Gut-Brain-axis: Targets for Improvement of Cognition in the Elderly

NCT ID: NCT04841668

Last Updated: 2025-12-12

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 136 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-04-10
• Study Completion Date: 2026-02-28

Brief Summary

Cognitive disorders increase with age and in the presence of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM). In addition, digestive disorders, changes in dietary pattern and decreased activity negatively influence the microbiome.

The hypothesis is that pharmacological intervention with metformin will modify the composition of the gut microbiota and cognition.

The study has a pilot longitudinal design, where each patient with T2DM will be followed for one year. Two groups will be recruited:

1. Group A: The aim will be to evaluate the associations between glucose (measured by continuous glucose monitoring (CGM)), cognitive function (by means of cognitive tests and magnetic resonance imaging (MRI)), physical activity (recorded by activity and sleep tracker devicer), metformin, diet (evaluated by nutritional survey) and composition of the microbiota (evaluated by metagenomics), during 12 months (6 months without metformin and 6 months with metformin treatment).

2. Group B: The aim will be to evaluate the associations between glucose, diet (evaluated by nutritional survey), cognitive function (by means of cognitive tests), physical activity (measured by activity and sleep tracker device), the treatment and composition of the microbiota (evaluated by metagenomics), during 12 months.

Detailed Description

Subjects and methods:

Longitudinal study:

Patients with T2DM previously scheduled at the Service of Endocrinology, Diabetes and Nutrition (UDEN) of the Hospital "Dr. Josep Trueta" of Girona (Spain) will be recruited and studied.

GROUP A

This study consists of an initial phase, where the patient will be submitted as the only treatment to a balanced diet with an energy intake, calculated individually according to whether he/she is normal weight (25 Kcal x Kg) or overweight (20 Kcal x Kg of weight).

After this initial phase, in addition to continuing with the balanced diet treatment, patients will start treatment with metformin administered orally at an initial dose of 425 mg/d every 12 hours during the first 15 days and then continue with doses of 850 mg/d until the end of the study.

A glycemia sensor will be inserted for ten days, as well as an activity and sleep tracker device (Fitbit) to record physical activity during this period of time. Interstitial subcutaneous glucose concentrations will be monitored on an outpatient basis for a period of time of 10 consecutive days using a glucose sensor validated by the FDA (Dexcom G6 ®). The sensor will be inserted on day 0 and it will retire on day 10 midmorning.

This process will be repeated 10 days prior to the start of the of treatment with Metformin and 10 days before the end of the 6 month study phase with metformin. During the study, 6 visits will be made and each patient will be inserted with a total of 3 glycemia sensors and 3 physical activity monitors. In summary, the glycemia sensor and physical activity monitoring will be started at visits 1, 3, 5 and will be removed at visits 2,4,6.

Visit 1(day 1): Physical examination, Nutritional survey, Bioimpedance, Densitometry, CGM and Activity and sleep tracker device. Consent form

Visit 2 (day 10): Sample: blood, urine and feces. Diet, Neuropsychological test, CGM withdrawal, Activity and sleep tracker device withdrawal, MRI.

Visit 3 (day 170): Physical examination, Nutritional survey, Bioimpedance, CGM and Activity and sleep tracker device

Visit 4 (day 180): Sample: blood, urine and feces. Dietary follow-up, Neuropsychological test, CGM withdrawal and Activity and sleep tracker device withdrawal. Start of metformin treatment.

Visit 5 (day 350): Physical examination, Nutritional survey, Bioimpedance, CGM and Activity and sleep tracker device.

Visit 6 (day 360): Sample: blood, urine and feces. Dietary follow-up, Neuropsychological test, CGM withdrawal and Activity and sleep tracker device withdrawal. Metformin withdrawal.

GROUP B:

During the study, 5 visits will be made for this group:

Visit 1(day 1): Physical examination, Nutritional survey, Bioimpedance, Densitometry and Activity and sleep tracker device. Consent form.

Visit 2 (day 10): Sample: blood, urine and feces. Diet, Neuropsychological test and Activity and sleep tracker device withdrawal.

Visit 3 (day 180): Diet follow-up.

