Genes may determine how early life exposures shape the gut microbiome

Genes may determine how early life exposures shape the gut microbiome

A mouse study shows that the long-term health effects of early nutrient and antibiotic exposure depend not only on what happens early in life, but also on who you inherit your genes from.

Study:The influence of early exposures on the growth and composition of adult gut microbiome composition depends on the genetic strain and parent of origin. Photo credit: Nejron Photo/Shutterstock.com

Environmental factors in early life can have long-term effects on offspring that extend into adulthood, driven in part by dysbiosis. A recently published study inMicrobiomeshows that genetic differences between individuals may make them more susceptible to gut dysbiosis by altering the host's susceptibility to such environmental factors.

introduction

Microbial colonization begins before birth and is deeply influenced by maternal genes, microbiota, and environmental factors such as maternal dietary or antibiotic exposures. Protein and vitamin D deficiencies are relatively common in pregnancy and lactation and have been linked to dysbiosis, which can also occur after antibiotic exposure.

Genetic makeup also influences how environmental factors affect offspring. For example, host genes and physiology can influence bile acid tabolites, antimicrobial compound levels, and intestinal mucosal structure, all of which influence the health and microbial communities in the gut.

Furthermore, the origin of specific genes, whether from the mother or the father, called the parent-of-origin (PO) effect, can significantly influence the final gut microbiota composition and developmental outcomes.

Not much is known about how these factors impact the gut microbiota and long-term health of offspring. The current study aimed to identify these findings in adult offspring exposed to early-life antibiotics, inadequate protein intake, and vitamin D deficiency. Attempts have also been made to find the role of genetic background and PO effect on the dysbiosis associated with these factors.

About the study

Three groups of female collaboration cross mice (CC) and their offspring were used along with a control group. The term CC refers to inbred mice whose genes arise from recombination of eight founder strains of mice from three main species. These may reflect the effects of gene-environment interactions 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 created 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.

Dams were placed on antibiotic-containing, low-protein, or low-vitamin D foods starting five weeks before conception and continuing until lactation was stopped (day 21). After weaning, all offspring were switched to a standardized rodent chow diet until eight weeks of age.

Study results

Antibiotic exposure

Microbial diversity was reduced across different 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 progeny had higher diversity than their reciprocal counterparts. However,β-Diversity depended on genetic background, with PO triggers accounting for from 20% to 50% of the variability in gut microbiota in the test group versus 20% to 40% in controls.

Differences in abundance were observed forBacteroidesPresentMuribaculaceaePresentAkkermansiaAndBifidobacterium. The effect varied between 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 in mutual cross-offspring pairs.

Protein deficiency

Protein deficiency did not alter the diversity indices between the test and control groups. However, like speciesAkkermansiaAndBifidobacteriumwere significantly less frequent in low-protein offspring than in controls.

Mutual cross-scoring revealed reduced α and reduced cross-scoringβ-Diversity in the offspring of CC001xcc011, showing the effect of genetic differences. Species-level diversity differed in mutual cross-offspring pairs and accounted for 14% to 20% of the microbiota variability.

The low-protein diet reduced adult offspring body weight by 15% in all test groups, independent of changes in microbial diversity. This is consistent with previous studies showing that protein deficiency is associated with reduced nutrient absorption.

Offspring from three crosses were lighter than the controls, but the mutual cross offspring was not. Furthermore, the progeny of CC011xcc001 was heavier than that from its mutual 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, confirming previous studies. However, the PO effect drove differences in diversity between mutual cross-offspring pairs, indicating that developmental deficiency in vitamin D could alter several important gut bacteria.

For example, the offspring of CC011xcc001 had significantly greater microbial diversity and body weight than their counterparts in the same group, although overall vitamin D deficiency alone did not affect these results.

While vitamin D deficiency did not cause a reduction in body weight in adult mice, the offspring from one cross were heavier than those from their cross.

Buttocks, body weight and gut microbiome

PO accounted for 20% to 58% of the variability in microbiota between mutual cross-offspring pairs within test groups. The microbiome influences body weight, which varies across the four groups and even within mutual cross-offspring pairs.AkkermansiaAndBlautiawere more common in CC051XCC041 offspring in lighter and heavier mice, respectively.

The PO effect was demonstrated in both the low protein and low vitamin D diets, as the offspring of CC011xcc001 mice were heavierFecalibaculumcompared to those from its mutual CC001XCC011. This bacterium protects against inflammatory bowel disease, colon cancer and diabetes, highlighting its importance in preventing intestinal dysbiosis.

This study found that PO-driven differences in body weight and microbiota were most consistent in the CC001xCC011 cross pairs, emphasizing the effects 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 may have long-term effects on growth and gut microbiota in adult mice modified by host PO effect genes. This is the first time these results 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 observed within a mutual pair in control, low-protein and low-vitamin D groups. Thus, this study also shows the effect of PO on body weight and gut microbiota in adult offspring for the first time.

The results 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 medications during pregnancy.

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