gut microbiota composition and function, as well as the host inflammatory response. Their application in CRC prevention is highlighted in this review, where we consider supportive in vitro, animal, and clinical studies. Based on emerging research, NGP and postbiotics hold promise in establishing innovative treatments for CRC by conferring physiological functions via the production of dominant natural products and metabolites that provide new host-microbiota signals to combat CRC. Although favorable results have been reported, further investigations focusing on strain and dose specificity are required to ensure the efficacy and safety of traditional probiotics, NGP, and postbiotics in CRC prevention and treatment.
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Affiliation(s)
- Monika Kvakova
- Center of Clinical and Preclinical Research MEDIPARK, Faculty of Medicine, P.J. Safarik University in Kosice, Kosice 04011, Slovakia
| | - Anna Kamlarova
- Center of Clinical and Preclinical Research MEDIPARK, Faculty of Medicine, P.J. Safarik University in Kosice, Kosice 04011, Slovakia
| | - Jana Stofilova
- Center of Clinical and Preclinical Research MEDIPARK, Faculty of Medicine, P.J. Safarik University in Kosice, Kosice 04011, Slovakia
| | - Veronika Benetinova
- Center of Clinical and Preclinical Research MEDIPARK, Faculty of Medicine, P.J. Safarik University in Kosice, Kosice 04011, Slovakia
| | - Izabela Bertkova
- Center of Clinical and Preclinical Research MEDIPARK, Faculty of Medicine, P.J. Safarik University in Kosice, Kosice 04011, Slovakia
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18
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Wang Y, Li H. Gut microbiota modulation: a tool for the management of colorectal cancer. J Transl Med 2022; 20:178. [PMID: 35449107 PMCID: PMC9022293 DOI: 10.1186/s12967-022-03378-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 04/03/2022] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is the second cause of cancer death and the third most frequently diagnosed cancer. Besides the lifestyle, genetic and epigenetic alterations, and environmental factors, gut microbiota also plays a vital role in CRC development. The interruption of the commensal relationship between gut microbiota and the host could lead to an imbalance in the bacteria population, in which the pathogenic bacteria become the predominant population in the gut. Different therapeutic strategies have been developed to modify the gut immune system, prevent pathogen colonization, and alter the activity and composition of gut microbiota, such as prebiotics, probiotics, postbiotics, antibiotics, and fecal microbiota transplantation (FMT). Even though the employed strategies exhibit promising results, their translation into the clinic requires evaluating potential implications and risks, as well as assessment of their long-term effects. This study was set to review the gut microbiota imbalances and their relationship with CRC and their effects on CRC therapy, including chemotherapy and immunotherapy. More importantly, we reviewed the strategies that have been used to modulate gut microbiota, their impact on the treatment of CRC, and the challenges of each strategy.
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Affiliation(s)
- Yan Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Hui Li
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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Zhou Y, Liu Z, Chen T. Gut Microbiota: A Promising Milestone in Enhancing the Efficacy of PD1/PD-L1 Blockade Therapy. Front Oncol 2022; 12:847350. [PMID: 35252014 PMCID: PMC8890472 DOI: 10.3389/fonc.2022.847350] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 01/27/2022] [Indexed: 12/12/2022] Open
Abstract
In the past few decades, immunotherapy has emerged as one of the most promising strategies among current treatments of cancer. In particular, the field of PD1/PD-L1 inhibitors has been boosted, widely applied into clinical practice with potent therapeutic efficacy and remarkable survival benefits on various cancers such as melanoma, non-small cell lung cancer (NSCLC), and urothelial carcinoma (UC). However, the application of PD1/PD-L1 blockade therapy is still quite restricted because of unexpected toxicities, limited response rate, as well as associated resistance. In consequence, searching for potential strategies that possibly resolve the existing limitations and enhance the therapeutic responsiveness of PD1/PD-L1 blockade is of great significance. Fortunately, the gut microbiome has been demonstrated to serve as a pivotal regulator in anti-PD1/PD-L1 therapy, providing an applicable tool to improve anti-PD1/PD-L1 clinical efficacy. In this review, we summarized published advancements about how microbiota modulated in anti-PD1/PD-L1 therapy and illustrated its underlying mechanisms, giving insights into putative manipulation of gut microbiota to facilitate PD1/PD-L1 blockade.
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Affiliation(s)
- Yuqing Zhou
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Queen Mary School, Nanchang University, Nanchang, China
| | - Zhaoxia Liu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Tingtao Chen
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,National Engineering Research Center for Bioengineering Drugs and Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China
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20
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Zhou B, Jin G, Pang X, Mo Q, Bao J, Liu T, Wu J, Xie R, Liu X, Liu J, Yang H, Xu X, Wang B, Cao H. Lactobacillus rhamnosus GG colonization in early life regulates gut-brain axis and relieves anxiety-like behavior in adulthood. Pharmacol Res 2022; 177:106090. [PMID: 35065201 DOI: 10.1016/j.phrs.2022.106090] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/25/2021] [Accepted: 01/17/2022] [Indexed: 12/13/2022]
Abstract
Evidence reveals that gut dysbiosis is involved in bidirectional interactions in gut-brain axis and participates in the progress of multiple disorders like anxiety. Gut microbes in early life are crucial for establishment of host health. We aimed to investigate whether early life probiotics Lactobacillus rhamnosus GG (LGG) colonization could relieve anxiety in adulthood through regulation of gut-brain axis. Live or fixed LGG was gavaged to C57BL/6 female mice from day 18 of pregnancy until natural birth, and newborn mice from day 1 to day 5 respectively. In this study, we found that live LGG could be effectively colonized in the intestine of offspring. LGG colonization increased intestinal villus length and colonic crypt depth, accompanied with barrier function protection before weaning. Microbiota composition by 16S rRNA sequencing showed that some beneficial bacteria, such as Akkermansia and Bifidobacteria, were abundant in LGG colonization group. The protective effect of LGG on gut microbiota persisted from weaning to adulthood. Intriguingly, behavioral results assessed by elevated plus mazed test and open field test demonstrated relief of anxiety-like behavior in adult LGG-colonized offspring. Mechanically, LGG colonization activated epithelial growth factor receptor (EGFR) and enhanced serotonin transporter (SERT) expression and modulated serotonergic system in the intestine, and increased brain-derived neurotrophic factor and γ-aminobutyric acid receptor levels in the hippocampus and amygdala. Blocking EGFR blunted LGG-induced the increased SERT and zonula occludens-1 expression. Collectively, early life LGG colonization could protect intestinal barrier of offspring and modulate gut-brain axis in association with relief of anxiety-like behavior in adulthood.
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Affiliation(s)
- Bingqian Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Ge Jin
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Xiaoqi Pang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Qi Mo
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Jie Bao
- Department of Rehabilitation Medicine, General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Tiaotiao Liu
- School of Biomedical Engineering and technology, Tianjin Medical University, Tianjin 300070, China
| | - Jingyi Wu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Runxiang Xie
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Xiang Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Jinghua Liu
- Department of Gastroenterology, Tianjin TEDA hospital, Tianjin 300457, China
| | - Hongwei Yang
- Geriatric Ward of Neurology, Tianjin Geriatrics Institute, General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Xin Xu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China.
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21
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Requena T, Pérez Martínez G. Probiotics, Prebiotics, Synbiotics, Postbiotics and Other Biotics. What's Next? COMPREHENSIVE GUT MICROBIOTA 2022:197-210. [DOI: 10.1016/b978-0-12-819265-8.00094-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Poluektova EU, Danilenko VN. Probiotic Bacteria in the Correction of Depression Symptoms, Their Active Genes and Proteins. RUSS J GENET+ 2021. [DOI: 10.1134/s102279542109009x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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23
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Roberto M, Carconi C, Cerreti M, Schipilliti FM, Botticelli A, Mazzuca F, Marchetti P. The Challenge of ICIs Resistance in Solid Tumours: Could Microbiota and Its Diversity Be Our Secret Weapon? Front Immunol 2021; 12:704942. [PMID: 34489956 PMCID: PMC8417795 DOI: 10.3389/fimmu.2021.704942] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/03/2021] [Indexed: 12/14/2022] Open
Abstract
The human microbiota and its functional interaction with the human body were recently returned to the spotlight of the scientific community. In light of the extensive implementation of newer and increasingly precise genome sequencing technologies, bioinformatics, and culturomic, we now have an extraordinary ability to study the microorganisms that live within the human body. Most of the recent studies only focused on the interaction between the intestinal microbiota and one other factor. Considering the complexity of gut microbiota and its role in the pathogenesis of numerous cancers, our aim was to investigate how microbiota is affected by intestinal microenvironment and how microenvironment alterations may influence the response to immune checkpoint inhibitors (ICIs). In this context, we show how diet is emerging as a fundamental determinant of microbiota’s community structure and function. Particularly, we describe the role of certain dietary factors, as well as the use of probiotics, prebiotics, postbiotics, and antibiotics in modifying the human microbiota. The modulation of gut microbiota may be a secret weapon to potentiate the efficacy of immunotherapies. In addition, this review sheds new light on the possibility of administering fecal microbiota transplantation to modulate the gut microbiota in cancer treatment. These concepts and how these findings can be translated into the therapeutic response to cancer immunotherapies will be presented.
