Fungal and bacterial commensal organisms play a complex role in the health of the human host. Expansion of commensal ecology after birth is a critical period in human immune development. However, the initial fungal colonization of the primordial gut remains undescribed. To investigate primordial fungal ecology, we performed amplicon sequencing and culture‐based techniques of first‐pass meconium, which forms in the intestine prior to birth, from a prospective observational cohort of term and preterm newborns. Here, we describe fungal ecologies in the primordial gut that develop complexity with advancing gestational age at birth. Our findings suggest homeostasis of fungal commensals may represent an important aspect of human biology present even before birth. Unlike bacterial communities that gradually develop complexity, the domination of the fungal communities of some preterm infants by Saccromycetes, specifically Candida, may suggest a pathologic association with preterm birth.—Willis, K. A., Purvis, J. H., Myers, E. D., Aziz, M. M., Karabayir, I., Gomes, C. K., Peters, B. M., Akbilgic, O., Talati, A. J., Pierre, J. F. Fungi form interkingdom microbial communities in the primordial human gut that develop with gestational age. FASEB J. 33, 12825–12837 (2019). http://www.fasebj.org

25Fungal and bacterial commensal organisms play a complex role in the health of the human host. 26Expansion of commensal ecology after birth is a critical period in human immune development. 27However, the initial fungal colonization of the primordial gut remains undescribed. To investigate 28 primordial fungal ecology, we performed amplicon sequencing and culture-based techniques of first-29 pass meconium, which forms in the fetal intestine prior to birth, from a prospective observational 30 cohort of term-born and preterm newborns. Here, we describe fungal ecologies in the primordial gut 31 that develop complexity with advancing gestational age at birth. Our findings suggest homeostasis of 32 fungal commensals may represent an important aspect of human biology present even before birth. 33Unlike bacterial communities which gradually develop complexity, the domination of the fungal 34 communities of some preterm infants by Saccromycetes, specifically Candida, may suggest a 35 pathologic association with preterm birth.36 37 38 39 42 colonize our barrier surfaces, such as the intestinal tract. The human gut microbiome is host to a 43 complex interkingdom ecology of bacteria, fungi, archaea, protozoa and viruses. While recent 44 research has led to a drastic expansion in our understanding of bacterial communities in the gut 1-4 , 45 little is known about the role of fungal organisms, collectively the mycobiome, particularly in relation to 46 their impact on the population dynamics of early-life colonization. 47 48 The tightly choreographed maturation of commensal microbial communities is crucial to mammalian 49 immune development 5 . Fungal organisms can form a crucial nidus for initial colonization 6 and may 50 play a vital role in facilitating early colonization of the neonatal gut. Disruption of this process could 51 produce pathogenic fungal overgrowth or invasive disease. Indeed, this mechanism may play a role in 52 the development of asthma and other metabolic and immunological diseases 7 . The intestinal 53 mycobiota likely confers unique physiologic effects to the host, in part by processing nutrients and 54 vitamins either separately or in conjunction with the microbiome. However, characterization of the 55 functional impact of early mycobiome is impaired by limited knowledge of the normal development of 56 these communities. To understand the functional impact of the early-life mycobiome on human health, 57 it is necessary to determine if the human primordial gut hosts fungal communities, if these 58 communities are established before or after birth and if the presence of fungi in the early gut impacts 59 neonatal physiology. 61Advances in next-generation sequencing techniques have pushed back the timing of initial 62 commensal colonization 3 which was initially thought to occur at birth 8,9 . Despite these advances, 63 interkingdom interactions within microbial communities and the influence of environmental factors on 64 the dynamics of microbial ecosystems remains poorly understood. Due to delayed prog...

Rationale: Bronchopulmonary dysplasia (BPD) is the most common morbidity affecting very preterm infants. Gut microbial communities contribute to multiple lung diseases, and alterations of the gut microbiome may be a factor in BPD pathogenesis. Objective: To determine if features of the multikingdom gut microbiome predict the development of BPD in very low birthweight newborns. Methods: We performed a prospective, observational cohort study comparing the multikingdom fecal microbiota of 147 very low birthweight infants with BPD or post-prematurity respiratory disease (PPRD) by sequencing bacterial 16S and fungal ITS2 ribosomal RNA. To address the potential causative relationship between gut dysbiosis and BPD, we used fecal microbiota transplant in an antibiotic-pseudohumanized mouse model. Comparisons were made using RNA sequencing, quantitative confocal microscopy, lung morphometry, and oscillometry. Measurements and Main Results: We analyzed 100 fecal microbiome samples collected during the second week of life. Infants who later developed BPD showed an obvious fungal dysbiosis as compared to infants with PPRD (P = 0.0209). Instead of fungal communities dominated by Candida and Saccharomyces, the microbiota of infants who developed BPD were characterized by the abundance of Aureobasidium and a greater diversity of rarer fungi in less interconnected community architectures. On successful colonization, the gut microbiota from infants with BPD augmented lung injury in the offspring of recipient animals. We identified alterations in the murine lung and intestinal microbiomes and transcriptional alterations associated with augmented lung injury. Conclusions: The gut fungal microbiome of infants who will develop BPD is dysbiotic and may contribute to disease pathogenesis.

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