Probiotics to improve the gut microbiome in premature infants: are we there yet?

Abstract

Gut microbiome maturation in infants born prematurely is uniquely influenced by the physiological, clinical, and environmental factors surrounding preterm birth and early life, leading to altered patterns of microbial succession relative to term infants during the first months of life. These differences in microbiome composition are implicated in acute clinical conditions that disproportionately affect preterm infants, including necrotizing enterocolitis (NEC) and late-onset sepsis (LOS). Probiotic supplementation initiated early in life is an effective prophylactic measure for preventing NEC, LOS, and other clinical concerns relevant to preterm infants. In parallel, reported benefits of probiotics on the preterm gut microbiome, metabolome, and immune function are beginning to emerge. This review summarizes the current literature on the influence of probiotics on the gut microbiome of preterm infants, outlines potential mechanisms by which these effects are exerted, and highlights important clinical considerations for determining the best practices for probiotic use in premature infants.

Keywords: Gut microbiome; early life; microbial succession; microbiome maturation; neonatal intensive care; prematurity; preterm infants; probiotic.

Figure 1.

Differences in gastrointestinal physiology, bacterial microbiome maturation patterns, and key early life factors contributing to establishment of the gut microbiome in infants born prematurely versus at term. The gut microbiome of infants born prematurely displays unique maturation patterns in the first weeks to months of life relative to term-born infants due to differences in the maturity of the gastrointestinal tract and early-life exposures. With prematurity, the gastrointestinal tract is markedly underdeveloped at birth, resulting in broad structural and functional delays that may contribute to microbial colonization patterns. This includes immaturity of the intestinal epithelium, under-expression of tight junction proteins, and a lack of mature goblet cells leading to a patchy mucus layer, among other factors – all of which influence intestinal barrier function and reduce resistance to pathogen colonization. Simultaneously, the immune system of premature infants displays immaturities, including fewer mature immune cells surveying the gut, reduced secretory IgA expression, and higher levels of pro-inflammatory cytokines and the inflammatory marker, calprotectin, both giving rise to and reflecting potentially maladaptive responses to microbial antigens that typically guide the development of homeostatic immune responses in term infants. Together with the influence of factors such as gestational age at birth, prolonged hospitalization, increased antibiotic exposure, and delayed enteral feeds, the gut microbiome of preterm infants is colonized by a higher proportion of aerobic and facultative anaerobic bacteria in the first weeks of life and displays lower alpha-diversity. This leads to aberrant successional patterns characterized by Staphylococcaceae, Enterococcaceae, and Enterobacteriaceae dominance prior to achieving communities abundant in Bifidobacteriaceae around 40 weeks postmenstrual age (PMA) or term-equivalent age. The delayed membership of Bifidobacteriaceae also contributes to the higher intestinal pH observed in preterm infants, as the metabolic activities of Bifidobacteriaceae lead to the production of metabolites that effectively lower intestinal pH, such as acetic acid. Subsequently, microbiome maturation patterns largely follow those of term infants in the first months of life. GA, gestational age; IgA, immunoglobulin A.

Figure 2.

Potential mechanisms of probiotic-induced shifts in the gut microbiome and host physiology of preterm infants. Probiotic supplementation in preterm infants may influence gut microbiome maturation via several dynamically related mechanisms. First, probiotics can alter microbiome composition and initiate term-like maturation patterns, leading to the occupation of ecological niches and generation of cross-feeding networks amongst microbes. This facilitates alterations in the metabolic profile, and subsequently, a reduction in intestinal pH due to the greater production of acidic metabolites, such as acetic acid. The combination of microbial and metabolic shifts in the gut microbiome facilitates immune and intestinal maturation, enhancing gut barrier function and homeostatic defense mechanisms. This is further reflected by a reduction in pro-inflammatory immune markers, such as IFN-γ, IL-4, IL-12 and fecal calprotectin. Ultimately, the combination of these factors increase the resistance to pathogen colonization, while pathogens may also be competitively excluded from persisting in gut microbial ecosystems directly by probiotic strains. Thus, the provision of probiotics to infants born prematurely has the potential to significantly alter gut microbial ecology and broader host physiological measures to facilitate changes more representative of infants born at term.