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Affiliation(s)
- Michela Roberto
- Department of Clinical and Molecular Medicine, Sant' Andrea University Hospital, Sapienza University of Rome, Rome, Italy.,Medical Oncology Unit, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Catia Carconi
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sant' Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Micaela Cerreti
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sant' Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Francesca Matilde Schipilliti
- Department of Clinical and Molecular Medicine, Sant' Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Andrea Botticelli
- Department of Clinical and Molecular Medicine, Sant' Andrea University Hospital, Sapienza University of Rome, Rome, Italy.,Medical Oncology Unit, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Federica Mazzuca
- Department of Clinical and Molecular Medicine, Sant' Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Paolo Marchetti
- Department of Clinical and Molecular Medicine, Sant' Andrea University Hospital, Sapienza University of Rome, Rome, Italy.,Medical Oncology Unit, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
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24
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The Putative Antidepressant Mechanisms of Probiotic Bacteria: Relevant Genes and Proteins. Nutrients 2021; 13:nu13051591. [PMID: 34068669 PMCID: PMC8150869 DOI: 10.3390/nu13051591] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/29/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
Probiotic bacteria are widely accepted as therapeutic agents against inflammatory bowel diseases for their immunostimulating effects. In the last decade, more evidence has emerged supporting the positive effects of probiotics on the course of neurodegenerative and psychiatric diseases. This brief review summarizes the data from clinical studies of probiotics possessing antidepressant properties and focuses on the potential genes and proteins underlying these mechanisms. Data from small-sample placebo-controlled pilot studies indicate that certain strains of bacteria can significantly reduce the symptoms of depression, especially in depressed patients. Despite the disparity between studies attempting to pinpoint the bacterial putative genes and proteins accounting for these mechanisms, they ultimately show that bacteria are a potential source of metabiotics—microbial metabolites or structural components. Since the constituents of cells—namely, secreted proteins, peptides and cell wall components—are most likely to be entangled in the gut–brain axis, they can serve as starting point in the search for probiotics with concrete properties.
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25
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Ren L, Ye J, Zhao B, Sun J, Cao P, Yang Y. The Role of Intestinal Microbiota in Colorectal Cancer. Front Pharmacol 2021; 12:674807. [PMID: 33959032 PMCID: PMC8093878 DOI: 10.3389/fphar.2021.674807] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 03/23/2021] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer is a multifactorial disease involving genetic, environmental, and lifestyle risk factors. Intestinal microbiota plays an important role in the occurrence and development of colorectal cancer. Studies have shown that the behavior of intestinal microbiota can lead to pathological changes in the host intestine, which can be divided into epigenetic changes and carcinogenic changes at the gene level, and ultimately promote the formation and development of colorectal cancer. Intestinal microbiota is mainly distributed in the intestinal epithelium, which is composed of a large number of microorganisms interacting with the host intestinal cells. It can affect the immune-inflammation and metabolism of the gastrointestinal tract, and may be used as a biomarker for disease diagnosis. Regulation of gut microbiota is a promising strategy for the prevention and treatment of colorectal cancer. This article reviews the role of intestinal microbiota in the development of colorectal cancer, including the related mechanisms of intestinal microbiota promoting colorectal cancer, the use of intestinal microbiota in the diagnosis of colorectal cancer, and the regulation of intestinal microbiota in the prevention or treatment of colorectal cancer.
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Affiliation(s)
- Lingli Ren
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Juan Ye
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Bing Zhao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jinbing Sun
- Department of General Surgery, Changshu No. 1 People's Hospital, Affiliated Changshu Hospital of Soochow University, Changshu, China
| | - Peng Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Yang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Yangtze River Pharmaceutical Group, Taizhou, China
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26
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Nanjundaiah YS, Wright DA, Baydoun AR, Khaled Z, Ali Z, Dean P, Sarker MH. Modulation of Macrophage Function by Lactobacillus-Conditioned Medium. Front Cell Dev Biol 2020; 8:723. [PMID: 32850839 PMCID: PMC7406691 DOI: 10.3389/fcell.2020.00723] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 07/14/2020] [Indexed: 02/05/2023] Open
Abstract
Probiotics are used as microbial food supplements for health and well-being. They are thought to have immunomodulatory effects although their exact physiological mechanism of action is not clear. This study investigated the influence of probiotic Lactobacillus rhamnosus GG conditioned media (LGG-CM) on macrophage phagocytosis of non-pathogenic Escherichia coli HfrC. The gentamicin protection assay was used to study the bacterial killing phases of phagocytosis. Macrophages co-incubated with E. coli for an hour allowed them to ingest bacteria and then the rate of E. coli killing was monitored for up to 300 min to determine the killing or digestion of the bacteria by recovering them from the macrophage lysate. We found that the LGG-CM significantly increased the bacterial killing by approximately 6-fold when compared with that of controls. By contrast, this killing process was found to be associated with enhanced free radical production via the activation of NADPH oxidase, stimulated by the LGG conditioned medium. We also found that the conditioned medium had small effect on nitric oxide (NO) generation, albeit to a lesser extent. This work suggests that LGG-CM may play an important role in suppressing the total microbial load within the macrophages and hence, the extent to which pro-inflammatory molecules such as free radicals and NO are generated. The modulation of inflammation-promoting signals by LGG-CM may be beneficial as it modulates bacterial killing, and thereby prevents any collateral damage to host.
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Affiliation(s)
| | - David A Wright
- School of Health and Life Sciences, Teesside University, Middlesbrough, United Kingdom
| | - Anwar R Baydoun
- Faculty of Health and Life Sciences, De Montfort University, Leicester, United Kingdom
| | - Zahangir Khaled
- Pediatric Gastroenterology, College of Medicine at Peoria, University of Illinois, Peoria, IL, United States
| | - Zulfiqur Ali
- School of Health and Life Sciences, Teesside University, Middlesbrough, United Kingdom
| | - Paul Dean
- School of Health and Life Sciences, Teesside University, Middlesbrough, United Kingdom
| | - Mosharraf H Sarker
- School of Health and Life Sciences, Teesside University, Middlesbrough, United Kingdom
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27
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Marsova M, Poluektova E, Odorskaya M, Ambaryan A, Revishchin A, Pavlova G, Danilenko V. Protective effects of Lactobacillus fermentum U-21 against paraquat-induced oxidative stress in Caenorhabditis elegans and mouse models. World J Microbiol Biotechnol 2020; 36:104. [PMID: 32632560 DOI: 10.1007/s11274-020-02879-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 06/27/2020] [Indexed: 12/19/2022]
Abstract
The aims of this work were to identify in vivo manifestations of antioxidant activity of Lactobacillus strains isolated from healthy human biotopes and to show the possibility of protective action of the selected strain on the model of oxidative stress induced by paraquat in the model of early Parkinson's disease (PD) in mice. We studied the protective effects of 14 Lactobacillus strains belonging to five species on the lifespan of the soil nematode Caenorhabditis elegans experiencing oxidative stress induced by paraquat. The Lactobacillus strains used in this study were selected previously based on their ability to reduce oxidative stress in vitro. One of the strains that showed promising results on C. elegans was tested in a mouse model of PD in which C57/BL6 mice were injected regularly with paraquat. We assessed the state of their internal organs, the preservation of dopaminergic neurons in the substantia nigra as well as their motor coordination. The positive impact of Lactobacillus fermentum U-21 strain supplementation on paraquat treated animals was observed. L. fermentum U-21 strain reduced the toxicity of paraquat in C. elegans model: the lifespan of the soil nematode C. elegans was extended by 25%. L. fermentum U-21 protected the mice against anatomical and behavioral changes typical of PD: there were no changes in the coordination of movement and the preservation of dopaminergic neurons in the brain. Life span of the nematode C. elegans pre-grown on a lawn of E. coli OP50 + Lactobacillus under oxidative stress conditions; the concentration of the oxidizing agent paraquat in the S medium was 50 mmol l-1.
