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New Insight brought back home from the Espghan 50th Annual Meeting, Prague 11–12 May 2017.

Breast-milk as the Natural Functional Food:

Nutrition and the gut microbiota to brain development

(A report by Saptawati Bardosono)

Following all the talks regarding to the use pre and probiotics during the two days meeting, the following are the reports:

Milk, is the only food ever “designed” specifically to feed human, in which its composition is used as gold standard for estimating nutrient and energy requirements for infants, and manufacturing infant formulas. We still need to understand thoroughly what is in human milk and what it all does may improve human health than other food, which makes human milk or breast milk as natural functional food.

Human milk has long been considered sterile unless contaminated or collected from infected gland. And, even as human milk banks it is a pasteurize milk, in which no one would have ever suggested adding bacteria back to the milk. Until recently, formula manufactures would not dream of adding bacteria to their products. But, why the paradigm shift? It is because of the evolution of methods and then the fact that nothing is likely sterile. As now we characterizing microbial communities in human milk, i.e. diverse bacterial genera identified in every sample with high level of variability among women and in which there are bacterial fingerprints within a woman (McGuire, Espghan 2017). Again, the paradigm shift as milk, even when produced by healthy women, contains bacteria, and many of these bacteria would/could be considered as potentially pathogenic.

There are several factors that are believed associated with variation in the milk microbiome, such as:

  • Time of postpartum, i.e. milk microbial community structure is relatively stable over time,

  • Delivery mode, i.e. C-section associated with decrease diversity in milk, increase total bacteria, and trend toward higher relative abundance of propionibacterium,

  • Maternal diet, i.e. there is positive correlations between fermiculates to total energy, lipids, carbohydrates and fiber in diet, additionally when women consume probiotic bacteria, they find their way to the milk,

  • Other milk components, i.e. HMO and immune cells. HMO stimulate growth of milk-derived Staphylococcus, and milk also have immune cell distributions in which there is a relationship between immune cells in milk ad microbial community in milk,

  • Childcare, i.e. increase of milk microbiome diversity related to the increase of social networks,

  • Maternal genetics and environmental microbial exposure, i.e. skin, infant mouth, environment and maternal GI tract are the origin of milk microbiota.

Starting to learn the evolution of gut symbiont, then Lactobacillus reuteri can be used as a model of vertebrae gut symbiont evolution. Along the way, there is a diversification of the gut symbiont Lactobacillus reuteri as a result of host-driven evolution. This happened to all vertebrae species, i.e. rodent, poultry, pig and also human. Specifically for Lactobacillus reuteri, the epithelial selection is highly specific in rodent as compare to the non-rodents, i.e. pig and human, because there is a fundamentally different trend of genome evolution in Lactobacillus reuteri. The phenomenon is caused by several factors, including the very homogeneous, smaller genome, reductive evolution, and population bottleneck. It is also evident in human population, in which the gut microbiota in rural Papua New Guineans significantly different as compared to the Americans.

What are the roles of Lactobacillus reuteri? From the animal study, firstly, it plays role as aryl hydrocarbon receptor (AHR) ligands derived from tryptophan catabolism from the diet that works in lamina propria of the gut as protection against colitis. Secondly, it plays role in the astrocyte as protection against central nervous system inflammation. Thus, Lactobacillus reuteri is beneficial both for gastrointestinal tract and the brain of the host. However, there is a harmful issue for the “modern” lifestyle that might have been unfavorable to L. reuteri. For further detailed, please find it in Marsland, Nature Medicine, 2016.

Next is, what is already known about L. reuteri?

  • Wu et al (2013) from Neurogastroenterol Motil 25, explained how L. reuteri DSM 17938 increased colon propulsive peristaltis. Dunn’s multiple comparisons tests shows how loperamide decreases propulsive contractile clusters frequency and velocity ex vivo and decreases defecation frequency in vivo. And, decreased motility ex vivo or in vivo is reversed by L. reuteri DSM 17938;

  • Perez-Burgos et al (2015) from J Physiol 593(17):3943-57 shows how L. reuteri DSM 17938 block the capsaicin stimulation of transient receptor potential cation channel subtype V1 (TRPV1) as receptor within minutes to reduce pain.

