Effects of Human Lactoferrin (effera ® ) at Two Doses versus Bovine Lactoferrin on the Adult Gut Microbiome and Fecal Short-Chain Fatty Acids: A Randomized, Double-Blind Trial

Abstract Background/Objectives Human lactoferrin (hLF) is glycoprotein of commercial interest as a food ingredient for gut health. Here, we report an exploratory analysis evaluating the effects of Helaina hLF (effera ® ), produced by Komagataella phaffii , on the adult gut microbiome and fecal metabolites in comparison to bovine LF (bLF). Methods In a randomized, double-blind, parallel-arm, controlled trial, 66 healthy adults received either high-dose (HD) effera ® (3.4 g/day), low-dose (LD) effera ® (0.34 g/day), or bLF (3.4 g/day) supplementation for 28 days. Fecal samples were collected at baseline (Day 0), Day 28, Day 56, and Day 84 and analyzed for microbial diversity, taxonomic shifts, and volatile fatty acids (VFA). Results Alpha-diversity remained stable across all groups. Beta-diversity showed no main effect of treatment; however, bLF was associated with significant visit-related shifts, as assessed by weighted UniFrac. At the phylum level, significant changes associated with effera ® were observed, including decreases in Bacillota (LD) and Verrucomicrobiota (HD), and notable genera increases in Lachnospira , Paraprevotella , and Faecalibacterium (HD), while bLF was associated with an increase in Roseburia . Both effera ® and bLF were associated with decreases in Blautia and Dorea . VFA analysis revealed that bLF increased absolute total short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs) concentrations, while both effera ® groups produced proportional changes in SCFAs, individual BCFAs, and acetate. Conclusions In healthy adults, effera ® supplementation promoted a proportional increase in acetate and supported potentially beneficial taxa while maintaining microbial diversity, without disrupting community structure. (clinicaltrials.gov: NCT06012669 ).