Impacts of Bariatric Surgery on the Microbiome and Brain Function

Understanding the Impact of Radical Changes in Diet and the Microbiome on Brain Function and Structure: the EMBRACE Study

Emerging evidence suggests that dietary and metabolic interventions could potentially target prevention and supportive therapies as well as treatments that may slow the clinical deterioration of neurodegenerative disorders. Though certain dietary patterns can impair specific cognitive domains, e.g., declines in reasoning and global cognition, there is still no consensus on the optimal diet to maintain brain health. Studies have also shown an association between the gut microbiome and neurocognition, as the microbiota can affect neuronal function through neurotransmitters and neuroactive microbial metabolites. Furthermore, studies indicate that diet may strongly influence the gut microbiota. However, the mechanisms for these complex relationships are still poorly understood. Bariatric procedures [i.e., weight loss surgeries] create a unique environment, in which a fast change in gut microbiota composition and dietary patterns occurs through surgery-induced intestinal and metabolic modifications, leading to changes in gut-brain communication. Interestingly, improvements in neurocognitive domains including memory and executive function have been reported post-bariatric surgery. However, there is large variability in these outcomes, indicating that the benefits are not universal. The goal of the current study is to explore the associations between dietary patterns and gut microbiota with cognition and brain structure, using bariatric surgery as an efficient naturalistic experimental design. This project will also explore potential mediators of diet-microbiome alterations as they relate to improvements in brain function and structure. A total of 120 adult patients (> 30y yrs.) scheduled to undergo a first bariatric surgery along with 60 age-, sex-, and BMI-matched waitlist control group will be recruited from the bariatric surgery clinic at the CIUSSS du Nord-de-l'Île-de-Montréal. These individuals will undergo assessments 3 months before surgery, as well as 6- and 12-months post-surgery, or an equivalent time for those on the waitlist. This study will also include 60 age-and sex-matched individuals who are not eligible for bariatric surgery as an additional healthy Canadian comparison group (only one assessment time point). Assessments taken during the data collection period will include: self-report information [e.g., sociodemographic and background information, health and diet behaviours]; information from medical records [e.g., medications usage, peri- and post-surgical complications, etc.]; physiological measures [i.e., blood, urine and fecal samples collection]; cognitive assessment [i.e., neuropsychological tests battery]; and brain imaging [i.e., structural MRI]. Collectively, this study is designed to provide critical information about potential individually targeted diet-based preventative strategies to reduce the development and progression of neurodegenerative disorders. Moreover, this project will explore potential mediators of diet-microbiome alterations as they relate to improvements in brain function and structure, and as such, it will provide essential information on key mechanisms, stimulating further research and the creation of parallel non-dietary therapeutic options.

Dietary patterns are associated with cognitive function and brain morphology. Though certain dietary patterns can impair specific cognitive domains, e.g., declines in reasoning and global cognition, there is still no consensus on the optimal 'brain diet'. Studies have also shown an association between the gut microbiome and neurocognition. The microbiota can affect neuronal function through neurotransmitters and neuroactive microbial metabolites. Furthermore, studies indicate that diet may strongly influence the gut microbiota, likely via intestinal permeability and inflammation. However, the mechanisms for this complex relationship between diet, gut microbiome and cognition are still poorly understood. Most of the work to date has focused on the negative effects of a Western style diet, with its subsequent microbiota alterations leading to cognitive impairment, via reduced barrier integrity, increased neuroinflammation, and impaired insulin signaling. However, very little is known about positive dietary-microbiome interactions, especially in humans. Bariatric surgery is considered the most effective treatment for severe obesity and it's related comorbidities, with the Sleeve gastrectomy (SG) being the most commonly performed procedures worldwide. These procedures create a unique environment, in which a fast change in gut microbiota composition occurs through surgery-induced intestinal and metabolic modifications, leading to changes in gut-brain communication. Moreover, these same post-surgical alterations to the gastrointestinal tract are accompanied by profound changes in dietary patterns that, in turn, influence microbiota composition. Following bariatric surgery, dietary intake is altered both in quantity and quality; however, considerable individual variations in surgically-induced dietary patterns have been previously demonstrated. Interestingly, improvements in neurocognitive domains including memory and executive function have been reported post-bariatric surgery. However, there is large variability in these outcomes, indicating that the benefits are not universal. Additionally, the extant literature is limited by a small number of studies, meaning that the underling mechanisms remain unclear. Importantly, how bariatric surgery-induced modifications in both dietary patterns and the gut microbiome effect cognitive function have yet to be explored. Finally, the overall changes in the gut microbiome and diet post-surgery may enhance biological pathways (e.g., gut hormones, inflammation, and neuroactive metabolites) which can affect brain function and structure, but the nature of these changes have not been studied extensively. The EMBRACE trial (Evaluation the impact of radical nutrition and Microbiome changes on BRAin funCtion and structurE) is a prospective, 15-month longitudinal study that aims to elucidate the associations between dietary patterns and gut microbiota with cognition and brain structure, using an efficient naturalistic experimental design which causes major disruptions to both diet and the microbiome, i.e., bariatric surgery. The main goal of this study is to evaluate how changes in gut microbiota composition and dietary patterns from pre- to post-bariatric surgery are linked to improved cognition and brain structure over the medium-term (12-months post-surgery). This project also aims to explore the potential mediating biological (e.g., inflammatory markers, hormonal changes, altered micronutrients levels and neuroactive microbial metabolites) pathways which might explain these relationships.