In conclusion on the issues, the following are the mode of action of L. reuteri DSM 17938:

  1. Decreased inflammation

  2. Reduced dysbiosis

  3. Improved gut motility

  4. Decreased visceral pain.

In clinical practice, there are evidences regarding to L. reuteri DSM 17938 and infant’s colic. RCT double-blinded studies design that showed the treatment success (i.e. decreasing crying time) in breast-fed infants by providing 108 CFU of L. reuteri as compared to placebo for 21–28 days are study by Savino (J Pediatr 2010), Szajewska (J Pediatr 2013), Chau (J Pediatr 2014), and Miu (2015). While one study by Sung (BMJ 2014) failed to prove it, which might be due to the use of mix breast-milk and formula milk. However, a meta-analytical approach by pooled results of the five RCTs in reporting on crying assessed on day-21 shows that L. reuteri DSM 17938 reduce the crying time in day-21 by 47 minutes (95%CI: -68 to -19). Another preventive trial (“Prophylactic use of a probiotic in the prevention of colic, regurgitation and functional constipation”) also shows approximately 40 minutes reduction in crying time in infants with infantile colic.

In the case of functional constipation in children, the evidences on the use of probiotics are shown by seven studies, i.e. Coccorullo (2010) by using L. reuteri DSM 17938, Guerra (2011) by using B. longum, and Bu (2007) by using L. casei rhamnosus Lcr 35, were significantly proven, while Wojtyniak (2017) by using L. casei rhamnosus Lcr 35, Banaszkiewicz (2005) by using LGG, Tobers (2011) by using B. lactis DN 173010, and Sadeghzadeh (2014) by using mixture of 7 strains, were not significantly proven.

And, in the case of functional abdominal pain, five RCTs with the use of L. reuteri DSM 17938 showed the evidences as follows:

  • Romano (2014) provided 2x108 CFU to 6–16 years old children for 4 weeks proved the reduction of both severity and frequency of pain;

  • Weizman (2016) provided 108 CFU to 6–15 years old children for 4 weeks proved the reduction of both severity and frequency of pain;

  • Jadresin (2016) provided 108 CFU to 4–18 years old children for 12 weeks proved the increased days free of pain;

  • Eftekhari (2015) provided 108 CFU to 4–16 years old children for 4 weeks showed no significant finding;

  • Maragdkoudaki (2017) provided 2x108 CFU to 5–16 years old children for 4 weeks showed no significant finding.

By a meta-analytical approach of pooled results from the four RCTs (minus Eftekhari), Szajewska (unpublished) shows on more than 50% reduction in pain score (95% CI of 42% to 68%) with relative benefit increased by 57% and number needed to treat (NNT) was 4 (3–8). However, given the positive evidences to use L. reuteri to help functional gastro-intestinal disorders (FGID), we should still consider the five steps of safety, tolerability, effectiveness, price and simplicity.

New issue is released on the association between periodontitis and preterm delivery. By definition, gingivitis is the inflammation of the gingival tissue without loss of teeth, in which gingivitis can advance to periodontitis or less and is considered a reversible form of periodontal disease. In which, periodontitis is a chronic infection that involves the destruction of the structures “around the tooth” to the loss of teeth themselves. Abhijit N Gurav (E World J Diab 2016;7:50-66) explain that there are associations between periodontitis and systemic disease, including preterm delivery. There is direct pathway to reach placenta, in which either trough vaginal or cesarean delivery, as stated as in utero colonization hypothesis: the placenta harbors its microbiome, i.e. colonization of the gut begins in utero. This is controversially to the sterile womb paradigm, i.e. fetus and placenta are sterile and the gut microbiome is acquired after birth (Perez-Munoz Microbiome, 2017).

In the oral cavity more than 900 species are present, and there is indirect pathway to reach placenta. First, it will reach the gut entering the epithelial villus to reach lamina propria and then it will be captured by lymphocyte to be able to flow through mesenteric lymph node to the blood stream.

In relation to preterm delivery, it starts from the maternal microbiomes’ status from the oral, vagina and intestinal, whether it is in a normal or dysbiosis condition. In a normal condition, it will lead to normal metabolome (e.g. short-chain fatty acids), normal inflammasome (e.g. IL-6, IL-8, IL-4 and IL-10), and normal T-cell subsets (Th-1, Th-17 and T-reg), resulting to a term delivery. On the other hand, a dysbiosis condition will lead to altered metabolome, inflammasome and T-cell subsets, resulting to a preterm delivery. Further explanation is through fetal intestine derived inflammation, in which there are bacterial translocation and induction of inflammation, resulting to the synthesis and release of uterotonins that trigger preterm labor. A related RCT on regular consumption of Lactobacillus reuteri-containing lozenges was proven to reduce pregnancy gingivitis (J Clin Periodontal, 2016). In conclusion, the oral microbiota plays an important role during pregnancy. Thus, the effects of the change of the oral microbiota with probiotic supplementation may have beneficial effects on pregnancy and the health of the newborn.

