Maternal obesity associated-microbiotas programs offspring food intake – MAMIPROOFFI

To reach our goals, in collaboration with the two partners, we apply an integrative research strategy combining the use of a specific rodent model of obesity, the performance and computation of sequencing analyses of the various microbiota, several protocols to investigate eating behaviour and the analysis of neurodevelopment associated to feeding behaviour.

To reach our first two objectives we had to implement microbiotal transfer experiments at birth and during lactation on a rat model. To minimize confounding factors (metabolic status of the obese rat during gestation and lactation, genetic determinism of obese rat strains) we chose to realize, from the first days of life to 15 days, a vertical transfer of microbiota (intestinal, vaginal or milk microbiota) of dams genetically predisposed to obesity into newborn rats from another strains. By that mean we can confirm that the effects obtained on modifications of eating behaviour of the offspring are the sole consequence of microbiota transfer.

For the last part of our project aiming at deciphering some mechanisms of how bacteria act to impair or favour neurodevelopment and eating behaviour we selected specific microbiota identified in the offspring for which strongest correlation with offspring phenotypes was identified in previous part of the project and we examined only culturable bacteria.

We first proved microbiotal differences between inoculas collected from vagina, feces and milk from Obese prone and obese resistant dams rats. We found that maternal transfer of microbiota differing in composition led to alterations in pups gut microbiota composition that did not last until adulthood. We demonstrated that pups, transferred at birth with the different microbiota, had specific eating behavior characteristics with higher risk of over consuming at subsequent periods of their life for the one transferred with microbiota from obese prone dams. Additionally, we identified few bacteria species that could be involved in such phenotype. Further demonstrations are still ongoing. These findings support the view that neonatal gut microbiotal transfer can program eating behavior, even without a significant long-lasting impact on adulthood microbiota composition.

To develop effective strategies to prevent childhood obesity it is essential to better understand its causes. Worldwide, the prevalence of overweight and obesity among children has risen dramatically over the last decades. As treatment of established obesity often fails, prevention is highly desirable. Consistent with the developmental origins of health and disease (DOHaD) concept, literature suggests obesity is ‘transmitted’ from mother to child, as the best predictor of the risk of obesity at 8 years of age is the mother's pre-gravid body mass index (BMI). Even though genetic, psychosocial, behavioral, and dietary factors play a role, the contribution of the various channels through which the risk of obesity is transmitted from mother to child remains unclear.
In obese humans and obese animal models, intestinal microbiota is altered as compared to lean counterparts. This holds true for obese gestational women. In adults, accumulating evidence suggests that intestinal microbiota is involved in the regulation of energy metabolism and body composition in the host.

The transmission of a microbiota, "signature" of the maternal obesity, to her child during early periods of development, could potentially affect his metabolism, since maternal microbiota is the main determinant of colonization of intestine of the child. It was also recently demonstrated in animal models that maternal obesity can induce alterations in the development of neonatal brain structures that regulate appetite and finally, that the microbiota interfere with brain development. We made the original assumption that the transfer of a specific microbiota of obese mother, would be responsible for modulation of hypothalamic nerve circuits and brain stem in the offspring, and contribute to changes in appetite regulation.

To explore the specific role of maternal microbiota, we built a scientific strategy combining animal experiments, characterizations of eating behavior and associated neuronal circuits of the offspring, and the performance and computation of high throughout microbiotas analyses with the following specific aims:
1) to demonstrate the impact of maternal obesity-associated microbiota on HT and/or DVC neurodevelopment and eating behavior in offspring;
2) to identify maternal microbiota(s) and bacterial species/gene responsible for altered HT/DVC neurodevelopment and eating behavior in offspring,
3) to prove the causative role of identified bacterial species in alteration of HT/DVC neurodevelopment and eating behavior in offspring.

To minimize confounding factors (metabolic status of the obese rat during gestation and lactation, genetic determinism of obese rat strains) we chose to realize, from the first days of life, a vertical transfer of microbiota (intestinal, vaginal or milk microbiota) from dams genetically predisposed to obesity (Sprague Dawley Obese Prone model under high-energy diet) into newborn rats born by caesarean section.

The project includes 3 work packages (WP), aimed at: (i) (WP0) managing the project (ii) (WP1) analysing in the progenythe impact of maternal obesity-associated microbiota transfer on brain structure and eating behavior, (iii) (WP2) Identifying the maternal microbiotas involved and bacterial species/genes candidate(s); (iv) (WP3) Assessing the causative role of the identified bacterial specieson neurodevelopmental processes and brain functions related to food intake.
This project will 1) produce novel knowledge concerning maternal microbiota as a channel of communication between mother and offspring, and 2) identify early biomarkers (bacterial species or genes) predictive of eating behavior alteration. Such findings could potentially lead to the identification of new targets to develop drugs or nutritional strategies to the mother or newborn for reversing the inheritance of metabolic disorders.