Microbiota fasting-related changes ameliorate cognitive decline in obesity and boost ex vivo microglial function through the gut-brain axis
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Study information
-
Quality control
- Retracted paper
- Contamination issues suspected
- Batch effect issues suspected
- Uncontrolled confounding suspected
- Results are suspect (various reasons)
- Tags applied
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI Uniform resource identifier for web resources.
Authors
Mela V., Heras V., Iesmantaite M., García-Martín M.L., Bernal M., Posligua-García J.D., Subiri-Verdugo A., Martínez-Montoro J.I., Gómez-Pérez A.M., Bandera B., Moreno-Indias I., Tinahones F.J.
Journal
Gut
Year
2025
Keywords:
diet, metabolomics, microbiome, neurobiology, obesity
BACKGROUND: Obesity-related cognitive decline is linked to gut microbiota dysbiosis, with emerging evidence suggesting that dietary interventions may ameliorate cognitive impairment via gut-brain axis modulation. The role of microglial cells in this process remains underexplored. OBJECTIVE: To investigate how diet-induced changes in gut microbiota influence cognitive function in individuals with obesity and their microglial activity, and to determine the impact of specific dietary interventions. DESIGN: This study included 96 participants with obesity who were randomised into three dietary intervention groups: Mediterranean diet (Med), alternate-day fasting (ADF) and ketogenic diet (Keto). Cognitive performance and microbiota composition were assessed pre-intervention and post-intervention. The effects of microbiota-related changes on microglial function were further evaluated in mice models through faecal transplantation and in vitro model with microbiota exosome treatment. RESULTS: Both the Keto and ADF groups demonstrated significant weight loss, but cognitive performance improved most notably in the ADF group, in association with reduced inflammation. Diet-related microbiota composition was correlated with the cognitive outcomes in the human study. Mice models confirmed that the cognitive benefits of ADF were microbiota-dependent and linked to enhanced microglial phagocytic capacity and reduced inflammation, accompanied by changes in microglia morphology. CONCLUSION: Fasting-induced modifications in gut microbiota contribute to cognitive improvement in individuals with obesity, with microglial cells playing a crucial mediatory role. Among the interventions, ADF most effectively enhanced microglial function and cognitive performance, suggesting its potential as a therapeutic strategy for obesity-related cognitive decline. Further studies are required to fully elucidate the underlying mechanisms. TRIAL REGISTRATION NUMBER: NCT04453150.
Experiment 1
Needs review
Subjects
- Location of subjects
- Spain
- Host species Species from which microbiome was sampled. Contact us to have more species added.
- Homo sapiens
- Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
- Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces
- Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
- Response to diet Response to diet,response to diet
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Obese individuals before Mediterranean diet intervention (Basal)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Obese individuals after 90 days of taking the Mediterranean diet (Final)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- The individuals took the Mediterranean diet (low ketone bodies increase from the diet) for a time span of 3 months. They were followed up every month to undertake Neuropsychological and psychometric tests.
- Group 0 sample size Number of subjects in the control (unexposed) group
- 32
- Group 1 sample size Number of subjects in the case (exposed) group
- 26
Lab analysis
- Sequencing type
- 16S
- 16S variable region One or more hypervariable region(s) of the bacterial 16S gene
- Not specified
- Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
- Ion Torrent
Statistical Analysis
- Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
- log transformation
- Statistical test
- ANCOM-BC
- Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
- 0.05
- MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
- No
Alpha Diversity
- Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample
- unchanged
Signature 1
Needs review
Source: Figure 2H
Description: Significantly enriched bacterial genera in individuals with Mediterranean diet
Abundance in Group 1: increased abundance in Obese individuals after 90 days of taking the Mediterranean diet (Final)
| NCBI | Quality Control | Links |
|---|---|---|
| Akkermansia | ||
| Pseudoflavonifractor | ||
| Eubacterium_ruminantiumEubacterium_ruminantium |
Revision editor(s): Saima-Younis
Experiment 2
Needs review
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Obese individuals before Ketogenic diet intervention (Basal)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Obese individuals after 90 days of taking the Ketogenic diet (Final)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- The individuals took the Ketogenic diet (high ketone bodies increase from the diet) for a time span of 3 months. They were followed up every month to undertake Neuropsychological and psychometric tests.