We know that human milk beside containing probiotic (e.g. Lactobacillus reuteri), it contains oligosaccharides that plays role as prebiotic, along with other macronutrients, i.e. protein 12%, fat 35%, lactose 65%, and oligosahharides 5–15 % (Bode L, J Nutr 2006;136:2127-30; Bode L, Nutr Rev 2009;67:S183-91; Bode L, Glycobiology 2012;22:1147-62; Bode L, Early Hum Dev 2015;91:619-22). If we compare them to the contents of cow’s milk, then cow’s milk containing protein 35%, fat 35%, lactose 45%, and oligosaccharides 0.05%. We also know that human milk oligosaccharides (HMO) are complex sugars, that can be broken down to glucose, galactose, fructose, N-acetyl-glucosamine, and N-acetylsuraminic acid sialic acid. There are 150–200 different HMO in accordance to its structural diversity and effects of the highly structure-specific, that could be affected by maternal factors as drivers of HMO composition, as follows: genetic (secretor/Lewis) factor, epigenetics (?), environment (diet, lifestyle/exercise), exposures (smoking, drugs etc.), health/disease, parity, and infant gender.

In relation to infant health and disease, there is a hypothesis that HMO contributes to lower necrotizing enterocolitis (NEC) incidence in breast-fed infants. Jantscher-Krenn E et al (Gut 2012;61:1417-25) can prove that:

  • HMO improve survival and reduce pathology scores,

  • HMO with two sialic acids are most effective in reducing pathology score,

  • HMO 2 (disialyl-lacto-N-tetraose) is most effective in reducing pathology scores.

Last but not least, for priming for health, there is a microbiome-gut-brain axis in early life (by Prof. John F. Cryan). By animation we can recall how “Geppetto”, made up and controlling the moving puppet “Pinocchio” by using several strings, and the control of the movement is actually the microbiome. The detailed explanations are by using articles on 1) neuroscience, molecular biology, and the childhood roots of health disparities, and 2) maternal prenatal stress is associated with the infant intestinal microbiota. There are prenatal and postnatal influences of infant’s microbiome, in which it is a missing part of the early life and we have to realize that we are living in a microbial world in each part of our body.

It is clearly understood that the uterus is sterile and the first major exposure to bacteria was during birth resulting to post natal colonization in the gut. Thus, the programming of the infant gut microbiota is from several sources, i.e. delivery mode, maternal microbiota status, first feeding, the use of antibiotics, etc. An infant born from a mother with maternal inflammation caused by prenatal stress, with gut microbiome dysbiosis and delivered by Caesarian section will have a gastro-intestinal dysfunction leaky gut. This will lead to metabolic disorders and disturbed crosstalk gut-brain system that result to cognitive and behavior deficits resulting from disturbance in signaling along the brain-gut-microbiota axis via the role of vagus nerve.

In relation to the signaling along the brain-gut microbiota axis, there is also a crosstalk between diet-derived macro and micronutrients, the microbiota and its metabolites, and the brain.

This will result to the fact that normal gut microbiota modulates brain development and behavior. Even it is proven to play role in the regulation of prefrontal cortex myelination, and also resulting to social deficit in mice lacking microbes. It is then leading toward effective probiotics for autism ad other neurodevelopment disorders. Thus, microbes are thought to be our friends with social benefits as drivers of brain evolution and development.

There are inter-connections between visceral pain, stress and microbiota, in which microbiota controls visceral hypersensitivity. Several studies show as follows:

  • There are changes in pain-related brain areas of germ free mice;

  • Early life antibiotic administration increases visceral pain in adulthood;

  • There are association between microbiota, neurodevelopment and metal illness

Thus, pre- and probiotics could play role as psychobiotics, as a novel class of psychotropic through a psychobiotic revolution. Prebiotics have anxiolytic and antidepressant-like effects and reserve the impact of chronic stress in mice. In the future, there might be a fecal microbiota transplantation that could modifiy behavior from healthy to depressed person.

We know already about feeding the brain and nurturing the mind but still lacking to know on the linking between nutrition and the gut microbiota to brain development. It was long postulated by Hippocrates to let food be our medicine. Thus, we can use foods to heal our body because there is association between stress and the microbiota-gut-brain axis in health and disease. And, our first food is breast-milk that it can be certainly called as functional food.

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