Maternal diet and breast milk: shaping the newborn immune system to fight early life infections

Abstract

[eng] Newborns have limited ability to fight infections due to an immature adaptative immune response. As a result, they depend on mechanisms of maternal immune transfer, such as placental transfer and intake of breast milk (BM) during lactation. These processes also play a vital role in the proper development of the infant immune system. The overall composition of BM changes through the lactation period and so does the content of immune components. Diet as well as other factors can influence the composition of BM. It is of considerable interest to investigate the potential of the maternal diet during gestation and lactation to contribute to the maturation of the infant immune system. This influence could confer benefits in terms of preventing and mitigating infections during the early stages of life. Thus, the aim of this thesis was to examine the effect of maternal diet during pregnancy and lactation on the immune profile of BM and on the infant’s capacity to fight against infections in the early stages of life. Additionally, the effect on the umbilical cord plasma (UCP) and maternal plasma (MP) immune composition was also studied. The levels of UCP immune factors were significantly different from those found in MP. Moreover, the levels of UCP IgE and IgG are highly associated with those found in MP. With regard to the composition of bioactive components in BM in the transition stage, a different profile between day 7 and day 15 was observed, with day 7 exhibiting the highest concentration of the analyzed immune factors. Furthermore, two groups of mothers were identified based on the evolution of their BM immune composition (BM immunotypes) between those days, primarily attributed to differences in specific types of Ig. This highlights the importance of considering the individual variations in BM immune factors for future studies. Another noteworthy finding was the identification of Gal-1, -3, and -9 for the first time in BM, which exhibited similar levels at both time points in the transitional stage. Finally, being a first-time mother or not, and a maternal infection, such as the SARS-CoV-2 infection, have shown to play a role in immune composition. Next, the influence of maternal diet and other perinatal factors during pregnancy and lactation on these bioactive components and the incidence of infections in the offspring was evaluated at clinical level. It was observed that maternal intake of dietary fiber, plant protein, and polyunsaturated fatty acids could potentially contribute to the development of the neonate's immune defense. This effect may be mediated through modifications in the maternal intestinal microbiota during pregnancy. The occurrence of early-life infections, both gastrointestinal and respiratory, within the first year of life was observed to be lower when mothers followed a dietary pattern rich in dietary fiber and vegetable protein and low in lipids during pregnancy and breastfeeding. In contrast, a maternal diet high in animal protein and lipids had the opposite effect, increasing the incidence of infant infections. This effect was associated with specific immune factors found in BM and on the infant microbiota diversity. Then, the maternal dietary profiles from the clinical cohort were adapted to conduct a preclinical nutritional intervention in dams to study the neonatal immune response in a model of acute rotavirus-induced gastroenteritis. The maternal diet fortified with vegetable protein, fiber, and fish oil had a beneficial impact on both the mothers and the infected offspring, as well as in the BM. Firstly, it was found to enhance maternal mucosal immunity and in addition, an an-obesogenic effect of the adipose tissue was also found. With regard to the offspring, the maternal diet contributed to an improvement of the RV-induced gastroenteritis, to the development of the immune system of the infant, to an enhanced RV-specific response and to changes in the microbiota composition. The present thesis gained insight into the influence of maternal nutrition during gestation and lactation on the enhancement of the newborn immune function to fight against infections. While this study revealed some evidence of the immunomodulatory effects of maternal diet on the BM and the offspring, further research is necessary to fully comprehend the underlying mechanisms.[cat] Els nounats tenen respostes immunitàries limitades i depenen dels mecanismes de transferència immunitària materna per a la defensa i el correcte desenvolupament immunitari. La investigació sobre la dieta materna i el seu impacte en la maduració del sistema immunitari infantil té una especial rellevància, ja que es creu que pot ajudar a prevenir i mitigar les infeccions durant la infància. Aquesta tesi té com a objectiu investigar els efectes de la dieta materna durant l'embaràs i la lactància en el desenvolupament immunitari del nadó i la seva capacitat per combatre les infeccions en el primer any de vida, així com explorar el paper dels components immunitaris de la llet materna en aquest context. En un estudi clínic, es van caracteritzar els nivells de factors immunitaris en el plasma matern i del nounat (cordó umbilical), així com en la llet materna. A més, es va investigar per una banda, l'impacte de la dieta materna durant l'embaràs i la lactància en les infeccions dels descendents a partir del registre de les infeccions fins a un any de vida. Per l’altra banda, a partir de l’anàlisi de les dietes maternes de l’estudi clínic es van establir dues dietes que es van administrar a rates gestants i lactants per tal d’avaluar el seu efecte sobre una infecció per rotavirus en les cries. Es va constatar que la llet materna presenta variabilitat en la composició immunitària (immunoglobulines, citocines i adipocines) durant l'etapa de transició, i aquests components no evolucionen de la mateixa manera en totes les mares. S'ha establert per una banda l’existència de dos immunotips de la llet materna en funció d’aquesta evolució i, per l’altra, la concentració de tres galectines en la llet de transició. A més, factors com el fet de tenir un fill previ i la infecció materna, com la de SARS-CoV-2, van influir en la composició d'aquests factors, especialment en les immunoglobulines. El consum matern de fibra dietètica, proteïna vegetal i àcids grassos poliinsaturats va disminuir la incidència d'infeccions en l'estudi clínic. Aquesta observació es va confirmar en la intervenció preclínica amb aquesta dieta, ja que va potenciar la resposta immunitària del binomi mare-fill, incloent la llet, i va reduir el curs de la infecció amb rotavirus. Així, dieta i llet materna, són factors que juguen un paper clau en les infeccions dels descendents. En conclusió, aquesta tesi doctoral tesi proporciona evidències sobre l'impacte de la nutrició materna en la funció immunitària del nounat i la prevenció d'infeccions