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Affiliation(s)
- Maria Marsova
- Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia.
- Moscow Institute of Physics and Technology (National Research University), Moscow, Russia.
| | - Elena Poluektova
- Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia
| | - Maya Odorskaya
- Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia
| | - Alexander Ambaryan
- A.N. Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences, Moscow, Russia
| | | | - Galina Pavlova
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - Valeriy Danilenko
- Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia
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Structure and Function of Bovine Whey Derived Oligosaccharides Showing Synbiotic Epithelial Barrier Protective Properties. Nutrients 2020; 12:nu12072007. [PMID: 32640639 PMCID: PMC7400958 DOI: 10.3390/nu12072007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 01/15/2023] Open
Abstract
Commensal gut microbiota and probiotics have numerous effects on the host’s metabolic and protective systems, which occur primarily through the intestinal epithelial cell interface. Prebiotics, like galacto-oligosaccharides (GOS) are widely used to modulate their function and abundance. However, important structure–function relations may exist, requiring a detailed structural characterization. Here, we detailed the structural characterization of bovine whey derived oligosaccharide preparations enriched with GOS or not, dubbed GOS-enriched milk oligosaccharides (GMOS) or MOS, respectively. We explore GMOS’s and MOS’s potential to improve intestinal epithelial barrier function, assessed in a model based on barrier disruptive effects of the Clostridioides difficile toxin A. GMOS and MOS contain mainly GOS species composed of β1-6- and β1-3-linked galactoses, and 3′- and 6′-sialyllactose. Both GMOS and MOS, combined with lactobacilli, like Lactobacillus rhamnosus (LPR, NCC4007), gave synergistic epithelial barrier protection, while no such effect was observed with Bifidobacterium longum (BL NCC3001), Escherichia coli (Nissle) or fructo-oligosaccharides. Mechanistically, for barrier protection with MOS, (i) viable LPR was required, (ii) acidification of growth medium was not enough, (iii) LPR did not directly neutralize toxin A, and (iv) physical proximity of LPR with the intestinal epithelial cells was necessary. This is the first study, highlighting the importance of structure–function specificity and the necessity of the simultaneous presence of prebiotic, probiotic and host cell interactions required for a biological effect.
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29
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Gut microbiota modulation: a novel strategy for prevention and treatment of colorectal cancer. Oncogene 2020; 39:4925-4943. [PMID: 32514151 PMCID: PMC7314664 DOI: 10.1038/s41388-020-1341-1] [Citation(s) in RCA: 366] [Impact Index Per Article: 73.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/17/2020] [Accepted: 05/27/2020] [Indexed: 02/08/2023]
Abstract
Research about the role of gut microbiome in colorectal cancer (CRC) is a newly emerging field of study. Gut microbiota modulation, with the aim to reverse established microbial dysbiosis, is a novel strategy for prevention and treatment of CRC. Different strategies including probiotics, prebiotics, postbiotics, antibiotics, and fecal microbiota transplantation (FMT) have been employed. Although these strategies show promising results, mechanistically by correcting microbiota composition, modulating innate immune system, enhancing gut barrier function, preventing pathogen colonization and exerting selective cytotoxicity against tumor cells, it should be noted that they are accompanied by risks and controversies that can potentially introduce clinical complications. During bench-to-bedside translation, evaluation of risk-and-benefit ratio, as well as patient selection, should be carefully performed. In view of the individualized host response to gut microbiome intervention, developing personalized microbiome therapy may be the key to successful clinical treatment.
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30
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Wedgwood S, Gerard K, Halloran K, Hanhauser A, Monacelli S, Warford C, Thai PN, Chiamvimonvat N, Lakshminrusimha S, Steinhorn RH, Underwood MA. Intestinal Dysbiosis and the Developing Lung: The Role of Toll-Like Receptor 4 in the Gut-Lung Axis. Front Immunol 2020; 11:357. [PMID: 32194566 PMCID: PMC7066082 DOI: 10.3389/fimmu.2020.00357] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 02/14/2020] [Indexed: 01/19/2023] Open
Abstract
Background In extremely premature infants, postnatal growth restriction (PNGR) is common and increases the risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Mechanisms by which poor nutrition impacts lung development are unknown, but alterations in the gut microbiota appear to play a role. In a rodent model, PNGR plus hyperoxia causes BPD and PH and increases intestinal Enterobacteriaceae, Gram-negative organisms that stimulate Toll-like receptor 4 (TLR4). We hypothesized that intestinal dysbiosis activates intestinal TLR4 triggering systemic inflammation which impacts lung development. Methods Rat pups were assigned to litters of 17 (PNGR) or 10 (normal growth) at birth and exposed to room air or 75% oxygen for 14 days. Half of the pups were treated with the TLR4 inhibitor TAK-242 from birth or beginning at day 3. After 14 days, pulmonary arterial pressure was evaluated by echocardiography and hearts were examined for right ventricular hypertrophy (RVH). Lungs and serum samples were analyzed by western blotting and immunohistochemistry. Results Postnatal growth restriction + hyperoxia increased pulmonary arterial pressure and RVH with trends toward increased plasma IL1β and decreased IκBα, the inhibitor of NFκB, in lung tissue. Treatment with the TLR4 inhibitor attenuated PH and inflammation. Conclusion Postnatal growth restriction induces an increase in intestinal Enterobacteriaceae leading to PH. Activation of the TLR4 pathway is a promising mechanism by which intestinal dysbiosis impacts the developing lung.
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Affiliation(s)
- Stephen Wedgwood
- Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, United States
| | - Kimberly Gerard
- Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, United States
| | - Katrina Halloran
- Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, United States
| | - Ashley Hanhauser
- Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, United States
| | - Sveva Monacelli
- Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, United States
| | - Cris Warford
- Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, United States
| | - Phung N Thai
- Division of Cardiovascular Medicine, Department of Internal Medicine, UC Davis Health System, Sacramento, CA, United States
| | - Nipavan Chiamvimonvat
- Division of Cardiovascular Medicine, Department of Internal Medicine, UC Davis Health System, Sacramento, CA, United States.,Department of Veterans Affairs, Northern California Health Care System, Mather, CA, United States
| | | | - Robin H Steinhorn
- Department of Hospital Medicine, Children's National Health System, Washington, DC, United States
| | - Mark A Underwood
- Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, United States
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31
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Abstract
Microbiome dysbiosis is strongly associated with alcoholic liver disease (ALD). Recent studies on comprehensive analyses of microbiome compositional and functional changes have begun to uncover the mechanistic relation between microbiome and the pathogenesis of ALD. Importantly, targeting the microbiome has become a potential strategy for the prevention and treatment of ALD. In this review, we summarize the clinical evidence of microbiome dysbiosis in ALD patients, and experimental advances in microbiome and metabolomic functional changes in animals with different species and genetic backgrounds in ALD. We also summarize the studies in humanized intestinal microbiome and fecal microbiota transplantation in mice. We introduce new developments in the studies on the role of the circulating bacterial microbiome, oral bacterial microbiome and fungal microbiome in the development of ALD. We highlight the potential mechanisms by which microbiome dysbiosis contributes to ALD, including short chain fatty acid changes, bile acid metabolism, intestinal barrier function, release of bacterial and fungal products, and inflammation. In addition, we summarize the recent developments targeting the microbiome in prevention and treatment of ALD, including dietary nutrient interference, herbal medicine, antibiotics, anti-fungal agents, probiotics, engineered bacterial therapy, fecal transplantation and oral hygiene. Although recent preclinical studies have advanced our understanding of the microbiome and ALD, clinical studies, especially prospective studies with large samples, are needed to better understand the cause-effect of microbiome dysbiosis in ALD. Identifying new precision-based strategies targeting the microbiome are expected to be developed as more effective therapies in ALD.
