Gastrointestinal Tolerability to Agavins and Impact on Host-gut Microbiota-metabolism Interactions Modulation

Diet has dramatically changed over the past decades with increased consumption of high-fat, high-sugar, high-sodium processed and refined foods, but with low or very low fiber-rich products. Microbiota-accessible carbohydrates (MACs) found for example in dietary fiber have been recognized as crucial for the microbial ecosystem in the gut; the lack of these available carbohydrates depletes the microbial community, causing alterations in its composition and performance. Perturbations in the gut microbiota have been related with several diseases, so as reduction in dietary fiber has been linked with an increased risk for developing chronic diseases, namely cardiovascular and metabolic ones, such as obesity and type 2 diabetes. Mexico is the second country with the highest obesity rates worldwide, which represents a major national public health challenge. Interestingly, national nutrition surveys have found that Mexican adults consume less than half the dietary intake recommendation for fiber, along with an alarming statistic of 7 in 10 adults being overweight or obese.

A change in dietary patterns intended to achieve adequate nutrient intake, dietary fiber included, is one strategy that could help modify this nutrition trend in the country, but another accessible alternative is the supplementation of prebiotic fiber, thus increasing fiber consumption and avoiding gut microbiota alterations simultaneously. Prebiotics, such as fructans, are substrates selectively used by gut microbes, modifying their activity and/or community composition, and conferring health benefits to the host. Clinical research has demonstrated their impact in reducing body weight, fat mass, hyperlipidemia, etc. Agave prebiotics, also known as agavins, are fructan-type carbohydrates that possess a unique molecular structure and are extracted as a complex multi-disperse mixture presenting different degrees of polymerization and/or branching. Previously, agavins have shown to induce weight loss, a significant reduction in glucose and total cholesterol levels, and promotion of satiety-related hormones in overweight mice through the increment in short-chain fatty acids (SCFA) and specific modulation of gut microbiota; more recently, fecal metabolomics have revealed interesting microbial-derived metabolites, detected after agavins supplementation in mouse models that could induce a beneficial effect on host health, but more research is needed.

Experts have stated that differences in dietary fiber structure guide its degradation: which microbes can metabolize these substrates, and the effects in the microbial community that overall, impact health. Additionally, structural differences in prebiotic fibers like agavins, may cause specific gastrointestinal (GI) adaptation and tolerance which is of great importance to promote their consumption and in determining an ideal amount or dose to further explore their impact.

In this study we propose a double-blind, placebo controlled, parallel groups, dose-escalation trial, where lean and obese subjects were assigned to either agavins or placebo group for a 5-week dose-escalation period. We aim to evaluate the evolution of GI tolerability and compared the records between lean and obese participants (Mexican adults), the impact in gut microbiota composition and activity through the determination of short-chain fatty acids and fecal metabolites, and metabolic status, all of this after a short period of time proposed to induce adaptation to agavins intake.

Inclusion criteria

• Males and females
• Age 30 - 60 years
• BMI ≥ 30 kg/m2
• Stable body weight for at least 1 month prior to the study

Exclusion criteria

• Type 1 and type 2 diabetes
• Hypothyroidism
• Currently following a weight loss diet or physical activity regime for the same purpose
• Weight loss >3 kg within 3 months before enrollment
• Use of prebiotics, probiotics, or dietary fiber supplements
• Long-term (and within the preceding month) use of antioxidants, omega-3, and omega-6 fatty acids supplements
• Strenuous exercise (>3 hours/week)
• Concomitant use of any medication influencing appetite, weight, metabolism
• Use of metformin
• Antibiotic use 1 week prior to the study
• Alcohol or substance abuse
• Diagnosis of neurological or psychiatric disorders, like anxiety, depression, Attention-Deficit/Hyperactivity Disorder (ADHD), schizophrenia
• Active smoker
• Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) enzymes concentration >2.5 times the highest limit value
• Creatinine >1.2 mg/dL
• Women: pregnancy or lactation
• Previous intestinal or bariatric surgery
• Heart, brain, or thyroid surgeries within the preceding 6 months
• History of liver or pancreatic disease
• History of renal failure
• Intestinal absorption disorder
• Inflammatory bowel disease
• Established cardiovascular disease
• Active or history of neoplasia within the preceding 5 years
• Chronic use of bulk laxatives and antacids