WANG et al .
1 | INTRODUCTION
multistrain probiotics with proven health benefits. Lactobacillus and Bifidobacterium strains/species are recognized as safe, natural components of the gut microbiota and fermented dairy formula - tions. Encouraging evidence illustrates that dietary supplementation utilizing these commensal constituents or, indeed, their protective metabolites are effective in partially attenuating disease progres - sion and, in turn, stimulate the growth of health-promoting bacte - ria in the colon of adults and infants (Di Cerbo et al., 2016; Mathur et al., 2020). Despite the lack of knowledge surrounding the mecha - nisms of action, it is generally accepted that probiotics function in a strain-specific manner. Thus, attempts to supplement young, vulner - able pediatric populations are considered desirable and, in doing so, it could provoke distinctive modulatory effects which may promote biological resilience against intestinal infection and acquisition of more favorable microorganisms throughout the life span. In this randomized, double-blind, placebo-controlled study, our aim was to investigate the efficacy and safety of Lactobacillus pa- racasei (LP N1115) as a probiotic to enhance digestive symptoms, salivary cortisol levels, gut microbiota composition, and short-chain fatty acids levels in infants and young children born by C-section. In a previous study, it was found that consumption of a yogurt supple - mented with LP N1115 for 12 weeks could reduce the risk of acute upper respiratory tract infections in healthy people (aged ≥45 years), via enhancing T cells ( CD + 3 ) that mediate the natural immune defense system (Guo et al., 2016; Pu et al., 2017). Subsequent studies have demonstrated its effectiveness in enhancing intestinal development in neonatal mice and its ability to increase defecation volume, mois - ture content, and intestinal propulsion rates in a constipated mouse model (Cao et al., 2018; Wang et al., 2016).
Delivery by caesarean section (C-section) is a common obstetrician procedure, and over the past two decades, C-section delivery by maternal request has increased dramatically. However, a number of physiological risk factors are often associated with this mode of de - livery such as postpartum sepsis, hemorrhage, and some morbidities relating to the neonate, and predisposition to illness later in child - hood may include respiratory distress, delayed maternal adaptation, obesity, and allergy (Betrán et al., 2016; Gupta & Saini, 2018). In re - cent years, researches have shown that the prevalence of C-section also coincides with an aberrant gut microbiota development in the neonate. There is an ever-increasing realization that bacterial commu - nities present in the gut during early life play crucial roles in gas - trointestinal maturation, immune development, and metabolism (Arrieta et al., 2014; Clemente et al., 2012; Rodríguez et al., 2015). Early microbial colonization of bacteria, archaea, eukaryotes, bacte - riophages, and viruses is considered a nonrandom essential process that is influenced by a series of prenatal and postnatal factors includ - ing mode of delivery (Dominguez-Bello et al., 2010; Hill et al., 2017; Neu & Rushing, 2011), gestational age at birth (Fouhy et al., 2019; Hill et al., 2017), feeding type (Bezirtzoglou et al., 2011), maternal health status (Collado et al., 2010), and exposure to intrapartum and postnatal antibiotics (Azad et al., 2016; Tapiainen et al., 2019). The microbial composition of spontaneous vaginally delivered in - fants differs significantly from C-section delivered infants (Azad et al., 2014; Bäckhed et al., 2015; Hill et al., 2017) and this is also the case for associated functional metabolites (Hill et al., 2017). Increased relative abundances of Bacteroides and Lactobacillus species are indicative of infants born vaginally as they are directly exposed to the mother's vaginal microbiota. In the case of C-section delivery, specifically elective caesarean, vertical microbial transmis - sion between the mother and infant is less pronounced; thus, these pioneer bacterial species are often depleted or delayed in the gut of these infants. Inevitably, bacteria are acquired from other body regions of the mother including the skin and mouth or nonmater - nal sources such as the hospital environment (Bäckhed et al., 2015; Milani et al., 2017; Shin et al., 2015). It is known that abnormal colonization patterns and concomitant antibiotic administration during infancy favor the growth of opportunistic pathogens and subsequent infection (Shao et al., 2019). Thus, alterations to the gut microbiota may have long-term implications with increased sus - ceptibility to noncommunicable diseases but not in all cases. These include allergic disease (Bager et al., 2008), immune-related disor - ders (Sevelsted et al., 2015), chronic inflammatory disease (Bager et al., 2012; Mårild et al., 2012), obesity (Kuhle et al., 2015), and type 1 diabetes (Cardwell et al., 2008). The clinical relevance of the changes that occur as a result of C-section and the impact on later microbiota–immune homeostasis is still unclear and therapeutic interventions are limited. One ef - fective strategy for positively modulating stress, microbial balance, and gastrointestinal symptoms is through the use of single- and
2 | MATERIALS AND METHODS
2.1 | Probiotic sample
The LP N1115 probiotics contained a single, live strain of L. para- casei N1115 (probiotic sample, 2.4 × 10 9 CFU/g) and the reference product contained maltodextrin without a bacterial strain (placebo sample) which were all provided by Shijiazhuang Junlebao Dairy Co. Ltd. All samples were stored at 4 ℃ , as well as away from direct heat and sunlight.
2.2 | Subjects
The healthy infants/young children were selected according to strict criteria, and all subjects were males and females aged ≥6 months and ≤3 years, who were born by C-section. Exclusion criteria included: (i) consumption of probiotics and/or prebiotics in any form within the past 2 weeks, (ii) unwillingness to avoid other probiotics/prebiotics for the duration of the study, (iii) food allergies or an allergy or hy - persensitivity to any component of the study products including milk protein allergy or cow's milk allergy, (iv) significant acute or chronic
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