Composition of the gut microbiota transcends genetic determinants of malaria infection severity and influences pregnancy outcome

Abstract

Background: Malaria infection in pregnancy is a major cause of maternal and foetal morbidity and mortality worldwide. Mouse models for gestational malaria allow for the exploration of the mechanisms linking maternal malaria infection and poor pregnancy outcomes in a tractable model system. The composition of the gut microbiota has been shown to influence susceptibility to malaria infection in inbred virgin mice. In this study, we explore the ability of the gut microbiota to modulate malaria infection severity in pregnant outbred Swiss Webster mice. Methods: In Swiss Webster mice, the composition of the gut microbiota was altered by disrupting the native gut microbes through broad-spectrum antibiotic treatment, followed by the administration of a faecal microbiota transplant derived from mice possessing gut microbes reported previously to confer susceptibility or resistance to malaria. Female mice were infected with P. chabaudi chabaudi AS in early gestation, and the progression of infection and pregnancy were tracked throughout gestation. To assess the impact of maternal infection on foetal outcomes, dams were sacrificed at term to assess foetal size and viability. Alternatively, pups were delivered by caesarean section and fostered to assess neonatal survival and pre-weaning growth in the absence of maternal morbidity. A group of dams was also euthanized at mid-gestation to assess infection and pregnancy outcomes. Findings: Susceptibility to infection varied significantly as a function of source of transplanted gut microbes. Parasite burden was negatively correlated with the abundance of five specific OTUs, including Akkermansia muciniphila and OTUs classified as Allobaculum, Lactobacillus, and S24-7 species. Reduced parasite burden was associated with reduced maternal morbidity and improved pregnancy outcomes. Pups produced by dams with high parasite burdens displayed a significant reduction in survival in the first days of life relative to those from malaria-resistant dams when placed with foster dams. At midgestation, plasma cytokine levels were similar across all groups, but expression of IFNγ in the conceptus was elevated in infected dams, and IL-10 only in susceptible dams. In the latter, transcriptional and microscopic evidence of monocytic infiltration was observed with high density infection; likewise, accumulation of malaria haemozoin was enhanced in this group. These responses, combined with reduced vascularization of the placenta in this group, may contribute to poor pregnancy outcomes. Thus, high maternal parasite burden and associated maternal responses, potentially dictated by the gut microbial community, negatively impacts term foetal health and survival in the early postnatal period. Interpretation: The composition of the gut microbiota in Plasmodium chabaudi chabaudi AS-infected pregnant Swiss Webster mice transcends the outbred genetics of the Swiss Webster mouse stock as a determinant of malaria infection severity, subsequently influencing pregnancy outcomes in malaria-exposed progeny.

A novel murine model for assessing fetal and birth outcomes following transgestational maternal malaria infection

“…A related study that we conducted recently supports this idea, and suggests that this impact likely outweighs maternal post-partum behavior. Neonates born to Swiss Webster dams that exhibited patterns of infection like those reported here displayed the same tendency to perish during the first four days of life, even when fostered on uninfected Swiss Webster dams 56 . In humans, low birth weight is associated with a significantly higher risk of infant death, regardless of etiology.…”

“…In this work, severe infection was associated with significant hemozoin accumulation, elevated transcripts for Ifng , Il10 , and Mgl2 , a marker for monocyte/macrophages in conceptuses, and reduced maternal vascular space in the placenta. These findings were coincident with reduced fetal weight at term and reduced survival in the first four days of life 56 . In addition to placental pathology, a stasis in pregnancy-associated weight gain was observed in infected mice between GD/ED 9 and GD/ED 11.…”

“…chabaudi chabaudi AS and P . berghei infected mice 34,56 . Among Mal+ dams, 9.8% to 18.2% of placental micrographs contained maternal blood vessels, while maternal blood vessels were observed in 32.0% to 38.6% of placental micrographs of Mal− placentae ( P < 0.0001; two-tailed Mann Whitney U test).…”

Germ-Free Swiss Webster Mice on a High-Fat Diet Develop Obesity, Hyperglycemia, and Dyslipidemia

“…Despite this, Swiss Webster mice do exhibit a genetic susceptibility to diabetes, as spontaneous development of obesity-associated polyuric, polydipsic, glucosuric, and hyperglycemic symptoms were observed previously [39]. Subsequently, Swiss Webster mice are reasonably prone to DIO, and the research community uses commercially available GF Swiss Webster mice for IMB transplant studies [36,[39][40][41][42][43][44][45][46][47]. Bäckhed and colleagues recently developed a simplified human IMB model using GF Swiss Webster mice that holds promise in the study of diet-host-microbiota interactions in relation to obesity and MetS [40].…”

Regulating Gut Microbiome: Therapeutic Strategy for Rheumatoid Arthritis During Pregnancy and Lactation

“…Recently, some scholars suggested that gut microbiome remodeling during pregnancy is a positive reaction of the mother and necessary for a successful pregnancy, which may contribute to the state of the immunity and metabolism (Konstantinov et al, 2013). However, more researchers believe that changes in gut microbiome during pregnancy are harmful to pregnant women and will cause related complications (Morffy Smith et al, 2019).…”