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32
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Ding L, Gong Y, Yang Z, Zou B, Liu X, Zhang B, Li J. Lactobacillus rhamnosus GG Ameliorates Liver Injury and Hypoxic Hepatitis in Rat Model of CLP-Induced Sepsis. Dig Dis Sci 2019; 64:2867-2877. [PMID: 31049763 DOI: 10.1007/s10620-019-05628-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 04/15/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Probiotic use to prevent gastrointestinal infections in critical care has shown great promise in recent clinical trials. Although well-documented benefits of probiotic use in intestinal disorders, the potential for probiotic treatment to ameliorate liver injury and hypoxic hepatitis following sepsis has not been well explored. METHODS In order to evaluate, if Lactobacillus rhamnosus GG (LGG) treatment in septic rats will protect against liver injury, this study used 20-22-week-old Sprague-Dawley rats which were subjected to cecal ligation and puncture to establish sepsis model and examine mRNA and protein levels of IL-1β, NLRP3, IL-6, TNF-a, VEGF, MCP1, NF-kB and HIF-1α in the liver via real-time PCR, Elisa and Western blot. RESULTS This study showed that LGG treatment significantly ameliorated liver injury following experimental infection and sepsis. Liver mRNA and protein levels of IL-1β, NLRP3, IL-6, TNF-a, VEGF, MCP1, NF-kB and HIF-1α were significantly reduced in rats receiving LGG. CONCLUSIONS Thus, our study demonstrated that LGG treatment can reduce liver injury following experimental infection and sepsis and is associated with improved hypoxic hepatitis. Probiotic therapy may be a promising intervention to ameliorate clinical liver injury and hypoxic hepatitis following systemic infection and sepsis.
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Affiliation(s)
- Lei Ding
- Department of Hepatobiliary Surgery, The 5th Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Yihang Gong
- Department of Hepatobiliary Surgery, The 5th Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Zhengfei Yang
- Emergency Department, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong Province, China
| | - Baojia Zou
- Department of Hepatobiliary Surgery, The 5th Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Xialei Liu
- Department of Hepatobiliary Surgery, The 5th Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Baimeng Zhang
- Department of Hepatobiliary Surgery, The 5th Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Jian Li
- Department of Hepatobiliary Surgery, The 5th Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China.
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33
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Bäuerl C, Abitayeva G, Sosa-Carrillo S, Mencher-Beltrán A, Navarro-Lleó N, Coll-Marqués JM, Zúñiga-Cabrera M, Shaikhin S, Pérez-Martinez G. P40 and P75 Are Singular Functional Muramidases Present in the Lactobacillus casei /paracasei/rhamnosus Taxon. Front Microbiol 2019; 10:1420. [PMID: 31297099 PMCID: PMC6607858 DOI: 10.3389/fmicb.2019.01420] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 06/05/2019] [Indexed: 01/29/2023] Open
Abstract
Lactobacillus casei and Lactobacillus rhamnosus proteins P40 and P75 belong to a large family of secreted cell wall proteins that contain a carboxy(C)-terminal CHAP or NlpC/P60 superfamily domains. In addition to their peptidoglycan hydrolases activity, proteins in this family are specific antigens of pathogens, frequently responsible of interactions with the host. L. rhamnosus GG and L. casei BL23 purified P40 and P75 proteins have antiapoptotic activity by inducing the EGF/Akt pathway. The aim of this work was to study the genetics, phylogeny and dissemination of this family of proteins in the genus Lactobacillus as well as their characteristics and likely function. The scrutiny of their DNA encoding sequences revealed the presence of minisatellite DNA in the P75 encoding gene of L. casei/paracasei strains (cmuB) with intraspecific indels that gave raise to four different alleles (cmuB1-4), which are exclusive of this species. Phylogenic analyses suggest that both proteins are present mainly in the L. casei and Lactobacillus sakei phylogenomic groups. A P40 ancestral gene was possibly present in the common ancestor of Enterococcaceae, Lactobacillaceae and Streptococcaceae. P75 is also present in L. casei and L. sakei groups, but its evolution is difficult to explain only by vertical transmission. Antibodies raised against the N-terminal regions of P40 and P75 improved their immunological detection in culture supernatants as they recognized almost exclusively proteins of L. casei/paracasei/rhamnosus strains, highlighting their structural similarity, that allowed to detect them in different fermented dairy products that contained probiotic L. casei strains. Purified P40 and P75 proteins showed no evident lytic activity but they complemented L. casei BL23 cmuA and cmuB defective mutants, respectively, thus proving that they actively participate in cell division.
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Affiliation(s)
- Christine Bäuerl
- Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos (C.S.I.C.), Valencia, Spain
| | - Gulyaim Abitayeva
- Department of Microbiology, L.N. Gumilyov Eurasian National University, Astana, Kazakhstan.,Laboratory of Genetics and Biochemistry of Microorganisms, Republican Collection of Microorganisms at Science Committee of Ministry of Education and Science RK, Astana, Kazakhstan
| | - Sebastián Sosa-Carrillo
- Computational Biology Department, Inria, Institut Pasteur and Université Paris Diderot, Paris, France
| | | | - Noemí Navarro-Lleó
- Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos (C.S.I.C.), Valencia, Spain
| | - José M Coll-Marqués
- Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos (C.S.I.C.), Valencia, Spain
| | - Manuel Zúñiga-Cabrera
- Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos (C.S.I.C.), Valencia, Spain
| | - Serik Shaikhin
- Department of Microbiology, L.N. Gumilyov Eurasian National University, Astana, Kazakhstan.,Laboratory of Genetics and Biochemistry of Microorganisms, Republican Collection of Microorganisms at Science Committee of Ministry of Education and Science RK, Astana, Kazakhstan
| | - Gaspar Pérez-Martinez
- Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos (C.S.I.C.), Valencia, Spain
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34
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Li T, Liu Z, Zhang X, Chen X, Wang S. Local Probiotic Lactobacillus crispatus and Lactobacillus delbrueckii Exhibit Strong Antifungal Effects Against Vulvovaginal Candidiasis in a Rat Model. Front Microbiol 2019; 10:1033. [PMID: 31139166 PMCID: PMC6519388 DOI: 10.3389/fmicb.2019.01033] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 04/24/2019] [Indexed: 01/08/2023] Open
Abstract
A comprehensive knowledge of the vaginal ecosystem is critical for the development of successful approaches to the treatment of infections. The role of Lactobacilli in preventing vulvovaginal candidiasis (VVC) is controversial. In this study, we investigated the therapeutic effects and mechanism of Lactobacillus crispatus or delbrueckii on vaginitis caused by Candida albicans in a Sprague–Dawley rat model. A microbiological evaluation was performed by Gram staining and fungal colonies were enumerated. The antifungal efficacy of the two Lactobacillus strains was assessed by hematoxylin and eosin (HE) staining, transmission electron microscopy (TEM), immunohistochemical detection of interferon-γ (IFN-γ), interleukin (IL)-4, IL-17, and epithelial-derived IgG (RP125). Our in vitro results showed that the inhibitory activity against Candida colony-forming unit (CFU) counts was demonstrated by the two Lactobacillus strains (P < 0.001). Our results indicated that Lactobacillus administration played an indispensable role in maintaining the immune homeostasis, and decreasing the Th1/Th2 ratio (IFN-γ/IL-4) by regulating the epithelial secretion of cytokines that inhibit epithelial proinflammatory cytokine release, while increasing epithelial-derived IgG expression (P < 0.05), suggesting antibody-mediated protection. Our results implicate L. crispatus and L. delbrueckii as a potential adjunct biotherapeutic agent in women with VVC, especially for those with drug resistance, adverse effects or contraindications when using antifungal agents. Further large, long-term, well-planned clinical studies should be performed in clinical practice to determine their clinical potential of L. crispatus and L. delbrueckii as an adjunct treatment for VVC.
