General integrated goal of the coordinated project:

To elucidate the role of succinate and other metabolites derived from the intestinal microbiota such as Short Chain Fatty Acids (SCFAs), as energy sensing metabolites in the context of obesity and type 2 diabetes (T2D).

Specific objectives of Subproject 1 (SP1): 1a. - To investigate whether intermittent fasting (IF) is better than Continued Daily Caloric Restriction (DCR) in terms of metabolic improvement through the study of: 1) the dynamics of gastrointestinal hormones and energy sensing metabolites, 2) the intestinal microbiome, 3) variability on succinate and SCFAs, MCFAs and Biliary Acid after weight loss; Methodology: clinical study: randomized, cross-over design, study participants (n=15) will consume either lifestyle recommendations for a healthy Mediterranean diet under a continued caloric restriction diet (DCR) or will undertake an intermittent (IF) protocol. Clinical, anthropometrical and functional studies. Metabolomics for gut derived metabolites in plasma. Enteroendocrine gastrointestinal dynamics. Metagenomic analysis.

To investigate whether IF is better than DCR in terms of metabolic improvement through the study of:

1. the dynamics of gastrointestinal hormones and energy sensing metabolites
2. the intestinal microbiome
3. variability on succinate and SCFAs MCFAs and BA after weight loss

Human study protocol:

A pilot clinical trial in human study participants will be assayed. Participants for intermittent fasting (IF) will be asked to fast for 24 hours on two days of the week (2/5 protocol).

1A.-Design: Utilizing a randomized, cross-over design, study participants (n=15) will consume either lifestyle recommendations for a healthy Mediterranean diet under a continued daily caloric restriction diet (DCR) or will undertake an intermittent (IF) protocol. Each study period will be 8 weeks - total study period will be 16 weeks + a 4-week washout period between dietary exposures. The study participants will be adults who have obesity with a Body Mass Index (BMI)25 kg/m2 and 40 kg/m2 and have no contraindications for intermittent fasting (see inclusion and exclusion criteria below).

Inclusion Criteria:

• White men and women between 18 and 65 years of age.
• BMI range between 25 and 40 kg/m2
• Absence of underlying pathology in medical and physical examination, except for those related to excess weight.
• Signature of the informed consent for participation in the study.

Exclusion Criteria:

• Serious systemic disease not related to obesity, such as cancer, kidney or severe liver disease.
• Systemic diseases with intrinsic inflammatory activity (autoimmune diseases such as rheumatoid arthritis and asthma)
• Pregnancy and lactation.
• Vegetarians or subjects subjected to an irregular diet.
• Patients with severe eating disorders.
• Patients with clinical symptoms and signs of infection in the previous month.
• Patients with chronic anti-inflammatory steroid treatments and/or nonsteroidal anti-inflammatory drugs.
• Recent antibiotic treatment.
• Psychiatric history.
• Uncontrolled alcoholism or drug abuse.

Data sharing will be upon request directly to the PI