Visit 4 (day 350): Physical examination, Nutritional survey, Bioimpedance and Activity and sleep tracker device.

Visit 5 (day 360): Sample: blood, urine and feces. Diet follow-up, Neuropsychological test and Activity and sleep tracker device withdrawal.

DATA COLLECTION OF SUBJECTS LONGITUDINAL STUDIES:

1. Subsidiary data: Age, sex and birth date.

2. Clinical variables:

• Weight
• height,
• body mass index
• waist and hip perimeters
• waist-to-hip ratio
• blood pressure (systolic and diastolic)
• fat mass and fat free-mass (bioelectric impedance and DEXA)
• smoking status
• alcohol intake
• registry of usual medicines
• personal history of blood transfusion and/or donation
• record of family history of obesity, cardiovascular events and diabetes
• psychiatric and eating disorder history.

3. Laboratory variables: 15cc of blood will be extracted from fasted subjects to determine the following variables using the usual routine techniques of the clinical laboratory:

• hemogram
• glucose
• bilirubin
• aspartate aminotransferase (AST/GOT)
• alanine aminotransferase (ALT/GPT)
• gamma-glutamyl transpeptidase (GGT)
• urea
• creatinine
• uric acid
• total proteins,
• albumin
• total cholesterol | HDL cholesterol | LDL cholesterol
• triglycerides,
• glycated haemoglobin (HbA1c)
• ferritin | soluble transferrin receptor
• ultrasensitive C reactive protein
• erythrocyte sedimentation rate
• lipopolysaccharide binding protein
• free thyroxine (free T4) | thyroid stimulating hormone (TSH) | baseline cortisol -plasma insulin
• inflammation markers | interleukin 6 (IL-6). An additional 15cc of blood (plasma-EDTA) will be extracted for further analyses.

4. Stool samples collection: A stool sample will be provided from each patient. The sample should be collected at home or in the hospital, sent to the laboratory within 4 hours from the collection, fragmented and stored at -80ºC.

-Analysis of intestinal microbiota in stool:

• Determination of bacterial DNA and mRNA and study of the LBP binding protein in blood for the detection of bacterial translocation. LBP binding protein in blood for the detection of bacterial translocation. Hiseq and Nextseq technology (qPCR and protein analysis (WB, ELISA), OMICS (RNAseq, 16S, Metabolomics, Metagenomics).
• Inflammatory and immunological markers will be determined using ELISA (enzyme-linked immunosorbent assay) and immunohistochemistry (IHC) equipment and quantitative real-time PCR validation. For qPCR, total RNA will be isolated from different tissues and will transcribe into cDNA.
• Determination of metabolic profile and metabolite analysis.

5. Intestinal barrier function:Exposure to a lactulose:mannitol test before/after surgery. Plasma samples will be used to measure intestinal permeability markers: bacterial endotoxin, sCD14, LBP, ZO-1, and I-FABP.

6. Urine sample collection: Necessary to determine alterations in the metabolic pathways involved in tryptophan metabolism, and to determine the role of the intestinal microbiota in these metabolic changes.

7. MRI: The necessary sequences will be acquired for the calculation of the BrainAGE biomarker and the characterization of the networks involved in cognitive functions. For the acquisition a 1.5 T scanner (Ingenia; Philips Medical Systems) will be used 1,5 T scanner (Ingenia; Philips Medical Systems) will be used for the acquisition. First, recovery-inversion sequence (T2-FLAIR) will be used to exclude subjects with pre-existing brain lesions. Subsequently, structural sequences will be acquired sequences will then be acquired to measure the integrity of cerebral gray matter (T1-weighted), tracts of weighted), of the white matter tracts (DTI), iron accumulation (R2*), and (R2*), and functional sequences in resting-state (T2*-weighted echo-planar imaging, EPI).

8. Neuropsychological examination: Different domains of cognition will be explored: memory (Test aprendizaje verbal-TAVEC, Rey-Osterrieth Complex Figure) attention and executive function(WAIS-IV, Trail making test (Part A y B), Stroop test). In addition, cognitive impairment will be evaluated with Lobo's Mini-Cognitive Exam. These tests will be useful to define the changes in the cognitive profile associated with the pharmacological intervention with metformin.

