A mouse study reveals that the long-term health effects of early nutritional and antibiotic exposure depend not just on what happens early in life but also on who you inherit your genes from.
Study: The impact of early-life exposures on growth and adult gut microbiome composition is dependent on genetic strain and parent- of- origin. Image credit: Nejron Photo/Shutterstock.com
Early-life environmental factors can have long-term impacts in offspring, extending into adulthood, partly driven by dysbiosis. A recent study published in Microbiome reveals that genetic differences between individuals may make them more prone to gut dysbiosis by modifying host susceptibility to such environmental factors.
Introduction
Microbial colonization begins before birth and is deeply influenced by maternal genes, microbiota, and environmental factors like dietary or antibiotic exposures of the mother. Protein and vitamin D deficiencies are relatively widespread in pregnancy and lactation, and have been associated with dysbiosis, which can also occur after antibiotic exposure.
Genetic make-up also influences how environmental factors affect offspring. For instance, host genes and physiology can shape bile acid metabolites, antimicrobial compound levels, and gut mucosal structure, all of which affect intestinal health and microbial communities.
Additionally, the origin of specific genes, whether inherited from the mother or father, known as the parent-of-origin (PO) effect, can significantly influence the final makeup of the gut microbiota and developmental outcomes.
Not much is known about how these factors impact gut microbiota and the long-term health of offspring. The current study aimed to identify these outcomes in adult offspring exposed in early life to antibiotics, inadequate protein intake, and vitamin D deficiency. It also sought to find the role of the genetic background and the PO effect on the dysbiosis associated with these factors.
About the study
Three groups of female Collaborative Cross (CC) mice and their offspring were used, along with a control group. The term CC refers to inbred mice whose genes arise by recombination from eight founder strains of mice belonging to three major species. These can reflect the effects of interactions between genes and the environment in complex phenotypes.
In this study, reciprocal crossing refers to breeding a female dam (e.g., CC001) with a male sire from a different strain (e.g., CC011), and vice versa. This produced genetically identical first-generation offspring except for their sex chromosomes and mitochondrial DNA, allowing researchers to isolate the PO effect while keeping nearly all other genetic factors constant.
The dams were put on antibiotic-containing, low-protein, or low-vitamin D food vs. control food beginning five weeks before conception and continuing until lactation stopped (day 21). After weaning, all offspring were switched to a standardized rodent chow diet until eight weeks.
Study findings
Antibiotic exposure
Microbial diversity was reduced across several genetic backgrounds, including CC011xCC001, CC004xCC017, CC017xCC004, and others depending on the metric used.
Reciprocal crosses showed similar α-diversity results, except for the control group where CC011xCC001 offspring had higher diversity than their reciprocal counterparts. However, β-diversity depended on the genetic background, with PO accounting for 20% to 50% of the variability in gut microbiota in the test group vs 20% to 40% in the controls.
Differences in abundance were observed for Bacteroides, Muribaculaceae, Akkermansia, and Bifidobacterium. The effect varied among species; some tripled in abundance while others increased threefold.
The body weight of these offspring was 15% lower than that of controls and also varied within reciprocal cross-offspring pairs.
Protein deficiency
Protein deficiency did not change diversity indices between the test and control groups. However, species like Akkermansia and Bifidobacterium were markedly less abundant in low-protein offspring than in controls.
Reciprocal cross evaluation revealed reduced α- and β-diversity in the offspring of CC001xCC011, showing the effect of genetic differences. Species-level diversity differed within reciprocal cross offspring pairs, accounting for 14% to 20% of the variability in the microbiota.
The low-protein diet reduced the adult offspring's body weight by 15% across all test groups, irrespective of changes in microbial diversity. This agrees with prior studies showing that protein deficiency is associated with reduced nutrient absorption.
Offspring from three crosses were lighter than the controls, but the reciprocal cross offspring were not. Moreover, offspring from CC011xCC001 were heavier than those from its reciprocal cross CC001xCC011, indicating the PO effect.
Notably, some crosses, such as CC041xCC051 and CC051xCC041, showed reduced body weight despite a non-significant change in microbiota diversity, suggesting that growth effects may also occur through non-microbiota-related mechanisms.
Vitamin D deficiency
Vitamin D deficiency did not reduce body weight or microbial diversity compared to controls, corroborating earlier studies. However, the PO effect drove differences in diversity between reciprocal cross-offspring pairs, indicating that developmental deficiency of vitamin D could alter several key gut bacteria.
For example, the offspring of CC011xCC001 had significantly greater microbial diversity and body weight than their reciprocal counterparts in the same group, even though overall vitamin D deficiency alone did not affect these outcomes.
While vitamin D deficiency did not cause a reduction in body weight in adult mice, offspring from one cross were heavier than those from their reciprocal cross.
PO, body weight, and gut microbiome
PO accounted for 20% to 58% of microbiota variability between reciprocal cross-offspring pairs within test groups. The microbiome affects body weight, which varied across the four groups and even within reciprocal cross-offspring pairs. Akkermansia and Blautia were more abundant in lighter and heavier mice, respectively, in CC051xCC041 offspring.
The PO effect was demonstrated in both the low-protein and low-vitamin D diets, as the offspring of CC011xCC001 mice were heavier, had higher microbial diversity, and increased abundances of several bacteria like Faecalibaculum, vs those from its reciprocal cross CC001xCC011. This bacterium protects against inflammatory bowel disease, colorectal cancer, and diabetes, highlighting its importance in preventing gut dysbiosis.
This study found that PO-driven differences in body weight and microbiota were most consistent in the CC001xCC011 cross pairs, emphasizing the impact of maternal genetic contributions and possibly epigenetic or mitochondrial mechanisms.
The PO effect could be due to differences in mitochondrial DNA or sex chromosomes, epigenetic regulation, or placental or uterine effects due to maternal genes.
Conclusions
Early-life antibiotic exposure or deficiencies in protein or vitamin D can have long-term impacts on growth and gut microbiota in adult mice, modified by the host’s genes with a PO effect. This is the first time these outcomes have been shown for developmental protein deficiency in adult life.
Body weight and fat content vary with the microbiome between groups. Body weight differences were also seen within a reciprocal pair in control, low-protein, and low vitamin D groups. Thus, this study also demonstrates the effect of PO on body weight and gut microbiota in the adult offspring for the first time.
The findings suggest that early environmental exposure interacts with inherited maternal factors to shape lifelong health trajectories and highlight the need for greater attention to maternal nutrition and medication during pregnancy.
Download your PDF copy now!
Popular painkiller use linked to gut microbiome shifts