Objective: This feasibility, proof-of-concept study aimed to assess the impact of maternal pre-pregnancy body mass index (BMI) on preterm infant fecal fermentation and microbiome. Study Design: An infant cohort study (n = 54) in the NICU at MUSC from June 2021 to September 2022 was grouped according to maternal pre-pregnancy BMI—normal weight (<25 kg/m²), overweight (25–29.9 kg/m²), and obese (≥30 kg/m²). All fecal samples were subjected to 16s rRNA isolation and analysis, as well as short chain fatty acid (SCFA) extraction and analysis. Results: Preterm infants born to overweight and obese mothers did not have differences in microbial diversities but did have different bacterial taxonomic composition and lower relative abundance levels of taxa than those born to normal-weight mothers. While controlling for covariates, we found SCFA propionic acid to be higher and more significant in infant stools born to mothers with a higher pre-pregnancy BMI. Conclusions: This is a novel study investigating the microbiome and SCFA in premature infants while considering maternal pre-pregnancy BMI. This study adds to the current literature, in that the preterm infant gut is generally lower in microbial diversity which can impact infant health. Thus, it is important to understand the mechanisms necessary to modulate the microbiome of preterm infants to improve their health outcomes.

Background: Increasing evidence suggests that breast milk and its bioactive components, including short-chain fatty acids and the milk microbiome, are influenced by maternal nutrition and body mass index (BMI). Bioactive components transferred to the infant through breast milk play a pivotal role in infant growth and development and have indications in the child’s future short- and long-term health outcomes. This study aimed to assess the impact of maternal pre-pregnancy BMI (PP-BMI) on human breast milk macronutrient composition, short- and long-chain fatty acid profiles, and breast milk microbiome profiles. Approach: This was an exploratory cohort study of forty-four lactating Caucasian women, two to fourteen weeks postpartum, divided into groups based on pre-pregnancy body mass index (BMI). Study participants signed informed consent, completed health and nutritional surveys, and provided a breast milk sample. Breast milk samples were subjected to proximate analysis, microbiome identification and short- and long-chain fatty acid extraction and analysis. Results: Maternal age, maternal physical activity, infant birth weight, and time of lactation at sample collection were not significantly different between the maternal PP-BMI groups. PP-BMI was significantly different between the two maternal groups. No significant differences were found between the maternal BMI groups concerning nutritional intake. No differences in breast milk microbiomes were observed in alpha diversity and beta diversity between the maternal PP-BMI groups. For long-chain fatty analysis in breast milk samples, myristic acid was significantly higher in the PP-BMI overweight/obese group while stearic acid was significantly higher in the PP-BMI normal-weight group. Butyric, valeric, and isocaproic acid concentrations in HBM were significantly higher in the PP-BMI normal-weight group and lower or undetectable in the PP-BMI overweight/obese group. Conclusions: Data from this exploratory cohort study indicate that maternal diet and pre-pregnancy BMI may be associated with differences in selected HBM fatty acids. There were no significant differences in microbiomes for alpha and beta diversity in breast milk between maternal PP-BMI groups; however, lower relative abundance was observed in the breast milk of the PP-BMI overweight/obese group. These findings should be interpreted in the context of the study’s limitations, including convenience recruitment from a Facebook group, the modest sample size, and restriction to Caucasian women from a single geographic region.

Background: Major depressive disorder (MDD) affects approximately 20% of the population, with over 30% of cases demonstrating treatment resistance. Postmortem analyses have revealed increased poly (ADP-ribose) polymerase 1 (PARP-1) expression in prefrontal cortical white matter of individuals with MDD, suggesting PARP-1 as a potential therapeutic target. Chronic stress, a major risk factor for depression, affects multiple physiological domains including behavior, cardiovascular function, neuroinflammation, and gut-brain axis signaling. Methods: We conducted a comprehensive multi-system investigation of PARP inhibition effects on stress-induced pathophysiology using the social defeat stress/chronic unpredictable stress (SDS+CUS) rodent model. In the primary study, male Sprague-Dawley rats (N=32) underwent 10 days of SDS+CUS while receiving daily treatment with the PARP inhibitor 3-aminobenzamide (3-AB; 40mg/kg), selective serotonin reuptake inhibitor fluoxetine (FLX; 10mg/kg), or saline (0.9% NaCl), with non-stressed controls included. Behavioral outcomes were assessed via sucrose preference and social interaction tests. Neurobiological analyses examined PARP-1 expression, microglial morphology, and proinflammatory cytokine levels (IL-1β, TNF-α, IL-6) in relevant brain regions. In a parallel cardiovascular study, a separate cohort of stressed rats (N=8) received either saline or 3-AB treatment while hemodynamic parameters were monitored via telemetry before, during, and after stress exposure. Exploratory gut microbiome analyses were also conducted (see Supplemental Materials). Results: Saline-treated stressed rats demonstrated significantly elevated anhedonia and social avoidance compared to all other groups, while 3-AB treatment prevented these behavioral deficits. Cardiovascular monitoring revealed that stressed saline-treated rats developed significant elevations in systolic and mean blood pressure with decreased heart rate compared to baseline, whereas 3-AB treatment prevented these hemodynamic changes. Neurobiological analyses showed that FLX-treated stressed rats unexpectedly exhibited elevated PARP-1 expression in prefrontal cortical gray matter. Microglial morphological analysis revealed significantly more prolate (activated) microglia in the saline-treated stressed rats compared to all other treatment groups. Saline-treated stressed rats exhibited significantly increased hippocampal proinflammatory cytokines, with 3-AB treatment specifically normalizing TNF-α levels. Conclusion: PARP inhibition with 3-AB provides multi-system protection against chronic stress effects, preventing behavioral deficits, cardiovascular dysfunction, and neuroinflammation. These findings establish PARP-1 as a key mediator in the systemic pathophysiology of chronic stress and highlight PARP inhibition as a promising therapeutic approach for stress-related disorders with treatment-resistant features. Significant Outcomes: PARP inhibition with 3-aminobenzamide (3-AB) prevented stress-induced behavioral deficits (anhedonia and social avoidance) in a validated rodent model combining social defeat and chronic unpredictable stress. 3-AB treatment prevented stress-induced increases in arterial blood pressure. PARP inhibition prevented microglial activation and reduced proinflammatory cytokine expression (IL-1β and TNF-α) in stress-sensitive brain regions, supporting an anti-neuroinflammatory mechanism of action. FLX-treated stressed rats unexpectedly showed elevated PARP-1 expression in prefrontal cortical gray matter, suggesting a previously unrecognized interaction between serotonergic antidepressants and PARP-1 signaling that warrants further investigation. The multi-system protective effects of PARP inhibition, spanning behavioral, cardiovascular, and neuroinflammatory domains, suggest therapeutic potential for treatment-resistant depression. Limitations: This study examined only male rats, limiting generalizability to female subjects despite the higher prevalence of MDD in women. Behavioral assessments were limited to anhedonia and social interaction; additional tests of other depression-relevant behaviors would provide a more comprehensive phenotypic profile. Long-term effects of 3-AB treatment beyond the 10-day stress paradigm remain unexplored.