ABSTRACT
n-3 PUFA are lipids that play crucial roles in immune-regulation, cardio-protection and neurodevelopment. However, little is known about the role that these essential dietary fats play in modulating caecal microbiota composition and the subsequent production of functional metabolites. To investigate this, female C57BL/6 mice were assigned to one of three diets (control (CON), n-3 supplemented (n3+) or n-3 deficient (n3-)) during gestation, following which their male offspring were continued on the same diets for 12 weeks. Caecal content of mothers and offspring were collected for 16S sequencing and metabolic phenotyping. n3- male offspring displayed significantly less % fat mass than n3+ and CON. n-3 Status also induced a number of changes to gut microbiota composition such that n3- offspring had greater abundance of Tenericutes, Anaeroplasma and Coriobacteriaceae. Metabolomics analysis revealed an increase in caecal metabolites involved in energy metabolism in n3+ including α-ketoglutaric acid, malic acid and fumaric acid. n3- animals displayed significantly reduced acetate, butyrate and total caecal SCFA production. These results demonstrate that dietary n-3 PUFA regulate gut microbiota homoeostasis whereby n-3 deficiency may induce a state of disturbance. Further studies are warranted to examine whether these microbial and metabolic disturbances are causally related to changes in metabolic health outcomes.
Subject(s)
Animal Nutritional Physiological Phenomena , Cecum/microbiology , Fatty Acids, Omega-3/deficiency , Gastrointestinal Microbiome , Animals , Body Composition , DNA, Bacterial/isolation & purification , Diet , Dietary Supplements , Fatty Acids/metabolism , Fatty Acids, Omega-3/blood , Female , Fumarates/metabolism , Ketoglutaric Acids/metabolism , Malates/metabolism , Male , Metabolome , Metabolomics , Mice , Mice, Inbred C57BL , RNA, Ribosomal, 16S/isolation & purification , Sequence Analysis, DNAABSTRACT
BACKGROUND: Neurodevelopment is strongly influenced by maternal and early-postnatal diet. Omega-3 polyunsaturated fatty acids (n-3 PUFA) are vital structural and functional components of the developing brain. The gut microbiota is also influenced by n-3 PUFA status, however, little is known about the role of maternal and early-life n-3 PUFA intake on offspring gut microbiota development and subsequent interactions with central nervous system functioning and behavioural outcomes. METHODS: Pregnant female C57BL/6 mice and their male offspring were fed a control (CON), omega-3 deficient (O3-) or omega-3 supplemented (O3+) diet. Cognitive, depressive and social behaviours were assessed through a battery of behaviour tests in the male offspring at both adolescence (week 4-5) and adulthood (week 11-13). Hypothalamic-pituitary-adrenal axis (HPA) activation was assessed by analysis of stress-induced corticosterone production. Fecal microbiota composition was analysed by 16S sequencing at both adolescent and adulthood. In addition, stimulated spleen cytokine levels were assessed. RESULTS: n-3 PUFA interventions induced subtle changes in offspring early-life and adolescent behaviours, which were further evident in adulthood, such that O3- animals displayed impaired communication, social and depression-related behaviours and O3+ animals displayed enhanced cognition. O3- mice displayed an elevated Firmicutes:Bacteroidetes ratio and blunted systemic LPS responsiveness. Contrastingly, O3+ mice displayed greater fecal Bifidobacterium and Lactobacillus abundance and dampened HPA-axis activity. CONCLUSIONS: Neurobehavioural development related to cognitive, anxiety and social behaviours, is highly dependent upon in utero and lifelong n-3 PUFA availability. In addition, neurobehavioural changes induced by altering n-3 PUFA status are closely associated with comprehensive alterations in gut microbiota composition, HPA-axis activity and inflammation.
Subject(s)
Behavior, Animal/physiology , Fatty Acids, Omega-3/physiology , Gastrointestinal Microbiome/physiology , Aging/psychology , Animals , Cognition , Corticosterone/blood , Cytokines/metabolism , Depression/psychology , Fatty Acids/metabolism , Fear , Female , Hypothalamo-Hypophyseal System/physiology , Male , Mice , Mice, Inbred C57BL , Pituitary-Adrenal System/physiology , Pregnancy , Recognition, Psychology , Social Behavior , Stress, Psychological/metabolism , Stress, Psychological/psychology , Swimming/psychology , Vocalization, AnimalABSTRACT
Human adolescence is a time of enormous developmental change, second only to infancy and early childhood in terms of brain shaping and growth. It is also a period in life when the young adult is faced with distinct environmental challenges and stressors. Interestingly, we now know that these external sources of stress all have an impact on the intestinal microbiota. Given that there is now a significant body of knowledge indicating a role for the microbiota-gut-brain axis in development and function of the brain, and potentially the emergence of psychiatric illnesses, we need to draw our attention to the intestinal microbiota in the adolescent. As psychiatric illnesses frequently first manifest during the teenage years it may be that the intestinal bacteria are playing an as yet unidentified role in disease pathogenesis. Identifying a role for the microbiota in psychiatric illnesses opens up an exciting opportunity for therapeutic advances via bacterial manipulation. This could prove to be a beneficial and novel avenue for treatment of mental illnesses in the developing teen.
