Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation

• Published in: Nature medicine Vol. 22; no. 10; pp. 1187 - 1191
• Main Authors: Fujimura, Kei E, Sitarik, Alexandra R, Havstad, Suzanne, Lin, Din L, Levan, Sophia, Fadrosh, Douglas, Panzer, Ariane R, LaMere, Brandon, Rackaityte, Elze, Lukacs, Nicholas W, Wegienka, Ganesa, Boushey, Homer A, Ownby, Dennis R, Zoratti, Edward M, Levin, Albert M, Johnson, Christine C, Lynch, Susan V
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2016; Nature Publishing Group
• Subjects: 101/58; 13/106; 13/31; 38/23; 38/77; 692/698/2741/2135; 692/699/249/2510/31; Abundance; Age; Asthma; Asthma - epidemiology; Asthma - immunology; Atopy; Bifidobacterium - genetics; Biomedicine; Cancer Research; Candida - genetics; CD25 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell culture; Cell differentiation; Cell Differentiation - immunology; Child, Preschool; Childhood; Childhood asthma; Children; Differentiation (biology); Dysbacteriosis; Faecalibacterium - genetics; Feces; Feces - chemistry; Female; Forkhead Transcription Factors - metabolism; Foxp3 protein; Fungi; Gastrointestinal Microbiome - genetics; Gastrointestinal Microbiome - immunology; Humans; Hypersensitivity - epidemiology; Hypersensitivity - immunology; Infant; Infant, Newborn; Infectious Diseases; Inflammation; Interleukin-2 Receptor alpha Subunit - metabolism; Interleukin-4 - immunology; Interleukins; Intestinal microflora; letter; Lymphocytes; Lymphocytes T; Male; Metabolic Diseases; Metabolites; Microbiomes; Microbiota; Microbiota (Symbiotic organisms); Molecular Medicine; Neonates; Neurosciences; Odds Ratio; Relative abundance; Rhodotorula - genetics; Risk; RNA, Ribosomal, 16S - genetics; rRNA 16S; Sequence Analysis, RNA; T-Lymphocytes - immunology
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4176

Differences in the composition of the gut microbiota of infants associate with relative risk of atopy in childhood, and metabolites linked with these distinct microbial states alter T cell differentiation ex vivo . Gut microbiota bacterial depletions and altered metabolic activity at 3 months are implicated in childhood atopy and asthma 1 . We hypothesized that compositionally distinct human neonatal gut microbiota (NGM) exist, and are differentially related to relative risk (RR) of childhood atopy and asthma. Using stool samples ( n = 298; aged 1–11 months) from a US birth cohort and 16S rRNA sequencing, neonates (median age, 35 d) were divisible into three microbiota composition states (NGM1–3). Each incurred a substantially different RR for multisensitized atopy at age 2 years and doctor-diagnosed asthma at age 4 years. The highest risk group, labeled NGM3, showed lower relative abundance of certain bacteria (for example, Bifidobacterium, Akkermansia and Faecalibacterium) , higher relative abundance of particular fungi ( Candida and Rhodotorula ) and a distinct fecal metabolome enriched for pro-inflammatory metabolites. Ex vivo culture of human adult peripheral T cells with sterile fecal water from NGM3 subjects increased the proportion of CD4 + cells producing interleukin (IL)-4 and reduced the relative abundance of CD4 + CD25 + FOXP3 + cells. 12,13-DiHOME, enriched in NGM3 versus lower-risk NGM states, recapitulated the effect of NGM3 fecal water on relative CD4 + CD25 + FOXP3 + cell abundance. These findings suggest that neonatal gut microbiome dysbiosis might promote CD4 + T cell dysfunction associated with childhood atopy.