The information will remain registered in a notebook and will be computerized in the database of the study.

STATICAL METHODS:

Sample size: Since this is intended as a pilot study, no formal sample size calculation is required. A general rule is to recruit 30 or more patients to estimate a parameter and 15-20 participants per group to obtain reasonable estimates for medium to large effect sizes.

Statistical analyses: It will be based on a descriptive analysis (mean, standard deviation, sample size, median, minimum and maximum) of the quantitative parameters and the indication of the frequency of the remaining categorical parameters. Comparisons between groups will be based on a paired samples t-test or a chi-square test. The results of these analyses may be useful to assess whether further analyses are needed to adjust for possible imbalance in the baseline characteristics of the patients.

The changes in the composition of the gut microbiota after the intervention with metformin will be analyzed using Heatmaps, Principal Component Analysis (PCA) and PLSDA. For the multivariate statistical analysis (PLSDA and hierarchical clustering). The variables that comprise the characteristics of the intestinal microbiota and cognitive tests will be logarithmically transformed, filtered with interquartile range estimation and staggered by autoscale calculation (mean and divided by the standard deviation of each variable) by using the Metaboanalyst platform.

The changes determined in the gut microbiota and cognition variables will be explored in relation to the changes in the secondary variables (metabolic, metabolome, inflammation parameters) by linear regression analysis in SPSS. Brain image variables will be analyzed with specialized programs (MATLAB, SPM12).

Conditions

Type 2 Diabetes Mellitus

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Patients with recently diagnosed T2DM

This group will consist of 36 recently diagnosed T2DM, according to the World Health Organization (WHO) patients (last 6 months), who have not received treatment with metformin.

Metformin

Intervention Type: DRUG

Patients will begin treatment with metformin administered orally at a starting dose of 425 mg / day every 12 hours for the first 15 days and then continue with a dose of 850 mg / day until the end of the study. The beginning of this treatment phase will be following the recommendations of the clinical guidelines (Comprehensive Approach to Type 2 Diabetes Mellitus, SEEN V2019.2)

Patients with long-term T2DM

The group will consist of 100 patients with long-term T2DM, according to the WHO classification, regardless of whether they take metformin or another treatment.

No interventions assigned to this group

Interventions

Metformin

Patients will begin treatment with metformin administered orally at a starting dose of 425 mg / day every 12 hours for the first 15 days and then continue with a dose of 850 mg / day until the end of the study. The beginning of this treatment phase will be following the recommendations of the clinical guidelines (Comprehensive Approach to Type 2 Diabetes Mellitus, SEEN V2019.2)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Age between 55 and 80 years.

2. Patients with recently diagnosed T2DM (last 6 months), according to the WHO classification.

3. Patients in whom written informed consent has been obtained for participation in the study.

1. Age between 65 and 80 years.

2. Patients with long-term T2DM according to the WHO classification

3. Patients in whom written informed consent has been obtained for participation in the study.

Exclusion Criteria

1. HbA1c ≥ 9%

2. Metformin treatment in the past 6 months

3. Creatinine greater than 1.2 and glomerular filtration rate less than 40

4. Serious systemic disease not related to obesity, including any type of cancer, severe kidney disease or liver disease, and known type 1 diabetes.

5. Systemic diseases with intrinsic inflammatory activity such as rheumatoid arthritis, Crohn's disease, asthma, or chronic infection (e.g., HIV, active tuberculosis) or any type of infectious disease.

6. Current treatment for malignant neoplasia, other than basal cell or squamous cell skin cancer.

7. Class III or IV heart disease, known ischemic cardiovascular disease

8. Kidney failure, history of kidney transplant, or current dialysis treatment

9. Serum liver enzymes (GOT, GPT) above twice the upper limit of normal. Obvious signs or symptoms of liver disease, acute or chronic hepatitis.

10. Chronic constipation (stool habit ≥ 7 days)

11. Pregnancy or breastfeeding

12. Treatments that affect glucose metabolism or the intestinal microbiota with biguanides, sulfonylurea secretagogues or non-sulfonylurea secretagogues, insulin sensitizers, insulin, thiazolidinediones, alpha glucosidase inhibitors, incretin mimetics, Dipeptidyl peptidase IV inhibitors, use of cathartics.

