Understanding Gut-brain Interactions and Effect of an Intervention in Obese and Depressive Patients

Wednesday, April 21, 2021
Understanding Gut-brain Interactions and Effect of an Intervention in Obese and Depressive Patients

Obesity‌ ‌and‌ ‌major‌ ‌depressive‌ ‌disorders‌ ‌(MDD)‌ ‌are‌ ‌among‌ ‌the‌ ‌most‌ ‌challenging‌ ‌public‌ ‌health‌ ‌problems‌ ‌with‌ ‌a‌ ‌rapidly‌ ‌increasing‌ ‌prevalence‌ ‌worldwide.‌ ‌MDD‌ ‌and‌ ‌obesity‌ ‌are‌ ‌highly‌ ‌comorbid,‌ ‌the‌ ‌“metabolic”‌ ‌(obese)‌ ‌subtype‌ ‌of‌ ‌MDD‌ ‌affects‌ ‌about‌ ‌one‌ ‌third‌ ‌of‌ ‌all‌ ‌individuals‌ ‌with‌ ‌MDD.‌ ‌Therefore,‌ ‌there‌ ‌is‌ ‌an‌ ‌urgent‌ ‌need‌ ‌to‌ ‌develop‌ ‌better‌ ‌preventive‌ ‌and‌ ‌therapeutic‌ ‌strategies,‌ ‌which‌ ‌may‌ ‌include‌ ‌specific‌ ‌dietary‌ ‌measures.‌ ‌Preclinical‌ ‌studies‌ ‌show‌ ‌that‌ ‌a‌ ‌diet‌ ‌low‌ ‌in‌ ‌carbohydrates‌ ‌(low-carb),‌ ‌effective‌ ‌in‌ ‌obesity‌ ‌and‌ ‌associated‌ ‌metabolic‌ ‌disorders,‌ ‌tHowever,‌ ‌no‌ ‌clinical‌ ‌trials‌ ‌on‌ ‌the‌ ‌role‌ ‌of‌ ‌low-carb‌ ‌diet‌ ‌in‌ ‌MDD‌ ‌have‌ ‌been‌ ‌performed‌ ‌to‌ ‌date.‌ ‌Furthermore,‌ ‌while‌ ‌clinical‌ ‌data‌ ‌on‌ ‌the‌ ‌effects‌ ‌of‌ ‌a‌ ‌low-carb‌ ‌diet‌ ‌in‌ ‌obese‌ ‌and‌ ‌diabetic‌ ‌patients‌ ‌is‌ ‌available,‌ ‌the‌ ‌underlying‌ ‌mechanisms‌ ‌were‌ ‌not‌ ‌yet‌ ‌studied.‌ ‌Recent‌ ‌data‌ ‌suggest‌ ‌a‌ ‌key‌ ‌role‌ ‌of‌ ‌factors‌ ‌acting‌ ‌that‌ ‌may‌ ‌act‌ ‌synergistically:‌ ‌i)‌ ‌gut‌ ‌microbiota,‌ ‌ii)‌ ‌neuroplasticity‌ ‌and‌ ‌iii)‌ ‌neuro-inflammation‌ ‌in‌ ‌both‌ ‌obesity‌ ‌and‌ ‌MDD,‌ ‌but‌ ‌their‌ ‌role‌ ‌in‌ ‌“metabolic”‌ ‌vs.‌ ‌“lean”‌ ‌(non-obese)‌ ‌MDD‌ ‌is‌ ‌unclear.‌ ‌ ‌

Exciting‌ ‌clinical‌ ‌and‌ ‌preclinical‌ ‌results‌ ‌suggest‌ ‌that‌ ‌obesity‌ ‌and‌ ‌even‌ ‌MDD-like‌ ‌features‌ ‌can‌ ‌be‌ ‌“transferred”‌ ‌from‌ ‌humans‌ ‌to‌ ‌humans‌ ‌or‌ ‌rodents‌ ‌by‌ ‌fecal‌ ‌material‌ ‌transplantation‌ ‌(FMT).‌ ‌Mice‌ ‌deficient‌ ‌for‌ ‌the‌ ‌key‌ ‌neuroplasticity,‌ ‌MDD-associated‌ ‌marker‌ ‌brain‌ ‌derived‌ ‌neuro-trophic‌ ‌factor‌ ‌(BDNF)‌ ‌display‌ ‌are‌ ‌susceptible‌ ‌to‌ ‌both‌ ‌stress/depression-like‌ ‌behavior‌ ‌and‌ ‌obesity‌ ‌(“vulnerability”).‌ ‌Conversely,‌ ‌mice‌ ‌lacking‌ ‌the‌ ‌microglial‌ ‌fractalkine‌ ‌receptor‌ ‌CX3CR1,‌ ‌a‌ ‌main‌ ‌modulator‌ ‌of‌ ‌neuro-inflammation,‌ ‌are‌ ‌resistant‌ ‌to‌ ‌both‌ ‌stress‌ ‌and‌ ‌obesity,‌ ‌when‌ ‌exposed‌ ‌to‌ ‌fat-enriched‌ ‌diet‌ ‌(“resilience”).‌ ‌However,‌ ‌the‌ ‌mechanistic‌ ‌interplay‌ ‌between‌ ‌these‌ ‌factors‌ ‌and‌ ‌their‌ ‌specific‌ ‌contribution‌ ‌to‌ ‌each‌ ‌disorder‌ ‌are‌ ‌not‌ ‌yet‌ ‌understood.‌ ‌

