Fecal microbiota transplants (FMT) of three distinct human communities to germ-free mice exacerbated inflammation and decreased lung function in their offspring.

Unlabelled: Despite explosive rise in allergies, little is known about early life gut microbiota effects on postnatal respiratory function. We hypothesized that -dominant gut microbiota from eczemic infants increases Type 2 inflammation and decreases lung function in transplanted mice, while -dominant gut microbiota from non-eczemic infants is protective. Fecal microbiota transplants (FMT) from eczemic infants "Infant A" and non-eczemic infants "Infant B" were successfully transplanted into germ-free C57BL/6 mice, passing to offspring unchanged. Infant A and B, Adult C-human-derived (positive control), and Mouse (negative control) microbiotas all in C57BL/6 mice were tested for effects on airway function in nonallergic (phosphate-buffered saline [PBS]) and allergic (house dust mite [HDM]) conditions. Baseline lung mechanics in mice with human microbiotas (microbiota) were significantly impaired compared to Mouse microbiota controls (microbiota) with or without HDM; respiratory system resistance (Rrs) was increased ( < 0.05- < 0.01), and respiratory system compliance (Crs) was decreased ( < 0.05- < 0.01). Microbiota mice showed a statistically significant impairment compared to microbiota mice in lung parameters Rrs, Ers, Rn, and G at baseline, and at multiple methacholine (MCh) doses with baseline removed. Impairment manifested as increased small airway resistance and tissue resistance. HDM significantly elevated IL-4, eosinophils, lung inflammation, and mucus cell metaplasia, and decreased macrophages and lung function ( < 0.05) in mice of all microbiotas, yet each microbiota produced distinct features. Infant B and Adult C mice had elevated basal levels of total IgE compared to microbiota and Infant A mice ( < 0.05). In microbiota mice given HDM, only Adult C had elevated IL-5 and IL-13 ( < 0.05), only Adult C and Infant B mice had elevated neutrophils ( < 0.05), and only Infant A had elevated lymphocytes ( < 0.01).

Importance: Fecal microbiota transplants (FMT) of three distinct human communities to germ-free mice exacerbated inflammation and decreased lung function in their offspring. Taxa formerly described to induce an allergic response (agonists) and pro-inflammatory taxa were abundant in microbiotas compared to microbiota controls, while taxa formerly described to reduce allergic responses (antagonists) and anti-inflammatory taxa were numerous in microbiotas and low in microbiotas. Thus, we largely rejected our hypotheses because data supported multiple pro-inflammatory allergy agonists functioning in a community-wide fashion to impair lung function in the absence of antagonistic anti-inflammatory taxa. Structure of microbiotas played a key role in determining varied allergic responses and resulting lung impairment, yet, strikingly, all mice with microbiotas had impaired lung function even in the absence of allergens. Using a comparative approach, we showed that composition of gut microbiota can alter innate/immune regulation in the gut-lung axis to increase baseline lung function responses and the risk of allergic sensitization.