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

Abstract

Despite explosive rise in allergies, little is known about early life gut microbiota effects on postnatal respiratory function. We hypothesized that Enterobacteriaceae-dominant gut microbiota from eczemic infants increases Type 2 inflammation and decreases lung function in transplanted mice, while Bacteroidaceae-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 (^HUmicrobiota) were significantly impaired compared to Mouse microbiota controls (^MOmicrobiota) with or without HDM; respiratory system resistance (Rrs) was increased (P < 0.05-P < 0.01), and respiratory system compliance (Crs) was decreased (P < 0.05-P < 0.01). ^HUMicrobiota mice showed a statistically significant impairment compared to ^MOmicrobiota 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 (P < 0.05) in mice of all microbiotas, yet each ^HUmicrobiota produced distinct features. Infant B and Adult C mice had elevated basal levels of total IgE compared to ^MOmicrobiota and Infant A mice (P < 0.05). In ^HUmicrobiota mice given HDM, only Adult C had elevated IL-5 and IL-13 (P < 0.05), only Adult C and Infant B mice had elevated neutrophils (P < 0.05), and only Infant A had elevated lymphocytes (P < 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 ^HUmicrobiotas compared to ^MOmicrobiota controls, while taxa formerly described to reduce allergic responses (antagonists) and anti-inflammatory taxa were numerous in ^MOmicrobiotas and low in ^HUmicrobiotas. 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 ^HUmicrobiotas played a key role in determining varied allergic responses and resulting lung impairment, yet, strikingly, all mice with ^HUmicrobiotas 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.