- Group 1 sample size Number of subjects in the case (exposed) group
- 28
Lab analysis
Statistical Analysis
Alpha Diversity
- Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample
- unchanged
Signature 1
Needs review
Source: Figure 2H
Description: Microbial genera which are enriched in obese individuals with Ketogenic diet
Abundance in Group 1: increased abundance in Obese individuals after 90 days of taking the Ketogenic diet (Final)
| NCBI | Quality Control | Links |
|---|---|---|
| Actinomyces | ||
| Aeromonas |
Revision editor(s): Saima-Younis
Signature 2
Needs review
Source: Figure 2H
Description: Microbial generas and species which are depleted in obese individuals with Ketogenic diet
Abundance in Group 1: decreased abundance in Obese individuals after 90 days of taking the Ketogenic diet (Final)
| NCBI | Quality Control | Links |
|---|---|---|
| Klebsiella | ||
| Muribaculaceae | ||
| Paraclostridium | ||
| Incertae_SedisIncertae_Sedis |
Revision editor(s): Saima-Younis
Experiment 3
Needs review
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Obese individuals before ADF diet intervention (Basal)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Obese individuals after 90 days of taking the ADF diet (Final)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- The individuals took the ADF diet (low ketone bodies increase from the diet) for a time span of 3 months. They were followed up every month to undertake Neuropsychological and psychometric tests.
- Group 1 sample size Number of subjects in the case (exposed) group
- 30
Lab analysis
Statistical Analysis
Alpha Diversity
- Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample
- unchanged
Signature 1
Needs review
Source: Figure 2H
Description: Microbial genera enriched in obese individuals with ADT diet
Abundance in Group 1: increased abundance in Obese individuals after 90 days of taking the ADF diet (Final)
| NCBI | Quality Control | Links |
|---|---|---|
| Leuconostoc | ||
| Victivallis | ||
| DTU014DTU014 | ||
| uncultured genus from Oscillospirales orderuncultured genus from Oscillospirales order |
Revision editor(s): Saima-Younis
Signature 2
Needs review
Source: Figure 2H
Description: Microbial genera depleted in obese individuals with ADT diet
Abundance in Group 1: decreased abundance in Obese individuals after 90 days of taking the ADF diet (Final)
| NCBI | Quality Control | Links |
|---|---|---|
| Dorea | ||
| Granulicatella | ||
| Romboutsia | ||
| TM7xTM7x | ||
| Eubacterium_hallii_groupEubacterium_hallii_group |
Revision editor(s): Saima-Younis
Experiment 4
Needs review
Differences from previous experiment shown
Subjects
- Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
- Cognitive function measurement Cognitive function measurement,cognitive function measurement
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Obese individuals prior diet intervention (Basal Stroop interference scores)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Obese individuals after diet intervention (Final Stroop interference scores)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- The individuals took either of Mediterranean (Med), Ketogenic (Keto) or alternate-day fasting (ADF) diets for the period of three months (90 days). The final readings of Stroop interference test were taken on last follow-up session after 90 days.
- Group 0 sample size Number of subjects in the control (unexposed) group
- 96
- Group 1 sample size Number of subjects in the case (exposed) group
- 84
Lab analysis
Statistical Analysis
- Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
- relative abundances
- Statistical test
- Spearman Correlation
Alpha Diversity
- Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample
- unchanged
Signature 1
Needs review
Source: Figure 2I
Description: Microbial genera which were found positively correlated with Stroop interference scores.
Abundance in Group 1: increased abundance in Obese individuals after diet intervention (Final Stroop interference scores)
| NCBI | Quality Control | Links |
|---|---|---|
| Akkermansia | ||
| Bilophila |
Revision editor(s): Saima-Younis
Experiment 5
Needs review
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Obese individuals prior diet intervention (Basal-Trail Making Test-TMT A score)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Obese individuals after diet intervention (Final-Trail Making Test-TMT A score)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- The individuals took either of Mediterranean (Med), Ketogenic (Keto) or alternate-day fasting (ADF) diets for the period of three months (90 days). The final readings of TMT A for rote memory, were taken on last follow-up session after 90 days.
