LIMOSILACTOBACILLUS REUTERI NORMALIZES BLOOD-BRAIN BARRIER DYSFUNCTION AND NEURODEVELOPMENT DEFICITS ASSOCIATED WITH PRENATAL EXPOSURE TO LIPOPOLYSACCHARIDE.

Background: Diet is known to alter the risk of depression. Increasing data also demonstrate a causal role of the gut microbiome in mental illness, via the gut-brain axis. However, it remains unclear how diet and the microbiome mechanistically influence depression risk in humans. Leveraging dietary, metabolomics, microbiome, and depression data, we assessed how gut microbial species and their pathways may mediate the association between depression and citrus, a food group that possibly protects against risk of depression.

Methods: We conducted a prospective study in the Nurses’ Health Study II (NHSII) between 2003 and 2017 among 32,427 middle-aged women free of depression at baseline. Citrus intake was determined using validated food frequency questionnaires collected every 4 years. Depression was defined according to physician-diagnosis and antidepressant use. Between 2013-2014, 207 NHSII participants enrolled in a nested substudy, providing up to 4 stool samples (profiled by shotgun metagenomics) and a blood sample (profiled by LC-MS-based metabolomics). Cox proportional hazard models were used to relate citrus intake with depression risk. Linear mixed effects models were used to relate diet with gut microbial features, and microbial features with depression. We also associated microbial features with a depression-risk score, derived according to levels of circulating serotonin and GABA. All models were adjusted for multiple dietary, medication and lifestyle variables including age, BMI, calorie/alcohol intake, and diet quality. We validated our findings in a subcohort of 307 men in the Health Professionals Follow-up Study (HPFS).

Results: Total citrus intake was associated with a lower risk of incident depression (p_trend 0.001), with a multivariable relative risk of 0.80 (95% CI, 0.68-0.93), comparing extreme quintiles. Within the NHSII substudy, greater citrus intake was associated with increased abundance of Faecalibacterium prausnitzii (β 0.026, FDR 0.17). In turn, levels of F. prausnitzii were higher in non-depressed individuals compared to depressed participants (p 0.003). Greater abundance of F. prausnitzii was also associated with our metabolomics-based depression-risk score in the NHSII (p 0.03), and in the HPFS validation study (p 0.02). In an exploratory analysis of gut microbial pathways, S-Adenosyl-L-Methionine (SAM) cycle I, encoded by F. prausnitzii, was reduced in depressed participants.

Conclusion: Greater citrus intake was prospectively associated with lower risk of depression, and with greater abundance of F. prausnitzii. In turn, participants with depression had lower levels of F. prausnitzii and lower abundance of its genes capable of producing SAM, a compound known to have antidepressant properties. These data offer a potential mechanism by which diet influences the gut microbiome to reduce risk of depression.

Background: Experiences of discrimination are associated with adverse health outcomes, including obesity and obesity-related comorbidities. However, the underlying whole-body mechanisms remain unclear. We investigated the impact of discrimination experiences on brain reactivity to food images and associated dysregulations in the brain-gut microbiome (BGM) system. Methods: Brain responses to healthy and unhealthy food cues were obtained by magnetic resonance imaging in 107 male and female participants. Fecal samples were collected to measure fecal metabolites. The Everyday Discrimination Scale was administered to assess perceived experiences of chronic and routine unfair treatment. Structural equation modeling (SEM) was used to evaluate complex relationships between discrimination and altered bidirectional communication within the BGM system in the context of reactivity to food stimuli. Results: Discrimination was associated with increased food-cue reactivity in frontal-striatal regions involved in reward processing, motivation, and executive control, especially for unhealthy foods, as well as altered glutamate-pathway metabolites involved in oxidative stress and inflammation. SEM analyses demonstrated a significant association between discrimination-related brain and gut signatures skewed towards unhealthy foods, after adjusting for key variables such as age, sex, diet, BMI, race and socioeconomic status. Conclusions: Discrimination, as a stressor, may contribute to enhanced food-cue reactivity and BGM system disruptions that can promote unhealthy eating behaviors, leading to increased risk for obesity and related diseases. Treatments that normalize these alterations may benefit individuals with discrimination-related stress exposure.

Maternal immune activation (MIA) derived from late gestational infection such as seen in chorioamnionitis poses a significantly increased risk for neurodevelopmental deficits in the offspring. Manipulating early microbiota through maternal probiotics supplementation has been shown to be an effective means to improve outcomes, however, the mechanisms remain unclear. In this study we modeled MIA by maternal lipopolysaccharide (LPS) exposure (i.p. injection at E16) and tested the hypothesis that maternal probiotic administration during lactation may rescue the adverse neurodevelopmental outcome of MIA on offspring through the impact on blood-brain barrier (BBB) development and function. T2W, Time of flight, and T1W MRI with contrast were used to evaluate BBB development and permeability at early postnatal age (two weeks of age). Morris water maze test was used to evaluate long term cognitive function at 12 weeks of age. The effects of MIA with or without maternal Limosilactobacillus reuteri (L. reuteri) exposure on gut microbiome and systemic and brain metabolites were investigated using 16S DNA sequencing of fecal samples and metabonomic analysis at both two and 12 weeks of age. We demonstrated that MIA modeled by exposing pregnant dams to LPS induced an underdevelopment of the blood vessels, an increase in permeability and astrogliosis of BBB at pre-wean age. The BBB developmental and functional deficits early in life impaired spatial learning later in life. Maternal L. reuteri supplementation starting at birth rescued the BBB underdevelopment and dysfunction-associated cognitive function. β-diversity was significantly affected by LPS with or without maternal L. reuteri exposure. We further identified two lipid metabolites that can cross the BBB upon LPS insult and fourteen metabolic products of lipid/bile acid metabolism associated with maternal L. reuteri exposure during lactation that can cross the BBB. We conclude that maternal L. reuteri-mediated alterations in β-diversity of the microbial community and metabolic responses in the offspring provide mechanisms and potential targets for promoting BBB integrity and long-term neurodevelopmental outcomes.