Gut Microbiome Development in Children

The study, at a glance

• The goal is to enhance gut development in kids who have been delivered through C section (6 months to 3-year-olds).
• 30 placebo, 30 real. 8 weeks long.
• Assessing stool consistency, bowel habits, salivary cortisol, fecal microbiota, and short-chain fatty acid metabolism were investigated.
• 58 subjects completed the study.

According to new research from the World Health Organization (WHO), caesarean section use continues to rise globally, now accounting for more than 1 in 5 (21%) of all childbirths. This number is set to continue increasing over the coming decade, with nearly a third (29%) of all births likely to take place by caesarean section by 2030, the research finds. However, the potential short and long-term risks of birth through C-section should not be understated, including postpartum sepsis, hemorrhage, and some morbidities relating to the neonate, and predisposition to illness later in childhood may include respiratory distress, delayed maternal adaptation, obesity, and allergy.

The microbiome is hallmarked by distinctive compositional and functional features across different life periods. Accumulating evidence has shown that microbes residing in the human body may play fundamental roles in infant development and the maturation of the immune system (Zhuang et al., 2019). Bacterial communities present in early life are empirical for gastrointestinal maturation, immune development, and metabolism (Arrieta et al., 2014).

“Until recently the gut microbes were viewed as harmless and of little benefit.  We now know that they play a major role in overall wellbeing. Alterations in the gut microbiota have been described in disorders as diverse as depression, diabetes, Parkinson’s disease, and autism.  We also see dramatic changes in the microbiota in those who are overweight and obese”.

• Professor Ted Dinan, Medical Director at Atlantia Clinical Trials.

The microbial composition of spontaneous vaginally delivered infants differs significantly from C-section delivered infants (Azad et al., 2014; Bäckhed et al., 2015; 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 transmission between the mother and infant is less pronounced; thus, these pioneer bacterial species are often depleted or delayed in the gut of these infants.

Though there has been a significant increase in clinical evidence and research conducted on the human microbiome, it has only been in the last 10 years that there has been a focus on infant gut health. Similarly, the clinical significance of the changes that occur as a result of C-section birth is unclear, and the therapeutic interventions are limited. However, an effective strategy for positively modulating stress, microbial balance, and gastrointestinal symptoms is using single- and multi-strain probiotics with proven health benefits.

Lactobacillus and Bifidobacterium strains/species have received rigorous research, and such are recognized as safe, natural components of the gut microbiota and fermented dairy formulations. Strong evidence has exemplified that dietary supplementation composed using these commensal ingredients can be effective in partially diminishing the progression of disease, which results in the stimulation of the growth of health-promoting bacteria in the colon/gut of adults and infants.

Regardless of the apparent lack of knowledge in terms of mechanisms of action, it is widely accepted that probiotics function in a strain-specific approach. Hence, there is significant scope to produce unique modulatory effects which would promote biological resilience against intestinal infection, particularly among younger more vulnerable paediatric populations.

Study Design

“In this randomized, double-blind, placebo-controlled study, our aim was to investigate the efficacy and safety of Lactobacillus paracasei (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” (Wang et al., 2021).

The study consisted of healthy infants/young children both male and female, under strict inclusion/exclusion criteria, which can be seen in the full publication HERE. The clinical trial involved at least four visits over an 8-week period and the subjects received the probiotic or placebo samples once a day (2g/day dose) with warm water or milk. The parent/guardian was required to record the number of bowel movements the subjects had each day, the stool consistency, and if they experienced any abdominal pain, bloating, or flatulence. Stool and saliva samples were collected on-site at Atlantia Clinical Trials during visits 2, 3, and 4 for analysis of microbiota composition, short-chain fatty acids (SCFAs), and cortisol.

Results

The study consisted of two groups: LP N1115 which received the probiotic sample, and the control group, which received the placebo. The pattern of stool data showed that the LP N1115 group moved from soft to normal and the control group remained soft. Similarly, it was determined that gender, the age of subjects represented as years and months, and LP N1115 treatment explained the largest proportion of variance in terms of the microbiota.

Upon examination of short-chain fatty (SCFAs) acids detected in the fecal samples, it was found that there was a significant difference in propanoic acid levels between LP N1115 and placebo groups, from baseline to postintervention, acetic acid and butanoic acid seemed to be significantly decreased in LP N1115 and placebo groups over time. Considering the 6–18 months subgroup, significant differences in acetic acid, propanoic acid, and butanoic acid were observed between LP N1115 and placebo groups.

The future of natural microbiome interventions

There is major global concern surrounding the short and long-term health implications of C-section delivery, particularly in the reduction of diversity in normal microbial composition. Clinical intervention utilizing single and multispecies probiotics have shown promising opportunities to provide therapies from an early age to treat and prevent devitalizing diseases in later life. There are mounting studies which have evaluated probiotic strains, prebiotics, and synbiotics as a way of mediating immune regulation, microbial function, and diversity in C-section delivered infants. Due to the success of such studies ((Chua et al., 2017; Garcia Rodenas et al., 2016; Hurkala et al., 2020; Korpela et al., 2018; Morais et al., 2020; Schultz et al., 2004), and the clinical benefits associated with probiotic products attributed to the objectives of this study. Namely, to evaluate the safety and efficacy of LP N1115 supplementation on gastrointestinal symptoms, salivary cortisol, gut microbiota, and SCFAs levels in a cohort of healthy, young children born by C-section.

A randomized, placebo-controlled design was employed to minimize bias when comparing efficacy data during the intervention. The probiotic was found to be safe and well-tolerated by all subjects throughout the study. Results showed that after 8 weeks of probiotic administration with a daily dose of 109 CFU, gastrointestinal symptoms, cortisol levels, and fecal characteristics were generally similar for the placebo and LP N1115 groups. However, this was expected given the ‘healthy’ nature of the study population, with any adverse effects being the primary focus. Interestingly, upon analysis of an additional subgroup (subjects ages 6-18 months), a much larger effect size between LP N1115 and placebo groups over time was found. However, Sample size was considered small in this subgroup, therefore, caution must be exercised when interpreting these findings.

Upon examination of short-chain fatty (SCFAs) acids detected in the fecal samples, it was found that there was a significant difference in propanoic acid levels between LP N1115 and placebo groups, from baseline to postintervention, acetic acid and butanoic acid seemed to be significantly decreased in LP N1115 and placebo groups over time. Considering the 6–18 months subgroup, significant differences in acetic acid, propanoic acid, and butanoic acid were observed between LP N1115 and placebo groups.