It is well known that gut microbiota in early life is linked to several immune-related diseases. It has been previously reported that during the first 100 days of life there is a window where microbe-based diagnostics and therapeutics may be useful to prevent the development of asthma in high-risk individuals.
A recent study, led by Prof. Susan Lynch from the Division of Gastroenterology at the Department of Medicine at University of California in San Francisco (California, USA), has found that neonatal gut microbiome dysbiosis may predict later atopy and asthma development in childhood.
By studying stool samples (n=298; aged 1-11 months) through 16S ribosomal ribonucleic acid (rRNA) sequencing from a United States birth cohort, neonates (median age 35 days) were divisible into three microbiota composition states (1: the lowest risk group; 2: the medium risk group, and 3: the highest risk group) representing three different risk groups. Neonatal gut microbiotas exhibited significantly different relative risk (RR) of predominantly multisensitized (PM) atopy development at age 2 years and of parental report of doctor-diagnosed asthma at age 4 years. PM atopy at age 2 years was defined using a statistical algorithm that clusters subjects according to their pattern of serum specific-immunoglobulin E responses to a panel of ten food and aeroallergens. The highest risk group (group 3) showed lower relative abundance of certain bacteria (including Bifidobacterium, Lactobacillus, Akkermansia and Faecalibacterium), higher relative abundance of particular fungi (Candida and Rhodotorula) and a distinct faecal metabolome enriched for pro-inflammatory metabolites, when compared to either of the lower-risk groups (groups 1 and 2). Neonatal gut dysbiosis in the highest risk group was consistent with previously described early-life (3 months of age) gut microbiota taxonomic depletions that increase infants’ risk of asthma. These data suggest that neonatal gut microbiota dysbiosis is characteristic of PM atopy and asthma development in later childhood.
Ex vivo culture of healthy human adult peripheral dendritic cells and autologously purified naïve CD4+ T cells with sterile faecal water from the highest neonatal risk group increased the proportion of CD4+ cells producing interleukin (IL)-4 and expression of IL-4, and reduced the relative abundance of CD4+CD25+FOXP3+ regulatory T (Treg) cells, indicating that the higher risk group’s gut environment promotes adaptive immune dysfunction associated with established atopic asthma. Besides this, a common subset of metabolites differentiated the highest risk group from the lower-risk groups. Specifically, neonates from the highest risk group exhibited faecal enrichment of primary and secondary bile metabolites and were consistently enriched for 12,13-DiHOME, stigma- and sitosterols, 8-hydroxyoctanoate, a-CEHC and g-tocopherol. The 12,13-DiHOME metabolite accounted for the significant reduction of the proportion of CD4+CD25+FOXP3+ cells.
When considering early-life interventions to target the gut microbiome for disease prevention, another study from the same research group emphasized that socioeconomic, environmental and demographic factors should be taken into account. According to a press release, “The researchers hope the findings of these two papers will spur development of tests to detect signs of an unhealthy gut microbiome in infants and to implement early-life interventions to shift microbial ecosystems toward a healthier state”.
In conclusion, these findings suggest that neonatal gut microbiota dysbiosis influences susceptibility to childhood allergic asthma through alterations in CD4+ T cell populations.
Fujimura KE, Sitarik AR, Havstad S, et al. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat Med. 2016. doi: 10.1038/nm.4176.
Levin AM, Sitarik AR, Havstad SL, et al. Joint effects of pregnancy, sociocultural, and environmental factors on early life gut microbiome structure and diversity. Sci Rep. 2016; 6:31775. doi: 10.1038/srep31775.