To‌ ‌clarify‌ ‌these‌ ‌aspects‌ ‌we‌ ‌aim:‌ ‌ ‌

a)‌ ‌to‌ ‌evaluate‌ ‌the‌ ‌therapeutic‌ ‌potential‌ ‌of‌ ‌dietary,‌ ‌potentially‌ ‌microbiome-influencing‌ ‌interventions‌ ‌(low-carb‌ ‌diet)‌ ‌on‌ ‌disease-associated‌ ‌parameters‌ ‌(psychometry,‌ ‌brain‌ ‌network‌ ‌activity,‌ ‌hypothalamic-pituitary-adrenal‌ ‌(HPA)‌ ‌axis,‌ ‌plasma‌ ‌BDNF/fractalkine‌ ‌levels,‌ ‌cytokines,‌ ‌gut‌ ‌microbiota‌ ‌composition,‌ ‌markers‌ ‌of‌ ‌leaky‌ ‌gut,‌ ‌metabolomics)‌ ‌in‌ ‌individuals‌ ‌suffering‌ ‌from‌ ‌MDD‌ ‌with‌ ‌or‌ ‌without‌ ‌obesity,‌ ‌towards‌ ‌better‌ ‌nosology‌ ‌of‌ ‌disease‌ ‌subtypes‌ ‌based‌ ‌on‌ ‌mechanisms‌ ‌and‌ ‌validation‌ ‌of‌ ‌possible‌ ‌new‌ ‌biomarkers‌ ‌(plasma‌ ‌BDNF/fractalkine,‌ ‌neuroimaging‌ ‌parameters);‌ ‌b)‌ ‌to‌ ‌assess‌ ‌molecular‌ ‌determinants‌ ‌of‌ ‌their‌ ‌effect‌ ‌in‌ ‌selected‌ ‌mouse‌ ‌models‌ ‌with‌ ‌deficiency‌ ‌of‌ ‌BDNF‌ ‌or‌ ‌CX3CR1;‌ ‌c)‌ ‌to‌ ‌clarify‌ ‌the‌ ‌contribution‌ ‌of‌ ‌changes‌ ‌in‌ ‌gut‌ ‌microbiota‌ ‌composition‌ ‌to‌ ‌the‌ ‌psychiatric/metabolic‌ ‌pathology‌ ‌by‌ ‌fecal‌ ‌material‌ ‌transplantation‌ ‌(FMT)‌ ‌of‌ ‌samples‌ ‌from‌ ‌patients‌ ‌with‌ ‌MDD,‌ ‌obesity‌ ‌or‌ ‌“metabolic”‌ ‌MDD,‌ ‌to‌ ‌the‌ ‌mouse‌ ‌lines‌ ‌upon‌ ‌microbiome‌ ‌depletion.‌ ‌Our‌ ‌project‌ ‌may‌ ‌be‌ ‌important‌ ‌for‌ ‌several‌ ‌biological‌ ‌and‌ ‌medical‌ ‌disciplines,‌ ‌facilitating‌ ‌better‌ ‌understanding‌ ‌of‌ ‌the‌ ‌mechanisms‌ ‌of‌ ‌obesity‌/MDD,‌ ‌towards‌ ‌novel‌ ‌early‌ ‌and‌ ‌cost-efficient‌ ‌interventions.

Our objectives, in this 4 year study are to evaluate systematically the therapeutic potential of dietary microbiome-influencing interventions (low-carb diet) on disease-associated parameters in MDD with or without obesity.

Primary objective:

Effects of a 6 months low-carb dietary intervention [delivered using Gro Health] on glycemic control (insulin, glucose, glucagon)  in obese and lean patients with and without major depressive disorder.

Secondary objectives:

Effects of a 6 months low-carb dietary intervention [delivered using Gro Health] on glycemic control (insulin, glucose, glucagon)  in obese and lean patients with and without major depressive disorder. Effects of a 6 months low-carb dietary intervention on blood lipids, uric acid, incretins, plasma BDNF levels, cytokines, gut microbiota composition, markers of leaky gut, metabolic markers, metabolomics, weight, body composition and liver fat fraction,  psychometry- brain network activity, hypothalamic-pituitary-adrenal, HPA axis, gastrointestinal tolerance.

Breakthrough study

This interventional study is a multi-centre, binational project looking at patients from both St. Clara Research Ltd at St. Claraspital Basel in Basel, Switzerland and Universitätsklinikum Schleswig-Holstein, Germany. The study was funded by the Swiss National Science Foundation through Sinergia, which promotes the interdisciplinary collaboration of two to four applicants who propose breakthrough research.

Full details are available here: https://clinicaltrials.gov/ct2/show/NCT04234373.

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