A human milk oligosaccharide alters the microbiome, circulating hormones, and metabolites in a randomized controlled trial of older adults

Matthew M Carter; Diane Demis; Dalia Perelman; Michelle St Onge; Christina Petlura; Kristen Cunanan; Kavita Mathi; Holden T Maecker; Jo May Chow; Jennifer L Robinson; Anice Sabag-Daigle; Erica D Sonnenburg; Rachael H Buck; Christopher D Gardner; Justin L Sonnenburg

doi:10.1016/j.xcrm.2025.102256

A human milk oligosaccharide alters the microbiome, circulating hormones, and metabolites in a randomized controlled trial of older adults

Cell Rep Med. 2025 Aug 19;6(8):102256. doi: 10.1016/j.xcrm.2025.102256. Epub 2025 Jul 29.

Authors

Affiliations

¹ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
² Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA.
³ Quantitative Sciences Unit, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Human Immune Monitoring Center, Stanford University, School of Medicine, Stanford, CA 94304, USA.
⁵ Abbott Nutrition, 3300 Stelzer Road, Columbus, OH 43219, USA.
⁶ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA; Center for Human Microbiome Studies, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: cgardner@stanford.edu.
⁸ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA; Center for Human Microbiome Studies, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: jsonnenburg@stanford.edu.

Abstract

Aging-related immune dysfunction is linked to cancer, atherosclerosis, and neurodegenerative diseases. This 6-week randomized controlled trial evaluated whether 2'-fucosyllactose (2'-FL), a human breast milk oligosaccharide with established benefits in infants and animal models, could improve gut microbiota and immune function in 89 healthy older adults (mean age 67.3 years). While the primary endpoint of cytokine response change was not met, 2'-FL supplementation increased gut Bifidobacterium levels and elevated serum insulin, high-density lipoprotein (HDL) cholesterol, and FGF21 hormone. Bifidobacterium "responders" experienced additional metabolic and proteomic changes and also performed better on a cognitive test of visual memory. Nonresponders were more likely to lack Bifidobacterium in their gut microbiota at the start of the intervention. Multi-omics analysis indicated a systemic response to 2'-FL, which could be detected in blood and urine, showcasing the potential of this prebiotic to provide diverse benefits for healthy aging. This trial was registered at ClinicalTrials.gov (NCT03690999).

Keywords: 2'-fucosyllactose; Bifidobacterium; Human milk oligosaccharide; aging; metabolomics; prebiotics.

Publication types

Randomized Controlled Trial

MeSH terms

Aged
Female
Gastrointestinal Microbiome* / drug effects
Hormones* / blood
Humans
Male
Middle Aged
Milk, Human* / chemistry
Oligosaccharides* / pharmacology
Prebiotics
Trisaccharides* / pharmacology

Substances

Oligosaccharides
2'-fucosyllactose
Hormones
Prebiotics
Trisaccharides

Associated data

ClinicalTrials.gov/NCT03690999