Primary aim: To evaluate the effect of surgery-induced changes in gut microbiota composition and dietary patterns from 3-M pre-surgery to 6-M post-surgery on 12-M post-surgical cognition, measured using sensitive neuropsychological tests.

Secondary aim: To evaluate the effect of surgery-induced changes in gut microbiota composition and dietary patterns from 3-M pre-surgery to 6-M post-surgery on 12-M post-surgical brain structure measured with magnetic resonance imaging (MRI) to assess brain volume, white-matter hyperintensities and cortical thickness.

Hypotheses for aims 1 and 2: Better quality microbiota and diet clusters (e.g., increased bacterial richness and diversity and greater low-saturated fat/high fibre intake) will be associated with increased performance on cognitive measures (higher total score on the neuropsychological test battery [primary] and its subscales [secondary]) and positive changes in brain measures (regional brain volume, hippocampal volume, cortical thickness and white-matter hyperintensities).

Exploratory aim: To examine biological changes (e.g., inflammatory state, hormonal changes, altered micronutrients levels and neuroactive microbial metabolites) pre- to post-surgery as potential mediating factors between microbiota/diet changes and cognitive/brain measures. Outcome: We will explore what post-surgical biological measures (e.g., reduced inflammatory markers, lower leptin levels, etc.) might mediate or moderate the links between specific microbiota and diet clusters and changes in cognitive function and brain measures.

A total of 120 adult patients (≥ 30y yrs.) scheduled to undergo a first bariatric surgery along with 60 age-, sex-, and BMI-matched waitlist control group will be recruited and undergo assessments 3 months before surgery, as well as 6- and 12-months post-surgery, or an equivalent time for those on the waitlist. This study will also include the recruitment of 60 age-and sex-matched individuals who are not eligible for bariatric surgery, as an additional non-bariatric comparison group. Evaluations will include standardized questionnaires on demographics, health behaviors and eating habits, physiological assessments (anthropometrics, inflammatory and blood-based measurements, 24-hour urine and fecal sample collection), cognitive assessment by neuropsychological tests, and structural magnetic resonance imaging (MRI).

Cluster analyses of the dietary and microbial alterations will define the various dietary patterns and microbiome profiles, then using repeated-measures mixed models, their associations with global cognitive changes and structural brain alterations will be explored.

Inclusion Criteria:

• Age 30 years or older
• Indeviduals planning to be available for two years of follow-up
• Ability ro read and speak French or English

Exclusion Criteria:

• A previous bariatric surgery
• Using long-term antibiotics
• Using commercially available prebiotic/probiotic in the past month
• A history of significant intestinal disease/disorder that would influence the microbiome (e.g., Crohn's disease)
• A non-bariatric surgery in the 6 months before being recruited
• A diagnosed neurologic disorder or deficits (e.g., dementia, stroke, or seizures)
• A diagnosis of a severe axis 1 psychotic disorder (e.g., schizophrenia) or bipolar disorder
• A current infection or a diagnosed infectious disease
• Pregnacy or breast feeding
• Active cancer
• Advanced kidney disease
• Advanced liver disease
• Past organ transplantation
• Having any contraindications for undergoing MRI [i.e., having a cardiac pacemaker (or pacemaker), defibrillator (a heart rhythm device), heart valve prosthesis (a prosthesis in the heart), Swan-Ganz catheter (a tube in the pulmonary artery on the chest), metal insulin or chemotherapy pump under the skin, neurostimulator, brain aneurysm clip (a clip in a blood vessel of the brain), metal prosthesis or rods (following surgery), metal cerclage (metal support on a bone), cochlear or ocular implant (an implant in the ear or eye), penile implant, an intraocular metal fragment (metal debris in the eye), an intrauterine device that does not conform with the MRI, any plastic implants (e.g., breasts) or a patch on the skin for the administration of a medication unless it can remove before scan session]. Additional requirements for MRI includes patients agreement to: 1) have a pregnancy test and remove makeup, 2) the removal of dentures (full or partial), and 3) provide information on all surgery and previous tattoos (tattoos made for many years or those made in some countries, as the ink contains metallic particles).
• For participants included in the non-bariatric eligible comparison group group, individuals with any physician diagnosed major non-communicable chronic disease, defined as cardiovascular disease, chronic obstructive lung disease, cancer, diabetes, or obesity, will be excluded.