# Human milk oligosaccharides promote synaptogenesis and neurite outgrowth in human cortical organoids **Authors:** Luisa Bulcão V.C, Natalia C.S. Moreira, Paulo C. Carvalho, Isabelle S. Luz, Juliana de S. da G. Fischer, Blake L. Tsu, Kristija Sejane, Celina Savo, Aline M.A. Martins, Lars Bode, Alysson R. Muotri PMC · DOI: 10.1016/j.bbrep.2026.102529 · Biochemistry and Biophysics Reports · 2026-02-28 ## TL;DR Human milk oligosaccharides boost brain development in lab-grown human brain models by enhancing nerve connections and growth. ## Contribution This study reveals a direct role of HMOs in promoting synaptogenesis and neurite outgrowth in human cortical organoids. ## Key findings - HMO treatment significantly enhanced neurite outgrowth and synaptogenesis in a dose-dependent manner. - Proteomic profiling showed upregulation of proteins linked to neuronal differentiation and synaptic maturation. - HMOs upregulate RNA splicing pathways in cortical organoids. ## Abstract The first 1000 days of a child's life represent a critical window for brain development, during which nutrition exerts profound effects on the trajectories of neurodevelopment. Human Milk Oligosaccharides (HMOs), a major component of human milk, are largely indigestible by infants and are known to influence immunity, microbiome composition, and gut-brain signaling, but their direct role in neurodevelopment remains poorly understood. Here, we investigated the impact of HMOs on human cortical organoids, a physiologically relevant in vitro model of early brain development. We found that HMO treatment significantly enhanced neurite outgrowth and synaptogenesis in a dose-dependent manner. Global proteomic profiling further demonstrated the upregulation of proteins associated with neuronal differentiation, synaptic maturation, and cytoskeletal remodeling. Our findings suggest that HMOs can influence neurodevelopmental processes and highlight a potential role for maternal milk components in early brain development. Image 1 •Human milk oligosaccharides (HMOs) modulate synaptic density in human cortical organoids.•HMOs influence neural connectivity during early development.•Genetic background shapes HMO-mediated effects.•HMOs upregulate RNA splicing pathways in cortical organoids. Human milk oligosaccharides (HMOs) modulate synaptic density in human cortical organoids. HMOs influence neural connectivity during early development. Genetic background shapes HMO-mediated effects. HMOs upregulate RNA splicing pathways in cortical organoids. ## Linked entities - **Species:** Homo sapiens (taxon 9606) ## Full-text entities - **Genes:** Ptbp1 (polypyrimidine tract binding protein 1) [NCBI Gene 19205] {aka HNRPI, PTB-1, PTB2, PTB3, PTB4, Ptb}, PKD1 (polycystin 1, transient receptor potential channel interacting) [NCBI Gene 5310] {aka PBP, PC1, Pc-1, TRPP1, eliosin}, HPRT1 (hypoxanthine phosphoribosyltransferase 1) [NCBI Gene 3251] {aka HGPRT, HPRT}, Nr2e1 (nuclear receptor subfamily 2, group E, member 1) [NCBI Gene 21907] {aka Mtl1, Mtll, TLL, Tlx, XTLL, fierce}, NGF (nerve growth factor) [NCBI Gene 4803] {aka Beta-NGF, HSAN5, NGFB}, MAP6 (microtubule