Exploratory Evaluation of the Effect of Cholestyramine on Serum Levels of POPs in Obese Female Patients

Environmental endocrine disruptors (EDCs) represent a major problem for human health. These chemical compounds from industry (pesticides, paints, plastics, etc.) are present in our daily lives, with exposure as early as foetal life. PEEs are capable of interfering with the endocrine system, but also of disrupting the signalling pathways of carbohydrate and lipid metabolism, and consequently of causing adverse effects on the health of an individual and/or his or her offspring. They are implicated in numerous pathologies, notably those linked to nervous system development, reproduction and chronic diseases such as obesity and diabetes. Thanks to their lipophilic nature, some PEEs can accumulate in the adipose tissue of the human body, and are known as persistent organic pollutants (POPs). Numerous longitudinal epidemiological studies have demonstrated higher concentrations of PEEs, particularly POPs, in obese and/or type 2 diabetic patients. In addition, these POPs pass easily across the placenta into fetal blood and, more readily, into breast milk. The developing fetus and infant are particularly sensitive to POPs, due to their lower volume of distribution and immature metabolism pathways.

In a recently published longitudinal study (PHRC POLOB), the investigators showed that massive weight loss during the first year after bariatric surgery is associated with a prolonged release of POPs from adipose tissue, directly dependent on pre-operative plasma levels. For some compounds, this release exceeds the health reference values set by ANSES, even one year after surgery. Short- and long-term consequences must therefore be considered, particularly for obese women of childbearing age (60% of the population undergoing bariatric surgery), because of the risks to the health of the unborn child in the event of pregnancy occurring early after surgery, even if a 6-month delay is recommended between surgery and the planning of a pregnancy.

While health education is an important lever for limiting daily exposure, identifying a treatment that can reduce the degree of exposure to EEPs is crucial, especially in a population where pregnancy is planned in the short term. Cholestyramine is a bile salt chelating resin used as a lipid-lowering treatment. It has been used off-label in a case of accidental acute contamination by certain POPs, reducing plasma levels without adverse effects, by promoting elimination through interaction with the enterohepatic cycle.

The investigators hypothesize that cholestyramine is capable, outside of acute exposure events, of promoting the elimination and release of POPs in the human population. Given this hypothesis, a treatment administered prior to bariatric surgery could reduce pre-operative plasma levels of POPs and thus, ultimately, minimize the concentrations reached post-operatively, which are dependent on lipolysis-induced release (massive and rapid weight loss) and pre-operative plasma concentrations. To confirm this hypothesis, the investigators propose to evaluate in an exploratory way, on a selected cohort of patients, the effect of pre-operative cholestyramine treatment on serum concentrations of different POPs before and after bariatric surgery.

If the results of this proof-of-concept study are positive, it will be possible to pursue the study of cholestyramine with more powerful and comparative studies, with a view to eventually considering a treatment to reduce the potentially harmful risks of POPs in cases of confirmed pregnancy.

Inclusion criteria

• Female patients with a retained indication for bariatric surgery (BMI > 40 kg/m2 or BMI > 35 kg/m2 with complication(s) amenable to improvement by surgery)
• Aged between 18 and 45
• Using effective contraception (oral contraception, hormonal or non-hormonal intrauterine device, progestin implant), which will be adapted in the perioperative period in accordance with current recommendations (HAS, BARIA-MAT)
• Affiliated to a social security scheme
• Have signed an informed consent form

Exclusion criteria

• Pregnant (urine pregnancy test) or breast-feeding women
• Known allergy or intolerance to cholestyramine
• Chronic constipation
• Chronic pathology likely to interfere with treatment efficacy (unbalanced diabetes characterized by HbA1c > 7%, known and treated dyslipidemia, chronic renal insufficiency with GFR < 60 ml/min, hepatocellular insufficiency)
• Patients receiving anti-vitamin K, digoxin or levothyroxine therapy, or likely to receive such therapy within 3 months of inclusion.
• Phenylketonuria
• Inability to give consent
• Patient under legal protection (guardianship, curatorship, safeguard of justice...)
• Patient deprived of liberty by judicial or administrative decision,
• Patients under psychiatric care which makes it impossible for them to consent to participation, or who are hospitalized under duress.
• Participation in another interventional study (outside the PaCO project).