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Affiliation(s)
- Ting Li
- Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Zhaohui Liu
- Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Xu Zhang
- Ultrastructural Pathology Center, Peking University First Hospital, Beijing, China
| | - Xi Chen
- Laboratory of Electron Microscopy, Department of Gynecology, Minimally Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Suxia Wang
- Laboratory of Electron Microscopy, Department of Gynecology, Minimally Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
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Gao J, Li Y, Wan Y, Hu T, Liu L, Yang S, Gong Z, Zeng Q, Wei Y, Yang W, Zeng Z, He X, Huang SH, Cao H. A Novel Postbiotic From Lactobacillus rhamnosus GG With a Beneficial Effect on Intestinal Barrier Function. Front Microbiol 2019; 10:477. [PMID: 30923519 PMCID: PMC6426789 DOI: 10.3389/fmicb.2019.00477] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 02/25/2019] [Indexed: 12/12/2022] Open
Abstract
It has long been known that probiotics can be used to maintain intestinal homeostasis and treat a number of gastrointestinal disorders, but the underlying mechanism has remained obscure. Recently, increasing evidence supports the notion that certain probiotic-derived components, such as bacteriocins, lipoteichoic acids, surface layer protein and secreted protein, have a similar protective role on intestinal barrier function as that of live probiotics. These bioactive components have been named 'postbiotics' in the most recent publications. We previously found that the Lactobacillus rhamnosus GG (LGG) culture supernatant is able to accelerate the maturation of neonatal intestinal defense and prevent neonatal rats from oral Escherichia coli K1 infection. However, the identity of the bioactive constituents has not yet been determined. In this study, using liquid chromatography-tandem mass spectrometry analysis, we identified a novel secreted protein (named HM0539 here) involved in the beneficial effect of LGG culture supernatant. HM0539 was recombinated, purified, and applied for exploring its potential bioactivity in vitro and in vivo. Our results showed that HM0539 exhibits a potent protective effect on the intestinal barrier, as reflected by enhancing intestinal mucin expression and preventing against lipopolysaccharide (LPS)- or tumor necrosis factor α (TNF-α)-induced intestinal barrier injury, including downregulation of intestinal mucin (MUC2), zonula occludens-1 (ZO-1) and disruption of the intestinal integrity. Using a neonatal rat model of E. coli K1 infection via the oral route, we verified that HM0539 is sufficient to promote development of neonatal intestinal defense and prevent against E. coli K1 pathogenesis. Moreover, we further extended the role of HM0539 and found it has potential to prevent dextran sulfate sodium (DSS)-induced colitis as well as LPS/D-galactosamine-induced bacterial translocation and liver injury. In conclusion, we identified a novel LGG postbiotic HM0539 which exerts a protective effect on intestinal barrier function. Our findings indicated that HM0539 has potential to become a useful agent for prevention and treatment of intestinal barrier dysfunction- related diseases.
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Affiliation(s)
- Jie Gao
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Yubin Li
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Yu Wan
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Tongtong Hu
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Liting Liu
- Department of Medical Microbiology and Immunology, Dali University, Dali, China
| | - Shaojie Yang
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Zelong Gong
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Qing Zeng
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Yi Wei
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Weijun Yang
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Zhijie Zeng
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Xiaolong He
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Sheng-He Huang
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.,Saban Research Institute, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, United States
| | - Hong Cao
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
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Abstract
Lactobacillus rhamnosus GG (LGG) was the first strain belonging to the genus Lactobacillus to be patented in 1989 thanks to its ability to survive and to proliferate at gastric acid pH and in medium containing bile, and to adhere to enterocytes. Furthermore LGG is able to produces both a biofilm that can mechanically protect the mucosa, and different soluble factors beneficial to the gut by enhancing intestinal crypt survival, diminishing apoptosis of the intestinal epithelium, and preserving cytoskeletal integrity. Moreover LGG thanks to its lectin-like protein 1 and 2 inhibits some pathogens such as Salmonella species. Finally LGG is able to promote type 1 immune-responsiveness by reducing the expression of several activation and inflammation markers on monocytes and by increasing the production of interleukin-10, interleukin-12 and tumor necrosis factor-α in macrophages. A large number of research data on Lactobacillus GG is the basis for the use of this probiotic for human health. In this review we have considered predominantly randomized controlled trials, meta-analysis, Cochrane Review, guide lines of Scientific Societies and anyway studies whose results were evaluated by means of relative risk, odds ratio, weighted mean difference 95% confidence interval. The effectiveness of LGG in gastrointestinal infections and diarrhea, antibiotic and Clostridium difficile associated diarrhea, irritable bowel syndrome, inflammatory bowel disease, respiratory tract infections, allergy, cardiovascular diseases, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, cystic fibrosis, cancer, elderly end sport were analyzed.
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Underwood MA. Probiotics and the prevention of necrotizing enterocolitis. J Pediatr Surg 2019; 54:405-412. [PMID: 30241961 DOI: 10.1016/j.jpedsurg.2018.08.055] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 07/19/2018] [Accepted: 08/16/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Immaturity of the host immune system and alterations in the intestinal microbiome appear to be key factors in the pathogenesis of necrotizing enterocolitis (NEC). The aim of this paper is to weigh the evidence for the use of probiotics to prevent NEC in premature infants. METHODS Animal studies, randomized controlled trials, observational cohort studies and meta-analyses involving administration of probiotic products for the prevention of NEC were reviewed. This review of the evidence summarizes the available preclinical and clinical data. RESULTS In animal models probiotic microbes alter the intestinal microbiome, decrease inflammation and intestinal permeability and decrease the incidence and severity of experimental NEC. In randomized, placebo-controlled trials and cohort studies of premature infants, probiotic microbes decrease the risk of NEC, death and sepsis. CONCLUSION Evidence is strong for the prevention of NEC with the use of combination probiotics in premature infants who receive breast milk. The potential risks and benefits of probiotic administration to premature infants should be carefully reviewed with parents. TYPE OF STUDY Therapeutic. LEVEL OF EVIDENCE I.
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Affiliation(s)
- Mark A Underwood
- Division of Neonatology, University of California Davis, Ticon 2, Suite 253, 2516 Stockton Blvd, Sacramento, CA 95817, USA.
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Rigo-Adrover MDM, Knipping K, Garssen J, van Limpt K, Knol J, Franch À, Castell M, Rodríguez-Lagunas MJ, Pérez-Cano FJ. Prevention of Rotavirus Diarrhea in Suckling Rats by a Specific Fermented Milk Concentrate with Prebiotic Mixture. Nutrients 2019; 11:nu11010189. [PMID: 30669251 PMCID: PMC6356616 DOI: 10.3390/nu11010189] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/14/2019] [Accepted: 01/14/2019] [Indexed: 01/18/2023] Open
Abstract
Several microbial modulatory concepts, such as certain probiotics and prebiotics, confer protection against gastrointestinal infections, among which is acute diarrhea caused by the rotavirus (RV). Other microbiota modulators, such as postbiotics, produced during fermentation, might also have the potential to counteract RV infection. In light of this, a fermented milk, made by using Bifidobacterium breve C50 (BbC50) and Streptococcus thermophilus 065 (St065) with a prebiotic mixture-short chain galactooligosaccharides/long chain fructooligosaccharides (scGOS/lcFOS 9:1)-with potential to impact the intestinal microbiota composition was tested. An RV infected rat model was used to evaluate the amelioration of the infectious process and the improvement of the immune response induced by the fermented milk with prebiotic mixture. The dietary intervention caused a reduction in the clinical symptoms of diarrhea, such as severity and incidence. Furthermore, a modulation of the immune response was observed, which might enhance the reduction of the associated diarrhea. In addition, the fermented milk with prebiotic mixture was able to bind the virus and reduce its clearance. In conclusion, the postbiotic components in the fermented milk in combination with the prebiotics used here showed protective properties against RV infection.
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Affiliation(s)
- Maria Del Mar Rigo-Adrover
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, University of Barcelona (UB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.
- Institut de Recerca en Nutrició i Seguretat Alimentària (INSA), C/ Prat de la Riba 171, Santa Coloma de Gramanet, 08921 Barcelona, Spain.
| | - Karen Knipping
- Danone Nutricia Research, 3584 Utrecht, The Netherlands.
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3512 Utrecht, The Netherlands.
| | - Johan Garssen
- Danone Nutricia Research, 3584 Utrecht, The Netherlands.
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3512 Utrecht, The Netherlands.
| | - Kees van Limpt
- Danone Nutricia Research, 3584 Utrecht, The Netherlands.
| | - Jan Knol
- Danone Nutricia Research, 3584 Utrecht, The Netherlands.
| | - Àngels Franch
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, University of Barcelona (UB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.
- Institut de Recerca en Nutrició i Seguretat Alimentària (INSA), C/ Prat de la Riba 171, Santa Coloma de Gramanet, 08921 Barcelona, Spain.
| | - Margarida Castell
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, University of Barcelona (UB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.
