3fe788ae1643080f4dd0821cb2eaa077 ijms-26-04507.pdf 73ebe16a8da0282f4fa57067a73a6f9b00ea0ef8 ijms-26-04507.pdf 5dae713dfd74e2d938cb3248319ced7947335b95101c9893604602d4d321cbd5 ijms-26-04507.pdf Title: Peroxisome Proliferator-Activated Receptors (PPARs) May Mediate the Neuroactive Effects of Probiotic Metabolites: An In Silico Approach Subject: It is well established that the gut-brain axis (GBA) is a bidirectional communication between the gut and the brain. This axis, critical in maintaining overall homeostasis, is regulated at the neuronal, endocrine, and immunological levels, all of which may be influenced by the gut microbiota (GM). Therefore, dysbiosis or disruption in the GM may have serious consequences including neuroinflammation due to overactivation of the immune system. Strategies to reestablish GM integrity via use of probiotics are being pursued as novel therapeutic intervention in a variety of central and peripheral diseases. The mechanisms leading to dysbiosis or efficacy of probiotics, however, are not fully evident. Here, we performed computational analysis on two major probiotics, namely Lactobacillus Lacticaseibacillus rhamnosus GG (formerly named Lactobacillus rhamnosus, L. rhamnosus GG) and Bifidobacterium animalis spp. lactis (B. lactis or B. animalis) to not only shed some light on their mechanism(s) of action but also to identify potential molecular targets for novel probiotics. Using the PubMed web page and BioCyc Database Collection platform we specifically analyzed proteins affected by metabolites of these bacteria. Our results indicate that peroxisome proliferator-activated receptors (PPARs), nuclear receptor proteins that are involved in regulation of inflammation are key mediators of the neuroactive effect of probiotics. Keywords: probiotics; metabolites; neuroprotection; neuroinflammation; gut-brain axis; gut microbiota; PPARs Author: Irving Parra, Alan Carrasco-Carballo, Victoria Palafox-Sanchez, Isabel Martínez-García, José Aguilera, José L. Góngora-Alfaro, Irma Isela Aranda-González, Yousef Tizabi and Liliana Mendieta Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Fri May 9 04:46:20 2025 CEST ModDate: Fri May 9 05:21:06 2025 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 33 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4371862 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- IWZTOL+VnURWPalladioL Type 1 Custom yes yes yes 10 0 LWQSMK+URWPalladioL-Roma Type 1 Custom yes yes yes 16 0 GGAUOC+URWPalladioL-Bold Type 1 Custom yes yes yes 22 0 SGUEWX+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 OYLTVA+CMSY10 Type 1 Builtin yes yes yes 68 0 DORTIW+EURM10 Type 1 Builtin yes yes yes 82 0 CHECII+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 133 0 CHECJJ+PalatinoLinotype-Roman 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1.12.4 (2023-03-16) LastModified: 2025-06-10 14:17:23 CEST Size: 4371862 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 709 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Structural Similarity Analysis Destination: subsection.2.1 Item: Title: Molecular Targets Selection Destination: subsection.2.2 Children: Item: Title: Reactome Destination: subsubsection.2.2.1 Item: Title: Interactome Destination: subsubsection.2.2.2 Item: Title: Enrichment, Strength and Validation Analysis of Protein Interactions Destination: subsubsection.2.2.3 Item: Title: Molecular Docking Studies Destination: subsection.2.3 Children: Item: Title: Choice of Ligands Destination: subsubsection.2.3.1 Item: Title: Molecular Interaction and Multiple Sequence Alignment Destination: subsubsection.2.3.2 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Database, Webpage and Software Destination: subsection.4.1 Item: Title: Data Collection Destination: subsection.4.2 