Lab analysis
Statistical Analysis
Alpha Diversity
- Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample
- unchanged
Signature 1
Needs review
Source: Figure 2I
Description: The microbial genus whose abundance was positively correlated with TMT A
Abundance in Group 1: increased abundance in Obese individuals after diet intervention (Final-Trail Making Test-TMT A score)
| NCBI | Quality Control | Links |
|---|---|---|
| Bilophila |
Revision editor(s): Saima-Younis
Experiment 6
Needs review
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Obese individuals prior diet intervention (Basal-Trial Making Test-TMT B Scores)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Obese individuals after diet intervention (Final -Trial Making Test-TMT B scores)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- The individuals took either of Mediterranean (Med), Ketogenic (Keto) or alternate-day fasting (ADF) diets for the period of three months (90 days). The final readings of TMT B (for executive functioning) were taken on last follow-up session after 90 days.
Lab analysis
Statistical Analysis
Alpha Diversity
- Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample
- unchanged
Signature 1
Needs review
Source: Figure 2I
Description: Microbial genus which was found positively correlated with TMT B
Abundance in Group 1: increased abundance in Obese individuals after diet intervention (Final -Trial Making Test-TMT B scores)
| NCBI | Quality Control | Links |
|---|---|---|
| Agathobacter |
Revision editor(s): Saima-Younis
Signature 2
Needs review
Source: Figure 2I
Description: Microbial genus which was negatively correlated with TMT B
Abundance in Group 1: decreased abundance in Obese individuals after diet intervention (Final -Trial Making Test-TMT B scores)
| NCBI | Quality Control | Links |
|---|---|---|
| Dorea |
Revision editor(s): Saima-Younis
Experiment 7
Needs review
Differences from previous experiment shown
Subjects
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Obese individuals prior diet intervention (Basal L&N scores)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Obese individuals after diet intervention (Final L&N scores)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- The individuals took either of Mediterranean (Med), Ketogenic (Keto) or alternate-day fasting (ADF) diets for the period of three months (90 days). The final readings of "Letters and Numbers (L & D) from the Wechsler Adult Intelligence Scale (WAIS)" were taken on last follow-up session after 90 days.
Lab analysis
Statistical Analysis
Alpha Diversity
- Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample
- unchanged
Signature 1
Needs review
Source: Figure 2I
Description: A microbial genus which was positively correlated with L&N score
Abundance in Group 1: increased abundance in Obese individuals after diet intervention (Final L&N scores)
| NCBI | Quality Control | Links |
|---|---|---|
| DTU014DTU014 |
Revision editor(s): Saima-Younis
Experiment 8
Needs review
Differences from previous experiment shown
Subjects
- Host species Species from which microbiome was sampled. Contact us to have more species added.
- Mus musculus
- Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
- Response to diet Response to diet,response to diet
- Group 0 name Corresponds to the control (unexposed) group for case-control studies
- Obese mice who received fecal transplant from Basal state human subjects prior to diet intervention (Con group)
- Group 1 name Corresponds to the case (exposed) group for case-control studies
- Obese mice who received fecal transplant from Final state of human subjects after 90 days of diet intervention (KB group)
- Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
- The mice received BHB supplement (KetoForce food supplement) in the drinking water to study the isolated effect of ketone bodies supplementation.
- Group 0 sample size Number of subjects in the control (unexposed) group
- 10
- Group 1 sample size Number of subjects in the case (exposed) group
- 10
- Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
- 2 Weeks
Lab analysis
Statistical Analysis
- Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
- log transformation
- Statistical test
- ANCOM-BC
- Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
- 0.001
Alpha Diversity
- Faith Phylogenetic diversity, takes into account phylogenetic distance of all taxa identified in a sample
- unchanged
Signature 1
Needs review
Source: Figure S2J
Description: Bacterial genus which were significantly enriched or depleted to ketone bodies supplementation in obese mice.
Abundance in Group 1: increased abundance in Obese mice who received fecal transplant from Final state of human subjects after 90 days of diet intervention (KB group)
Revision editor(s): Saima-Younis
Signature 2
Needs review
Source: Figure S2J
Description: Bacterial genera which were significantly depleted due to ketone bodies supplementation in obese mice
Abundance in Group 1: decreased abundance in Obese mice who received fecal transplant from Final state of human subjects after 90 days of diet intervention (KB group)
Revision editor(s): Saima-Younis
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