Yeast protein modulates metabolites derived from the human gut microbiota of older male adults ex vivo to strengthen gut barrier function and reduce inflammation

Introduction The rising global demand for protein is accelerating interest in sustainable alternatives with health benefits. While glycans are well-known for supporting gut health, the role of dietary proteins in promoting healthy aging via microbiome modulation is less understood. Yeast protein (YP) represents a sustainable, non-animal, hypoallergenic option. Methods Using the clinically predictive ex vivo SIFR ® technology (Systemic Intestinal Fermentation Research), we examined how YP influences the microbiome of older human adults (50–65 years, n = 6), comparing its effects to whey protein isolate (WPI) and soy protein isolate (SPI). Results At a dose equivalent to 40 g/day, all protein sources supported gut barrier integrity and reduced inflammation, reflected by decreased pro-inflammatory markers and increased IL-10. These benefits were linked to higher short-chain fatty acid (SCFA) production, mainly from Bacillota and Bacteroidota, including microbial markers associated with healthy aging. YP and SPI specifically restored butyrate-producing microbes and increased microbial diversity, which is linked to longevity. Untargeted metabolomics revealed numerous beneficial amino acid-derived metabolites, including indoles and polyamines, known to act through gut-organ axes to extend health span. Despite similar overall profiles, product-specific differences emerged: YP most strongly reinforced barrier integrity, produced the lowest gas levels (suggesting superior tolerability), and yielded the lowest trimethylamine N -oxide, a compound linked to increased mortality in older adults. Discussion Collectively, these findings highlight the potential of YP as a sustainable protein source that modulates the microbiome and metabolome, reduces inflammation, and reinforces gut barrier function, which are key mechanisms for preserving health span and mitigating age-related decline.