The Impact of Low-Lactose, High Galacto-Oligosaccharides Milk on Gut Microbiome and Plasma Metabolome in Healthy Adults: A Randomized, Double-Blind, Controlled Clinical Trial Complemented by Ex Vivo Experiments

Abstract

Background

Galacto-oligosaccharides (GOS) intake has been linked to health benefits via modulation of the gut microbiome. Milk, where the majority of lactose is enzymatically converted to GOS (called here Novel or “N milk”), retains milk’s nutritional value with reduced lactose and a high amount of prebiotic GOS.

Objectives

The aim of this study was to investigate the effect of N milk on the gut microbiome and related changes in health-related biomarkers, complemented by ex vivo fermentation experiments.

Methods

In a 2-arm crossover, double-blind, randomized controlled clinical trial, 26 healthy adults consumed either N milk (containing 9 g GOS and 1.7 g of lactose per serving) or lactose-free milk (control), for 2 wk with a 2-wk washout period. Stool and fasting blood samples were collected at the start and the end of the intervention periods. Gut microbiome was analyzed using shotgun metagenomics, and metabolites using both targeted and untargeted methods. In addition, we tested lactose-free milk, N milk, and GOS in ex vivo colonic fermentation to obtain insights into the bacterial processing of substrates.

Results

N milk intake led to a 3-fold increase in median gut bifidobacteria (P < 0.0001) and significant increases in plasma acetate, octanoic acid, β-alanine, and nicotinamide (all P < 0.05). Untargeted plasma metabolomics revealed a shift in amino acid metabolism, with an increase in 3-indole propionate, accompanied by a decrease in 2 uremic toxins, p-cresol sulfate, and indoxyl-sulfate (P < 0.05 without false discovery rate adjustment). Ex vivo fermentation experiments supported the results of the clinical study, whereby N milk increased bifidobacteria accompanied by higher production of short-chain fatty acids and a shift in microbial tryptophan metabolism, and indicated unique effects of N milk compared with GOS.

Conclusions

N milk resulted in a significant increase in gut bifidobacteria, along with changes in plasma metabolites previously associated with immune and metabolic health benefits.

This study was registered at clinicaltrials.gov as NCT05207839.