- Institut de Recerca en Nutrició i Seguretat Alimentària (INSA), C/ Prat de la Riba 171, Santa Coloma de Gramanet, 08921 Barcelona, Spain.
| | - Maria J Rodríguez-Lagunas
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, University of Barcelona (UB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.
- Institut de Recerca en Nutrició i Seguretat Alimentària (INSA), C/ Prat de la Riba 171, Santa Coloma de Gramanet, 08921 Barcelona, Spain.
| | - Francisco J Pérez-Cano
- Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, University of Barcelona (UB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.
- Institut de Recerca en Nutrició i Seguretat Alimentària (INSA), C/ Prat de la Riba 171, Santa Coloma de Gramanet, 08921 Barcelona, Spain.
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Kleerebezem M, Binda S, Bron PA, Gross G, Hill C, van Hylckama Vlieg JE, Lebeer S, Satokari R, Ouwehand AC. Understanding mode of action can drive the translational pipeline towards more reliable health benefits for probiotics. Curr Opin Biotechnol 2018; 56:55-60. [PMID: 30296737 DOI: 10.1016/j.copbio.2018.09.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 08/28/2018] [Accepted: 09/07/2018] [Indexed: 12/18/2022]
Abstract
The different levels of knowledge described in a translational pipeline (the connection of molecular mechanisms with pre-clinical physiological and human health effects) are not complete for many probiotics. At present, we are not in a position to fully understand the mechanistic basis of many well established probiotic health benefits which, in turn, limits our ability to use mechanisms to predict which probiotics are likely to be effective in any given population. Here we suggest that this concept of a translation pipeline connecting mechanistic insights to probiotic efficacy can support the selection and production of improved probiotic products. Such a conceptual pipeline would also provide a framework for the design of clinical trials to convincingly demonstrate the benefit of probiotics to human health in well-defined subpopulations.
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Affiliation(s)
- Michiel Kleerebezem
- Host Microbe Interactomics Group, Wageningen University, Wageningen, The Netherlands.
| | - Sylvie Binda
- Danone Nutricia Research, Centre Daniel Carasso, Palaiseau, France
| | | | - Gabriele Gross
- Innovative Health Sciences, Reckitt Benckiser, Nijmegen, The Netherlands
| | - Colin Hill
- School of Microbiology and APC Microbiome Ireland, University College Cork, Cork, Ireland
| | | | - Sarah Lebeer
- Department of Bioscience Engineering, University of Antwerp, Antwerp, Belgium
| | - Reetta Satokari
- Immunobiology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Arthur C Ouwehand
- Global Health and Nutrition Sciences, DuPont Nutrition and Health, Kantvik, Finland
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40
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Bron PA, Kleerebezem M. Lactic Acid Bacteria for Delivery of Endogenous or Engineered Therapeutic Molecules. Front Microbiol 2018; 9:1821. [PMID: 30123213 PMCID: PMC6085456 DOI: 10.3389/fmicb.2018.01821] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Accepted: 07/20/2018] [Indexed: 12/12/2022] Open
Abstract
Food-grade lactic acid bacteria (LAB) are considered suitable vehicles for the production and/or delivery of health promoting or therapeutic, bioactive molecules. The molecules considered for health-beneficial use include the endogenous effector molecules produced by probiotics (mostly lactobacilli), as well as heterologous bioactives that can be produced in LAB by genetic engineering (mostly using lactococci). Both strategies aim to deliver appropriate dosages of specific bioactive molecules to the site of action. This review uses specific examples of both strategies to illustrate the different avenues of research involved in these applications as well as their translation to human health-promoting applications. These examples pinpoint that despite the promising perspectives of these approaches, the evidence for their effective applications in human populations is lagging behind.
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Affiliation(s)
- Peter A Bron
- NIZO Food Research BV, Ede, Netherlands.,BE-Basic Foundation, Delft, Netherlands
| | - Michiel Kleerebezem
- BE-Basic Foundation, Delft, Netherlands.,Host-Microbe Interactomics Group, Department of Animal Sciences, Wageningen University & Research, Wageningen, Netherlands
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41
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Rangan KJ, Hang HC. Biochemical Mechanisms of Pathogen Restriction by Intestinal Bacteria. Trends Biochem Sci 2017; 42:887-898. [PMID: 28927699 PMCID: PMC6038137 DOI: 10.1016/j.tibs.2017.08.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 08/14/2017] [Accepted: 08/16/2017] [Indexed: 12/15/2022]
Abstract
The intestine is a highly complex ecosystem where many bacterial species interact with each other and host cells to influence animal physiology and susceptibility to pathogens. Genomic methods have provided a broad framework for understanding how alterations in microbial communities are associated with host physiology and infection, but the biochemical mechanisms of specific intestinal bacterial species are only emerging. In this review, we focus on recent studies that have characterized the biochemical mechanisms by which intestinal bacteria interact with other bacteria and host pathways to restrict pathogen infection. Understanding the biochemical mechanisms of intestinal microbiota function should provide new opportunities for therapeutic development towards a variety of infectious diseases.
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Affiliation(s)
- Kavita J Rangan
- Laboratory of Chemical Biology and Microbial Pathogenesis, New York, NY 10065, USA
| | - Howard C Hang
- Laboratory of Chemical Biology and Microbial Pathogenesis, New York, NY 10065, USA.
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42
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Celiberto LS, Bedani R, Dejani NN, Ivo de Medeiros A, Sampaio Zuanon JA, Spolidorio LC, Tallarico Adorno MA, Amâncio Varesche MB, Carrilho Galvão F, Valentini SR, Font de Valdez G, Rossi EA, Cavallini DCU. Effect of a probiotic beverage consumption (Enterococcus faecium CRL 183 and Bifidobacterium longum ATCC 15707) in rats with chemically induced colitis. PLoS One 2017; 12:e0175935. [PMID: 28437455 PMCID: PMC5402984 DOI: 10.1371/journal.pone.0175935] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 04/03/2017] [Indexed: 12/11/2022] Open
Abstract
Background Some probiotic strains have the potential to assist in relieving the symptoms of inflammatory bowel disease. The impact of daily ingestion of a soy-based product fermented by Enterococcus faecium CRL 183 and Lactobacillus helveticus 416 with the addition of Bifidobacterium longum ATCC 15707 on chemically induced colitis has been investigated thereof within a period of 30 days. Methods Colitis was induced by dextran sulfate sodium. The animals were randomly assigned into five groups: Group C: negative control; Group CL: positive control; Group CLF: DSS with the fermented product; Group CLP: DSS with the non-fermented product (placebo); Group CLS: DSS with sulfasalazine. The following parameters were monitored: disease activity index, fecal microbial analyses, gastrointestinal survival of probiotic microorganisms and short-chain fatty acids concentration in the feces. At the end of the protocol the animals’ colons were removed so as to conduct a macroscopical and histopathological analysis, cytokines and nitrite quantification. Results Animals belonging to the CLF group showed fewer symptoms of colitis during the induction period and a lower degree of inflammation and ulceration in their colon compared to the CL, CLS and CLP groups (p<0.05). The colon of the animals in groups CL and CLS presented severe crypt damage, which was absent in CLF and CLP groups. A significant increase in the population of Lactobacillus spp. and Bifidobacterium spp. at the end of the protocol was verified only in the CLF animals (p<0.05). This group also showed an increase in short-chain fatty acids (propionate and acetate). Furthermore, the intestinal survival of E. faecium CRL 183 and B. longum ATCC 15707 in the CLF group has been confirmed by biochemical and molecular analyzes. Conclusions The obtained results suggest that a regular intake of the probiotic product, and placebo to a lesser extent, can reduce the severity of DSS-induced colitis on rats.
