Effect of inulin on breath hydrogen, postprandial glycemia, gut hormone release, and appetite perception in RYGB patients: a prospective, randomized, cross-over pilot study

Roux-en-Y gastric bypass (RYGB) surgery is highly effective in treating obesity and type 2 diabetes mellitus (T2DM). The gastrointestinal (GI) tract and the secretion of GI peptides play a crucial role in this efficacy, but the involvement of the large intestinal microbiome and its metabolic products remains unclear. Studies have shown that RYGB surgery alters gut microbial composition and metabolic activity, often reducing fecal short-chain fatty acids (SCFAs). SCFAs, such as acetic, propionic, and butyric acid, are produced by colonic fermentation and are believed to contribute to the benefits of a healthy gut microbiome by stimulating the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), which are involved in appetite regulation and glucose homeostasis. However, the reduction in fecal SCFAs post-RYGB seems to contradict this proposed mechanism of action. This is because the majority of SCFAs are absorbed within the colon, and only a small percentage is excreted in feces. Furthermore, in humans with obesity, fecal SCFAs are often elevated. The delay between meal consumption and arrival of food in the large intestine (3-6 hours or more) raises questions about the involvement of SCFAs in the acute regulation of appetite and glycemia. Instead, the 'second-meal effect' is proposed, where fermentable fibers influence glycemic responses in later meals due to prolonged colonic fermentation and SCFA production. The researchers hypothesized that RYGB surgery accelerates the transit of fermentable fiber to the large intestine, leading to faster and more pronounced fermentation, SCFA production, GLP-1 and PYY secretion, and improved meal-related glycemia and appetite. To test this, they conducted a study comparing inulin (a fermentable fiber) and maltodextrin (a non-fermentable control) in RYGB patients before and after surgery, analyzing breath hydrogen (as a fermentation marker), plasma SCFAs, gut hormone secretion, glycemia, and appetite.

The introduction section extensively reviews the literature on RYGB surgery's effects on gut microbiota, SCFAs, and incretin hormones like GLP-1 and PYY. It highlights the conflicting observations regarding changes in fecal SCFA levels post-surgery and discusses the time lag between meal ingestion and colonic fermentation. The concept of the 'second-meal effect' of fermentable fibers is introduced, emphasizing that the impact of colonic fermentation on appetite and glycemia may not be immediately apparent but rather manifest in subsequent meals. The researchers cite studies demonstrating the impact of RYGB on gut microbial composition and metabolic activity, showing reductions in fecal short-chain fatty acids (SCFAs) after surgery. These studies suggest an alteration in the gut microbiome's capacity to metabolize dietary fibers, impacting the production of SCFAs which have implications for metabolic health. The literature review also touches on the role of SCFAs in stimulating GLP-1 and PYY secretion, highlighting their involvement in appetite regulation and glucose control. However, the apparent contradiction between the reduction in fecal SCFAs and the beneficial metabolic effects of RYGB surgery is addressed. This is explained by considering the significant absorption of SCFAs in the colon, leaving only a small portion to be excreted in feces. The review notes conflicting data on fecal SCFA concentrations in obese and lean individuals, and the role of SCFA extraction from the diet as an energy source. The introduction also discusses the time course of colonic fermentation and its influence on the acute and second-meal effects on appetite and glycemia.

This prospective, randomized, crossover pilot study involved eight obese patients (one male, seven female) undergoing RYGB surgery. Participants were assessed pre- and post-operatively (~8 months). On separate days, after an overnight fast, they received 300 ml of orange juice containing either 25 g of inulin or an equicaloric load of 15.5 g maltodextrin (MDX). Blood samples were taken over 5 hours to measure glucose, insulin, GLP-1, and PYY. Breath hydrogen (a marker of intestinal fermentation) was also measured, and appetite was assessed using visual analog scales (VAS). A fixed-portion snack was given at 3 hours postprandially. Plasma SCFAs were measured using ultra-high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS). Statistical analysis included linear mixed models (LMM) to account for the small sample size and repeated measurements. The study was approved by the Cantonal Ethical Committee of Zurich, and all participants provided informed consent.

RYGB surgery significantly reduced BMI, fasting insulin, and fasting blood glucose levels. Postprandially, surgery decreased glucose and insulin increments in response to both inulin and MDX. Surgery also significantly increased postprandial GLP-1 and PYY concentrations in response to both test substances. Inulin accelerated large intestinal fermentation (indicated by breath hydrogen), with a quicker onset post-surgery but a less pronounced magnitude. However, plasma SCFA levels were not affected by inulin, MDX, or surgery. Interestingly, inulin further potentiated the early-phase glucose-lowering and second-meal appetite-suppressing effects of surgery. Post-surgery, there was a strong inverse correlation between early-phase breath hydrogen and second-meal "desire to eat" ratings in response to inulin.

The study demonstrated that RYGB surgery accelerated large intestinal fermentation of inulin, but this did not translate into increased plasma SCFAs or GLP-1/PYY levels. The early-phase glucose-lowering effect of inulin post-surgery might be linked to increased orange juice viscosity, slowing glucose absorption. The study's findings support the notion that accelerated fermentation post-RYGB may contribute to improved appetite control, potentially via mechanisms other than increased plasma GLP-1 and PYY, which warrants further investigation. The lack of a clear relationship between SCFA production and hormonal responses highlights the complexity of gut-brain interactions in regulating appetite and metabolism. The inverse correlation between early-phase breath hydrogen (reflecting rapid fermentation) and late-phase appetite suggests that this rapid fermentation might contribute to improved appetite control via other, yet unidentified, mechanisms. The results emphasize the potential role of prebiotic fibers in post-bariatric dietary management but highlight the need for longer-term studies to fully understand their mechanisms of action.

RYGB surgery accelerates inulin fermentation without affecting plasma SCFAs or GLP-1/PYY. Inulin potentiates surgery's glucose-lowering and appetite-suppressive effects, possibly due to increased viscosity and additional, yet unidentified mechanisms linked to accelerated fermentation. Further research is needed, particularly larger-scale, longer-term studies to confirm these findings and explore the complete mechanisms of action.

The small sample size (n=8) limits the generalizability of the findings. The study only included seven women and one man, which needs to be addressed in future studies with larger cohorts to properly assess sex differences in responses. Plasma samples were collected only up to 5 hours postprandially. Longer sampling duration and longer-term fiber supplementation may be required to capture the full spectrum of the second-meal effect. The absence of other relevant hormone measurements may have hindered a complete understanding of the complete mechanism of action. It also did not analyze other organic acids, potentially leading to an incomplete assessment of SCFA dynamics.