Children: Item: Title: Theoretical Metabolites Collection Destination: subsubsection.4.2.1 Item: Title: Reported Metabolites Collection Destination: subsubsection.4.2.2 Item: Title: Natural Metabolites and Reference Drugs of Target Chosen Collection Destination: subsubsection.4.2.3 Item: Title: Target Key Molecules Destination: subsection.4.3 Children: Item: Title: Choice of Ligands Destination: subsubsection.4.3.1 Item: Title: Choice of Target Proteins Destination: subsubsection.4.3.2 Item: Title: Frequency Discrimination Destination: subsubsection.4.3.3 Item: Title: Enrichment Analysis Discrimination Destination: subsubsection.4.3.4 Item: Title: Docking Analysis Destination: subsection.4.4 Children: Item: Title: Metabolites, Ligand, and Protein Preparation Destination: subsubsection.4.4.1 Item: Title: Ligand Structure Obtention Destination: subsubsection.4.4.2 Item: Title: Protein Structure Obtention Destination: subsubsection.4.4.3 Item: Title: Statistical Analysis, Validation and Exclusion Criteria Destination: subsection.4.5 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: appendix.A. Info: Title: Peroxisome Proliferator-Activated Receptors (PPARs) May Mediate the Neuroactive Effects of Probiotic Metabolites: An In Silico Approach Author: Irving Parra, Alan Carrasco-Carballo, Victoria Palafox-Sanchez, Isabel Martínez-García, José Aguilera, José L. Góngora-Alfaro, Irma Isela Aranda-González, Yousef Tizabi and Liliana Mendieta Subject: ぉぴ〠どび〠ぷづぬぬ〠づびぴちぢぬどびとづつ〠ぴとちぴ〠ぴとづ〠でふぴ〭ぢひちどの〠ちへどび〠〨ぇあぁ〩〠どび〠ち〠ぢどつどひづっぴどはのちぬ〠っはねねふのどっちぴどはの〠ぢづぴぷづづの〠ぴとづ〠でふぴ〠ちのつ〠ぴとづ〠ぢひちどの〮〠ごとどび〠ちへどび〬〠っひどぴどっちぬ〠どの〠ねちどのぴちどのどので〠はぶづひちぬぬ〠とはねづはびぴちびどび〬〠どび〠ひづでふぬちぴづつ〠ちぴ〠ぴとづ〠のづふひはのちぬ〬〠づのつはっひどのづ〬〠ちのつ〠どねねふのはぬはでどっちぬ〠ぬづぶづぬび〬〠ちぬぬ〠はて〠ぷとどっと〠ねちべ〠ぢづ〠どのてぬふづのっづつ〠ぢべ〠ぴとづ〠でふぴ〠ねどっひはぢどはぴち〠〨ぇき〩〮〠ごとづひづてはひづ〬〠つべびぢどはびどび〠はひ〠つどびひふばぴどはの〠どの〠ぴとづ〠ぇき〠ねちべ〠とちぶづ〠びづひどはふび〠っはのびづぱふづのっづび〠どのっぬふつどので〠のづふひはどのてぬちねねちぴどはの〠つふづ〠ぴは〠はぶづひちっぴどぶちぴどはの〠はて〠ぴとづ〠どねねふのづ〠びべびぴづね〮〠こぴひちぴづでどづび〠ぴは〠ひづづびぴちぢぬどびと〠ぇき〠どのぴづでひどぴべ〠ぶどち〠ふびづ〠はて〠ばひはぢどはぴどっび〠ちひづ〠ぢづどので〠ばふひびふづつ〠ちび〠のはぶづぬ〠ぴとづひちばづふぴどっ〠どのぴづひぶづのぴどはの〠どの〠ち〠ぶちひどづぴべ〠はて〠っづのぴひちぬ〠ちのつ〠ばづひどばとづひちぬ〠つどびづちびづび〮〠ごとづ〠ねづっとちのどびねび〠ぬづちつどので〠ぴは〠つべびぢどはびどび〠はひ〠づててどっちっべ〠はて〠ばひはぢどはぴどっび〬〠とはぷづぶづひ〬〠ちひづ〠のはぴ〠てふぬぬべ〠づぶどつづのぴ〮〠えづひづ〬〠ぷづ〠ばづひてはひねづつ〠っはねばふぴちぴどはのちぬ〠ちのちぬべびどび〠はの〠ぴぷは〠ねちなはひ〠ばひはぢどはぴどっび〬〠のちねづぬべ〠がちっぴはぢちっどぬぬふび〠がちっぴどっちびづどぢちっどぬぬふび〠ひとちねのはびふび〠ぇぇ〠〨てはひねづひぬべ〠のちねづつ〠がちっぴはぢちっどぬぬふび〠ひとちねのはびふび〬〠が〮〠ひとちねのはびふび〠ぇぇ〩〠ちのつ〠あどてどつはぢちっぴづひどふね゠ちのどねちぬどび〠びばば〮〠ぬちっぴどび〠〨あ〮〠ぬちっぴどび〠はひ〠あ〮〠ちのどねちぬどび〩〠ぴは〠のはぴ〠はのぬべ〠びとづつ〠びはねづ〠ぬどでとぴ〠はの〠ぴとづどひ〠ねづっとちのどびね〨び〩〠はて〠ちっぴどはの〠ぢふぴ〠ちぬびは〠ぴは〠どつづのぴどてべ〠ばはぴづのぴどちぬ〠ねはぬづっふぬちひ〠ぴちひでづぴび〠てはひ〠のはぶづぬ〠ばひはぢどはぴどっび〮〠さびどので〠ぴとづ〠ぐふぢきづつ〠ぷづぢ〠ばちでづ〠ちのつ〠あどはぃべっ〠いちぴちぢちびづ〠ぃはぬぬづっぴどはの〠ばぬちぴてはひね〠ぷづ〠びばづっどてどっちぬぬべ〠ちのちぬべぺづつ〠ばひはぴづどのび〠ちててづっぴづつ〠ぢべ〠ねづぴちぢはぬどぴづび〠はて〠ぴとづびづ〠ぢちっぴづひどち〮〠くふひ〠ひづびふぬぴび〠どのつどっちぴづ〠ぴとちぴ〠ばづひはへどびはねづ〠ばひはぬどてづひちぴはひ〭ちっぴどぶちぴづつ〠ひづっづばぴはひび〠〨ぐぐぁげび〩〬〠のふっぬづちひ〠ひづっづばぴはひ〠ばひはぴづどのび〠ぴとちぴ〠ちひづ〠どのぶはぬぶづつ〠どの〠ひづでふぬちぴどはの〠はて〠どのてぬちねねちぴどはの〠ちひづ〠にづべ〠ねづつどちぴはひび〠はて〠ぴとづ〠のづふひはちっぴどぶづ〠づててづっぴ〠はて〠ばひはぢどはぴどっび〮 Keywords: probiotics; metabolites; neuroprotection; neuroinflammation; gut-brain axis; gut microbiota; PPARs Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Fri May 09 04:46:20 CEST 2025 ModDate: Fri May 09 05:21:06 CEST 2025 ID: 0x39e250b29efaa090c7b28217c534ea20, 0x39e250b29efaa090c7b28217c534ea20 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: LWQSMK+URWPalladioL-Roma FontSubset: true FirstChar: 1 LastChar: 252 FontDescriptor: FontName: LWQSMK+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: DORTIW+EURM10 FontSubset: true FirstChar: 11 LastChar: 14 FontDescriptor: FontName: DORTIW+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true ToUnicode: true Font: BaseFont: OYLTVA+CMSY10 FontSubset: true FirstChar: 0 LastChar: 48 FontDescriptor: FontName: OYLTVA+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true 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