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Affiliation(s)
- Larissa Sbaglia Celiberto
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Alimentos e Nutrição, SP, Brasil
| | - Raquel Bedani
- Departamento de Tecnologia Bioquímico-Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Naiara Naiana Dejani
- Universidade de São Paulo (USP), Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto. Departamento de Bioquimica e Imunologia, SP, Brasil
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | - Alexandra Ivo de Medeiros
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | - José Antonio Sampaio Zuanon
- Universidade Estadual Paulista (UNESP), Faculdade de Odontologia, Araraquara. Departametno de Fisiologia e Patologia, SP, Brasil
| | - Luis Carlos Spolidorio
- Universidade Estadual Paulista (UNESP), Faculdade de Odontologia, Araraquara. Departametno de Fisiologia e Patologia, SP, Brasil
| | - Maria Angela Tallarico Adorno
- Universidade de São Paulo (USP), Faculdade de Engenharia, São Carlos. Departamento de Hidraúlica e Saneamento, SP, Brasil
| | | | - Fábio Carrilho Galvão
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | - Sandro Roberto Valentini
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Ciências Biológicas, SP, Brasil
| | | | - Elizeu Antonio Rossi
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Alimentos e Nutrição, SP, Brasil
| | - Daniela Cardoso Umbelino Cavallini
- Universidade Estadual Paulista (UNESP), Faculdade de Ciências Farmacêuticas, Araraquara. Departamento de Alimentos e Nutrição, SP, Brasil
- * E-mail:
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43
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Secretions of Bifidobacterium infantis and Lactobacillus acidophilus Protect Intestinal Epithelial Barrier Function. J Pediatr Gastroenterol Nutr 2017; 64:404-412. [PMID: 28230606 DOI: 10.1097/mpg.0000000000001310] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The secreted metabolites of probiotics are cytoprotective to intestinal epithelium and have been shown to attenuate inflammation and reduce gut permeability. The present study was designed to determine the protective effects of probiotic conditioned media (PCM) from Bifidobacterium infantis (BCM) and Lactobacillus acidophilus (LCM) on interleukin (IL)-1β-induced intestinal barrier compromise. METHODS The epithelial barrier was determined by measuring the transepithelial electrical resistance (TER) across a Caco-2 cell monolayer using a Transwell model. The paracellular permeability was determined by fluorescein isothiocyanate-labeled dextran flux. The expression of tight junction (TJ) proteins and nuclear factor-kappa B (NF-κB) p65 were determined using Western blot and the distribution of NF-κB p65 was determined by immunofluorescence staining. RESULTS BCM and LCM induced a dose-dependent increase in Caco-2 TER after 4 and 24 hours of incubation (P < 0.05). The maximal increase of Caco-2 TER occurred at 4 hours of treatment with a PCM concentration of 15%. Preincubation with BCM and LCM for 4 hours significantly prevented the decrease of Caco-2 TER induced by 24 hours of stimulation with 10 ng/mL IL-1β. BCM and LCM decreased paracellular permeability in both stimulated and unstimulated Caco-2 monolayers (P < 0.05). IL-1β stimulation decreased occludin expression and increased claudin-1 expression in Caco-2 cells (P < 0.05), which was prevented in cells treated with BCM or LCM. The changes of claudin-1 expression in H4 cells were similar to Caco-2 cells in response to PCM treatment and IL-1β stimulation; however, a similar response in occludin was not demonstrated. The IL-1β-induced nuclear translocation of NF-κB p65 in Caco-2 cells was prevented by pretreatment with both PCMs. CONCLUSIONS BCM and LCM protected the intestinal barrier against IL-1β stimulation by normalizing the protein expression of occludin and claudin-1 and preventing IL-1β-induced NF-κB activation in Caco-2 cells, which may be partly responsible for the preservation of intestinal permeability.
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Abstract
A large number of randomized placebo-controlled clinical trials and cohort studies have demonstrated a decrease in the incidence of necrotizing enterocolitis with administration of probiotic microbes. These studies have prompted many neonatologists to adopt routine prophylactic administration of probiotics while others await more definitive studies and/or probiotic products with demonstrated purity and stable numbers of live organisms. Cross-contamination and inadequate sample size limit the value of further traditional placebo-controlled randomized controlled trials. Key areas for future research include mechanisms of protection, optimum probiotic species or strains (or combinations thereof) and duration of treatment, interactions between diet and the administered probiotic, and the influence of genetic polymorphisms in the mother and infant on probiotic response. Next generation probiotics selected based on bacterial genetics rather than ease of production and large cluster-randomized clinical trials hold great promise for NEC prevention.
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Affiliation(s)
- Mark A Underwood
- Division of Neonatology, UC Davis School of Medicine, Ticon 2, 2516 Stockton Blvd, Sacramento, CA 95817.
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45
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Ettinger G, Burton JP, Gloor GB, Reid G. Lactobacillus rhamnosus GR-1 Attenuates Induction of Hypertrophy in Cardiomyocytes but Not through Secreted Protein MSP-1 (p75). PLoS One 2017; 12:e0168622. [PMID: 28085895 PMCID: PMC5234775 DOI: 10.1371/journal.pone.0168622] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 12/02/2016] [Indexed: 12/14/2022] Open
Abstract
Previous animal studies have shown that the administration of probiotic Lactobacillus rhamnosus can provide a protective effect against ischemia/reperfusion and necrotic injury to the intestine, liver, and heart, as well as a therapeutic effect to the outcome of ischemic injury to the heart, including cardiac hypertrophy and heart failure. We hypothesized that L. rhamnosus GR-1 major secreted protein 1 (MSP-1), also known as p75, plays a major role in this phenomenon. Experiments using neonatal rat ventricular cardiomyocytes showed that live and dead GR-1 bacteria, probiotic-conditioned media, and other probiotic species and strains inhibited the α1-adrenergic receptor agonist phenylephrine-induced hypertrophy as assessed by markers atrial natriuretic peptide and α-skeletal actin. However, using a mutant strain, we showed that this MSP-1 was not required for the inhibition. The ability of factors produced by lactobacilli to improve cardiac function warrants further study for the management of cardiac hypertrophy and heart failure.
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Affiliation(s)
- Grace Ettinger
- Lawson Health Research Institute, London, Ontario, Canada
- Department of Microbiology and Immunology, University of Western Ontario, London, Canada
| | - Jeremy P. Burton
- Lawson Health Research Institute, London, Ontario, Canada
- Department of Microbiology and Immunology, University of Western Ontario, London, Canada
- Department of Surgery (Urology), University of Western Ontario, London, Canada
| | - Gregory B. Gloor
- Lawson Health Research Institute, London, Ontario, Canada
- Department of Biochemistry, University of Western Ontario, London, Canada
| | - Gregor Reid
- Lawson Health Research Institute, London, Ontario, Canada
- Department of Microbiology and Immunology, University of Western Ontario, London, Canada
- Department of Surgery (Urology), University of Western Ontario, London, Canada
- * E-mail:
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Johansson MA, Björkander S, Mata Forsberg M, Qazi KR, Salvany Celades M, Bittmann J, Eberl M, Sverremark-Ekström E. Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells. Front Immunol 2016; 7:273. [PMID: 27462316 PMCID: PMC4939411 DOI: 10.3389/fimmu.2016.00273] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 06/29/2016] [Indexed: 12/17/2022] Open
Abstract
Lactobacilli are probiotic commensal bacteria and potent modulators of immunity. When present in the gut or supplemented as probiotics, they beneficially modulate ex vivo immune responsiveness. Further, factors derived from several lactobacilli strains act immune regulatory in vitro. In contrast, Staphylococcus aureus (S. aureus) is known to induce excessive T cell activation. In this study, we aimed to investigate S. aureus-induced activation of human mucosal-associated invariant T cells (MAIT cells), γδ T cells, NK cells, as well as of conventional CD4+ and CD8+ T cells in vitro. Further, we investigated if lactobacilli-derived factors could modulate their activation. PBMC were cultured with S. aureus 161:2 cell-free supernatants (CFS), staphylococcal enterotoxin A or CD3/CD28-beads alone, or in combination with Lactobacillus rhamnosus GG-CFS or Lactobacillus reuteri DSM 17938-CFS and activation of T and NK cells was evaluated. S. aureus-CFS induced IFN-γ and CD107a expression as well as proliferation. Costimulation with lactobacilli-CFS dampened lymphocyte-activation in all cell types analyzed. Preincubation with lactobacilli-CFS was enough to reduce subsequent activation, and the absence of APC or APC-derived IL-10 did not prevent lactobacilli-mediated dampening. Finally, lactate selectively dampened activation of unconventional T cells and NK cells. In summary, we show that molecules present in the lactobacilli-CFS are able to directly dampen in vitro activation of conventional and unconventional T cells and of NK cells. This study provides novel insights on the immune-modulatory nature of probiotic lactobacilli and suggests a role for lactobacilli in the modulation of induced T and NK cell activation.
