Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring

Abstract

SUMMARY Maternal obesity during pregnancy has been associated with increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. Here we report that maternal high fat diet (MHFD) induces a shift in microbial ecology that negatively impacts offspring social behavior. Social deficits and gut microbiota dysbiosis in MHFD offspring are prevented by co-housing with offspring of mothers on a regular diet (MRD) and transferable to germ-free mice. In addition, social interaction induces synaptic potentiation (LTP) in the ventral tegmental area (VTA) of MRD, but not MHFD offspring. Moreover, MHFD offspring had fewer oxytocin immunoreactive neurons in the hypothalamus. Using metagenomics and precision microbiota reconstitution, we identified a single commensal strain that corrects oxytocin levels, LTP, and social deficits in MHFD offspring. Our findings causally link maternal diet, gut microbial imbalance, VTA plasticity and behavior, and suggest that probiotic treatment may relieve specific behavioral abnormalities associated with neurodevelopmental disorders.

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling

“…Social deficits in mice (less interest in social interaction, poor memory for social partners) [110,113] Reversal of social deficits in murine models of ASD [111,115] Reversal of antibiotic-induced social deficits in mice [113] Reduced risk for ASD [116] , reduced symptom severity in children with ASD (open pilot) [117] Transplant of standardized human gut microbiota to children with ASD improved ASD symptoms in open-label pilot [118] Pain Visceral hypersensitivity in mice [119] Visceral hypersensitivity in healthy mice [94,120,135] Reversal of visceral hypersensitivity in stressed mice [122] Increased risk for IBS in humans [51] Positive effects on pain in IBS patients [127] Reversal of stressinduced visceral hypersensitivity in rats [121] Reversal of antibiotic-induced visceral hypersensitivity in mice [135] Positive effects on IBS symptoms in humans [127] Transplant from IBS donors increases GI symptoms (accelerated gastrointestinal transit, increased intestinal permeability) in mice [125,126] Transplant from healthy donors reduces GI symptoms (constipation, diarrhea, indigestion, abdominal pain) in children with ASD (open-label pilot) [118] www.advancedsciencenews.com www.bioessays-journal.com been several studies reporting no effect of probiotics on these measures, [99] these disparate results may be explained by straindependent effects or a moderating effect of symptom severity because it has been reported that the beneficial effects are greatest for those with the most negative symptoms at baseline. [100] …”

“…Like humans, rodents are naturally social animals, but GF rats and mice exhibit deficits in social behaviors such that they show less interest in social interaction and poorer memory for social partners. [89,[110][111][112] Deficits in social behavior are also observed following antibiotic-induced depletion of the microbiota. [72,113] The microbiota also plays a role in murine models of ASD, where treatment with specific bacteria has been shown to reverse many of the social deficits observed in these animals.…”

“…[72,113] The microbiota also plays a role in murine models of ASD, where treatment with specific bacteria has been shown to reverse many of the social deficits observed in these animals. [111,114] There is some promising early evidence that this approach may translate to clinical settings. Individuals with ASD often exhibit gastrointestinal problems and alterations in the microbiota.…”

The Gut Microbiota - The Environmental Causative Factor and the Potential Therapeutic Targets of Autism Spectrum Disorder

“…The results supported the gut-microbiome-brain connection in the mouse model of ASD and identified a potential therapeutic target. Another recent report also indicated that maternal high-fat diet could induce a shift in gut microbial ecology and negatively impact offspring's ASD-like social behavior [25]. Clinical case study also observed reduced severity of abdominal symptoms and improvement of ASD core symptoms after a multi-strain mixture of ten probiotics treatment for 4 weeks and followed by a four month followup observation on a 12 year old boy with ASD and severe cognitive disabilities [26].…”

Control of immune-mediated pathology via the aryl hydrocarbon receptor

“…Third, these data point to a new gut-brain signaling axis in controlling the development of inflammatory and degenerative pathology in humans. These findings also add to recent advancements made in studies of neuropsychiatric disease where the gut microbiota modulate transcriptional programs that control social behavior (92), modulate synaptic dysfunction (93), and can modulate phenotypes associated with autism (94). It should also be kept in mind that, besides acting as a CNS sensor for immunomodulatory metabolites produced in the gut, based on its effects on gut immunity AhR may also shape the gut flora, impacting the gut-brain axis at multiple levels.…”