associated protein 6) [NCBI Gene 4135] {aka MAP6-N, MTAP6, N-STOP, STOP}, VIM (vimentin) [NCBI Gene 7431], NT-3 [NCBI Gene 4877], EFNB3 (ephrin B3) [NCBI Gene 1949] {aka EFL6, EPLG8, LERK8}, SOX2 (SRY-box transcription factor 2) [NCBI Gene 6657] {aka ANOP3, MCOPS3}, HNRNPL (heterogeneous nuclear ribonucleoprotein L) [NCBI Gene 3191] {aka HNRPL, P/OKcl.14, hnRNP-L}, SYNCRIP (synaptotagmin binding cytoplasmic RNA interacting protein) [NCBI Gene 10492] {aka GRY-RBP, GRYRBP, HNRNPQ, HNRPQ1, NSAP1, PP68}, PAX6 (paired box 6) [NCBI Gene 286857] {aka pax-6}, HOMER1 (homer scaffold protein 1) [NCBI Gene 9456] {aka HOMER, HOMER1A, HOMER1B, HOMER1C, SYN47, Ves-1}, C1QBP (complement C1q binding protein) [NCBI Gene 708] {aka COXPD33, GC1QBP, HABP1, SF2AP32, SF2p32, gC1Q-R}, FOXG1 (forkhead box G1) [NCBI Gene 2290] {aka BF1, BF2, FHKL3, FKH2, FKHL1, FKHL2}, EFNB1 (ephrin B1) [NCBI Gene 1947] {aka CFND, CFNS, EFB1, EFL3, EPLG2, Elk-L}, PTBP1 (polypyrimidine tract binding protein 1) [NCBI Gene 5725] {aka HNRNP-I, HNRNPI, HNRPI, PTB, PTB-1, PTB-T}, EGF (epidermal growth factor) [NCBI Gene 1950] {aka HOMG4, URG}, GDNF (glial cell derived neurotrophic factor) [NCBI Gene 2668] {aka ATF, ATF1, ATF2, HFB1-GDNF, HSCR3}, LSM3 (LSM3 homolog, U6 small nuclear RNA and mRNA degradation associated) [NCBI Gene 27258] {aka SMX4, USS2, YLR438C}, APOE (apolipoprotein E) [NCBI Gene 348] {aka AD2, APO-E, ApoE4, LDLCQ5, LPG}, PAX6 (paired box 6) [NCBI Gene 5080] {aka AN, AN1, AN2, ASGD5, D11S812E, FVH1}, ENO2 (enolase 2) [NCBI Gene 2026] {aka HEL-S-279, NSE}, FLNA (filamin A) [NCBI Gene 2316] {aka ABP-280, ABPX, CSBS, CVD1, FGS2, FLN}, NOVA1 (NOVA alternative splicing regulator 1) [NCBI Gene 4857] {aka Nova-1}, IQGAP1 (IQ motif containing GTPase activating protein 1) [NCBI Gene 8826] {aka HUMORFA01, SAR1, p195}, VGF (VGF nerve growth factor inducible) [NCBI Gene 7425] {aka SCG7, SgVII}, BDNF (brain derived neurotrophic factor) [NCBI Gene 627] {aka ANON2, BULN2}, FGF2 (fibroblast growth factor 2) [NCBI Gene 2247] {aka BFGF, FGF-2, FGFB, HBGF-2}, NTF3 (neurotrophin 3) [NCBI Gene 4908] {aka HDNF, NGF-2, NGF2, NT-3, NT3}, GFAP (glial fibrillary acidic protein) [NCBI Gene 2670] {aka ALXDRD}, SOX2 (SRY-box transcription factor 2) [NCBI Gene 784383], NR2E1 (nuclear receptor subfamily 2 group E member 1) [NCBI Gene 7101] {aka TLL, TLX, XTLL}, Hspa8 (heat shock protein family A (Hsp70) member 8) [NCBI Gene 15481] {aka 2410008N15Rik, Hsc70, Hsc71, Hsc73, Hsp73, Hspa10}, TENM2 (teneurin transmembrane protein 2) [NCBI Gene 57451] {aka ODZ2, TEN-M2, TEN2, TNM2, ten-2}, HNRNPK (heterogeneous nuclear ribonucleoprotein K) [NCBI Gene 3190] {aka AUKS, CSBP, HNRPK, TUNP}, NFASC (neurofascin) [NCBI Gene 23114] {aka NEDCPMD, NF, NRCAML}, SLC17A7 (solute carrier family 17 member 7) [NCBI Gene 57030] {aka BNPI, VGLUT1}, IVNS1ABP (influenza virus NS1A binding protein) [NCBI Gene 10625] {aka ARA3, FLARA3, HSPC068, IMD70, KLHL39, ND1}, TUBB2B (tubulin beta 2B class IIb) [NCBI Gene 347733] {aka CDCBM7, PMGYSA, bA506K6.1}, GAP43 (growth associated protein 43) [NCBI Gene 2596] {aka B-50, GAP-43, PP46}, MAP2 (microtubule associated protein 2) [NCBI Gene 281294], ALB (albumin) [NCBI Gene 280717], VCL (vinculin) [NCBI Gene 7414] {aka CMD1W, CMH15, HEL114, MV, MVCL, VINC}, MAP2 (microtubule associated protein 2) [NCBI Gene 4133] {aka MAP-2, MAP2A, MAP2B, MAP2C}, CADPS (calcium dependent secretion activator) [NCBI Gene 8618] {aka CADPS1, CAPS, CAPS1, UNC-31}, SLIT2 (slit guidance ligand 2) [NCBI Gene 9353] {aka SLIL3, Slit-2}, LOC101905308 (uncharacterized LOC101905308) [NCBI Gene 101905308], IGF2BP1 (insulin like growth factor 2 mRNA binding protein 1) [NCBI Gene 10642] {aka CRD-BP, CRDBP, IMP-1, IMP1, VICKZ1, ZBP1}, Napb (N-ethylmaleimide sensitive fusion protein attachment protein beta) [NCBI Gene 17957] {aka Brp14, E161, I47, SNARE, b-SNAP}, ATP1A3 (ATPase Na+/K+ transporting subunit alpha 3) [NCBI Gene 478] {aka AHC2, CAPOS, DEE99, DYT12, RDP}, HNRNPM (heterogeneous nuclear ribonucleoprotein M) [NCBI Gene 4670] {aka CEAR, HNRNPM4, HNRPM, HNRPM4, HTGR1, NAGR1}, Srsf1 (serine and arginine-rich splicing factor 1) [NCBI Gene 110809] {aka 1110054N12Rik, 5730507C05Rik, 6330415C05Rik, Asf, Sf2, Sfrs1}, RMDN2 (regulator of microtubule dynamics 2) [NCBI Gene 151393] {aka BLOCK18, FAM82A, FAM82A1, PRO34163, PYST9371, RMD-2}, Rbm39 (RNA binding motif protein 39) [NCBI Gene 170791] {aka 1500012C14Rik, 2310040E03Rik, B330012G18Rik, Rnpc2, caper} - **Diseases:** HMOs (MESH:D016269), autism (MESH:D001321), inflammatory diseases (MESH:D007249), neurological disorders (MESH:D009461), NPC (MESH:D052556), deficits in attention, memory (MESH:D001289), impaired cognitive functions (MESH:D003072) - **Chemicals:** N2 (MESH:D009584), Lactose (MESH:D007785), DPBS (MESH:C012939), Dorsomorphin (MESH:C516138), Streptomycin (MESH:D013307), sialic acid (MESH:D019158), acetonitrile (MESH:C032159), Triton X-100 (MESH:D017830), methionine (MESH:D008715), FA (MESH:C030544), sugars (MESH:D000073893), salts (MESH:D012492), l-ascorbic acid (MESH:D001205), GlutaMAX (MESH:C054122), Ethanol (MESH:D000431), E (MESH:D004540), water (MESH:D014867), Peptides (MESH:D010455), urea (MESH:D014508), sialyllactose (MESH:C000020), carbohydrate (MESH:D002241), chloroacetamide (MESH:C013874), S (MESH:D013455), BioRender (-), Penicillin (MESH:D010406), Oligosaccharides (MESH:D009844), PBS (MESH:D007854), calcium (MESH:D002118), dibutyryl-cAMP (MESH:D003994), BCA (MESH:C047117), DIA (MESH:C076868), TEAB (MESH:C041737), SB431542 (MESH:C459179), 6'-sialyllactose (MESH:C403777), LPS (MESH:D008070), paraformaldehyde (MESH:C003043), cysteine (MESH:D003545), lipid (MESH:D008055), sucrose (MESH:D013395) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], gut metagenome (species) [taxon 749906], Bos taurus (bovine, species) [taxon 9913] - **Mutations:** V511A - **Cell lines:** WT83 — Homo sapiens (Human), Glioblastoma, Cancer cell line (CVCL_C6IZ), KOLF — Homo sapiens (Human), Induced pluripotent stem cell (CVCL_AE29) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12966747/full.md ## Figures 6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12966747/full.md ## References 81 references — full list in the complete paper: https://tomesphere.com/paper/PMC12966747/full.md --- Source: https://tomesphere.com/paper/PMC12966747