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Affiliation(s)
- Maria A Johansson
- Arrhenius Laboratories for Natural Sciences, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , Stockholm , Sweden
| | - Sophia Björkander
- Arrhenius Laboratories for Natural Sciences, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , Stockholm , Sweden
| | - Manuel Mata Forsberg
- Arrhenius Laboratories for Natural Sciences, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , Stockholm , Sweden
| | - Khaleda Rahman Qazi
- Arrhenius Laboratories for Natural Sciences, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , Stockholm , Sweden
| | - Maria Salvany Celades
- Arrhenius Laboratories for Natural Sciences, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , Stockholm , Sweden
| | - Julia Bittmann
- Arrhenius Laboratories for Natural Sciences, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , Stockholm , Sweden
| | - Matthias Eberl
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK; Systems Immunity Research Institute, Cardiff University, Cardiff, UK
| | - Eva Sverremark-Ekström
- Arrhenius Laboratories for Natural Sciences, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , Stockholm , Sweden
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47
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Seenappanahalli Nanjundaiah Y, Wright DA, Baydoun AR, O'Hare WT, Ali Z, Khaled Z, Sarker MH. Lactobacillus rhamnosus GG conditioned media modulates acute reactive oxygen species and nitric oxide in J774 murine macrophages. Biochem Biophys Rep 2016; 6:68-75. [PMID: 28955864 PMCID: PMC5600347 DOI: 10.1016/j.bbrep.2016.03.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 03/01/2016] [Accepted: 03/03/2016] [Indexed: 12/22/2022] Open
Abstract
Phagocytes such as macrophages are capable of detecting and killing pathogenic bacteria by producing reactive oxygen and nitrogen species. Formation of free radicals in macrophages may be regulated by probiotics or by factors released by probiotics but yet to be identified. Thus, studies were carried out to determine whether cell-free conditioned medium obtained from cultures of Lactobacillus rhamnosus GG (LGG-CM) regulate production of reactive oxygen species (ROS) and/or nitric oxide (NO) in macrophages. J774 macrophages in culture were loaded with either H2DCFDA for monitoring ROS or with DAFFM-DA for NO detection. Free radical production was measured on a fluorescence microplate reader and changes were analysed by Cumulative sum (CuSum) calculations. Low concentration of LGG-CM (10% LGG-CM) or LPS did not cause any significant change in basal levels of ROS or NO production. In contrast, high concentration of LGG-CM (75% and 100%) significantly enhanced ROS generation but also significantly reduced NO level. These findings are novel and suggest for the first time that probiotics may release factors in culture which enhance ROS production and may additionally reduce deleterious effects associated with excessive nitrogen species by suppressing NO level. These events may account, in part, for the beneficial bactericidal and anti-inflammatory actions ascribed to probiotics and may be of clinical relevance.
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Affiliation(s)
| | - David A Wright
- School of Science and Engineering, Teesside University, TS1 3BA, UK
| | - Anwar R Baydoun
- School of Life and Medical Sciences, University of Hertfordshire, AL 10 9AB, UK
| | - William T O'Hare
- School of Science and Engineering, Teesside University, TS1 3BA, UK
| | - Zulfiqur Ali
- School of Science and Engineering, Teesside University, TS1 3BA, UK
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48
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Vongbhavit K, Underwood MA. Prevention of Necrotizing Enterocolitis Through Manipulation of the Intestinal Microbiota of the Premature Infant. Clin Ther 2016; 38:716-32. [PMID: 26872618 DOI: 10.1016/j.clinthera.2016.01.006] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 12/30/2015] [Indexed: 12/17/2022]
Abstract
PURPOSE In spite of four decades of research, necrotizing enterocolitis (NEC) remains the most common gastrointestinal complication in premature infants with high mortality and long-term morbidity. The composition of the intestinal microbiota of the premature infant differs dramatically from that of the healthy term infant and appears to be an important risk factor for NEC. METHODS We review the evidence of an association between intestinal dysbiosis and NEC and summarize published English language clinical trials and cohort studies involving attempts to manipulate the intestinal microbiota in premature infants. FINDINGS Promising NEC prevention strategies that alter the intestinal microbiota include probiotics, prebiotics, synbiotics, lacteroferrin, and human milk feeding. IMPLICATIONS Shaping the intestinal microbiota of the premature infant through human milk feeding and dietary supplements decreases the risk of NEC. Further studies to identify the ideal microbial composition and the most effective combination of supplements are indicated.
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Affiliation(s)
- Kannikar Vongbhavit
- Department of Pediatrics, HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, Nakornayok, Thailand; Department of Pediatrics, University of California Davis, Sacramento, California
| | - Mark A Underwood
- Department of Pediatrics, University of California Davis, Sacramento, California.
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49
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Abstract
Despite extensive research, alcohol remains one of the most common causes of liver disease in the United States. Alcoholic liver disease (ALD) encompasses a broad spectrum of disorders, including steatosis, steatohepatitis, and cirrhosis. Although many agents and approaches have been tested in patients with ALD and in animals with experimental ALD in the past, there is still no FDA (Food and Drug Administration) approved therapy for any stage of ALD. With the increasing recognition of the importance of gut microbiota in the onset and development of a variety of diseases, the potential use of probiotics in ALD is receiving increasing investigative and clinical attention. In this review, we summarize recent studies on probiotic intervention in the prevention and treatment of ALD in experimental animal models and patients. Potential mechanisms underlying the probiotic function are also discussed.
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50
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Cicenia A, Santangelo F, Gambardella L, Pallotta L, Iebba V, Scirocco A, Marignani M, Tellan G, Carabotti M, Corazziari ES, Schippa S, Severi C. Protective Role of Postbiotic Mediators Secreted by Lactobacillus rhamnosus GG Versus Lipopolysaccharide-induced Damage in Human Colonic Smooth Muscle Cells. J Clin Gastroenterol 2016; 50 Suppl 2, Proceedings from the 8th Probiotics, Prebiotics & New Foods for Microbiota and Human Health meeting held in Rome, Italy on September 13-15, 2015:S140-S144. [PMID: 27741159 DOI: 10.1097/mcg.0000000000000681] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Some beneficial effects of probiotics may be due to secreted probiotic-derived factors, identified as "postbiotic" mediators. The aim of this study was to evaluate whether supernatants harvested from Lactobacillus rhamnosus GG (LGG) cultures (ATCC53103 strain) protect colonic human smooth muscle cells (HSMCs) from lipopolysaccharide (LPS)-induced myogenic damage. MATERIALS AND METHODS LGG was grown in de Man, Rogosa, Share medium at 37°C and samples were collected in middle and late exponential, stationary, and overnight phases. Supernatants were recovered by centrifugation, filtered, and stored at -20°C. The primary HSMCs culture was exposed for 24 hours to purified LPS of a pathogen strain of Escherichia coli (O111:B4) (1 μg/mL) with and without supernatants. Postbiotic effects were evaluated on the basis of HSMCs morphofunctional alterations and interleukin-6 (IL-6) production. Data are expressed as mean±SE (P<0.05 significant). RESULTS LPS induced persistent, significant, 20.5%±0.7% cell shortening and 34.5%±2.2% decrease in acetylcholine-induced contraction of human HSMCs. These morphofunctional alterations were paralleled to a 365.65%±203.13% increase in IL-6 production. All these effects were dose-dependently reduced by LGG supernatants. Supernatants of the middle exponential phase already partially restored LPS-induced cell shortening by 57.34%±12.7% and IL-6 increase by 145.8%±4.3% but had no effect on LPS-induced inhibition of contraction. Maximal protective effects were obtained with supernatants of the late stationary phase with LPS-induced cell shortening restored by 84.1%±4.7%, inhibition of contraction by 85.5%±6.4%, and IL-6 basal production by 92.7%±1.2%. CONCLUSIONS LGG-derived products are able to protect human SMCs from LPS-induced myogenic damage. Novel insights have been provided for the possibility that LGG-derived products could reduce the risk of progression to postinfective motor disorders.
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Affiliation(s)
- Alessia Cicenia
- Departments of *Internal Medicine and Medical Specialties †Public Health and Infectious Diseases ∥Cardiovascular, Respiratory, Nephrologic, Anesthetic and Geriatric Sciences, University Sapienza ‡Department of Therapeutic Research and Medicine Evaluation, Italian National Institute of Health §Department of Digestive and Liver Disease, S.Andrea Hospital, S. Andrea, Rome, Italy
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