13. Chronic anti-inflammatory treatment with steroidal drugs (during the previous 3 months).

14. Symptoms and / or clinical signs of infection in the previous month.

15. Antibiotic, antifungal or antiviral treatment active in the previous 3 months.

16. Treatment with glucocorticoids chronic or during the 2 months prior to inclusion in the study.

17. Treatment with a weight loss product during the previous two months

18. Immunosuppressant treatment.

19. Excessive alcohol consumption (alcohol intake greater than 40 g per day (women) or 80 g / day (men)) either acute or chronic, or drug use. History of drug or alcohol abuse.

20. Patients with severe eating disorders

21. History of alterations in iron balance (known chronic hemoglobinopathies or anemia, genetic hemochromatosis, hemosiderosis from any cause, atransferrinemia, paroxysmal nocturnal hemoglobinuria).

22. Important psychiatric history.

23. Participation in any other study.

24. People whose freedom is under legal or administrative requirement.

Group B

1. HbA1c ≥ 9%

2. Creatinine greater than 1.2 and glomerular filtration rate less than 40

3. Serious systemic disease not related to obesity, including any type of cancer, severe kidney disease or liver disease, and known type 1 diabetes.

4. Systemic diseases with intrinsic inflammatory activity such as rheumatoid arthritis, Crohn's disease, asthma, or chronic infection (e.g., HIV, active tuberculosis) or any type of infectious disease.

5. Current treatment for malignant neoplasia, other than basal cell or squamous cell skin cancer.

6. Class III or IV heart disease, known ischemic cardiovascular disease.

7. Kidney failure, history of kidney transplant, or current dialysis treatment

8. Serum liver enzymes (GOT, GPT) above twice the upper limit of normal. Obvious signs or symptoms of liver disease, acute or chronic hepatitis.

9. Chronic constipation (stool habit ≥ 7 days)

10. Pregnancy or breastfeeding

11. Chronic anti-inflammatory treatment with steroidal drugs (during the previous 3 months).

12. Symptoms and / or clinical signs of infection in the previous month.

13. Antibiotic, antifungal or antiviral treatment active in the previous 3 months.

14. Treatment with glucocorticoids chronic or during the 2 months prior to inclusion in the study.

15. Treatment with a weight loss product during the previous two months.

16. Immunosuppressant treatment.

17. Excessive alcohol consumption (alcohol intake greater than 40 g per day (women) or 80 g / day (men)) either acute or chronic, or drug use. History of drug or alcohol abuse.

18. Patients with severe eating disorders

19. History of alterations in iron balance (known chronic hemoglobinopathies or anemia, genetic hemochromatosis, hemosiderosis from any cause, atransferrinemia, paroxysmal nocturnal hemoglobinuria).

20. Important psychiatric history.

21. Participation in any other study.

22. People whose freedom is under legal or administrative requirement.

• Minimum Eligible Age: 65 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta

OTHER

Sponsor Role: lead

Responsible Party

José Manuel Fernández-Real

Principal investigator, clinical professor, section chief of Endocrinology and Nutrition Department of Josep Trueta University Hospital

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

José M Fernández-Real, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Institut d'Investigació Biomèdica de Girona (IDIBGI)

Locations

Institut d'Investigació Biomèdica de Girona (IDIBGI)

Girona, Girona, Spain

Site Status: RECRUITING

Countries

Spain

Central Contacts

José M. Fernández-Real, Ph.D.

Role: CONTACT

jmfreal@idibgi.org

+34 972 94 02 00 ext. 2325

Marisel Rosell Díaz, M.D.

Role: CONTACT

mrosell@idibgi.org

+34 972 94 02 00 ext. 2325

Facility Contacts

Yenny Leal, Ph.D.

Role: primary

yleal@idibgi.org

0034 972940200 ext. 2325

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Other Identifiers

SMARTAGE-2020.133

Identifier Type: -

Identifier Source: org_study_id