TABLE 1

Animal models linking gut microbiota changes to ASD-like behavioral disruptions

PublicationAnimal ModelType of TreatmentMajor Finding
Sudo et al. (2004)GF and SPF mice• The gut of GF mice was reconstituted with B. infantis via oral administration to the parents with transmission to the offspring at the neonatal stage.• Adult GF mice subjected to restraint stress exhibited hypersecretion of ACTH and corticosterone.
• GF mice received fecal transplantation from SPF animals (0.5 ml of 1 × 10−2 dilution of fresh SPF mouse feces 1 or 3 weeks prior to the stress protocol at 9 or 17 weeks of age).• Adult GF mice had suppression of neurotropin, BDNF, and NR2A in the cerebral cortex and hippocampus.
• Reconstitution with B. infantis alleviated the exaggerated HPA responses.
• Feces from SPF partially reversed the hormonal abnormalities in GF mice, but only if done early in life.
Diaz Heijtz et al. (2011); Gareau et al. (2011); Neufeld et al. (2011b); Clarke et al. (2013); Desbonnet et al. (2014)GF and conventionally colonized mice• No treatment in Diaz Heijtz et al. (2011), Gareau et al. (2011), Neufeld et al. (2011b), and Clarke et al. (2013).• Combined studies indicate GF mice demonstrate reduced anxiety-like but increased exploratory behaviors and cognitive deficits in nonspatial and working memory tasks, and males, especially, avoided social situations.
• Postweaning bacterial colonization (details not specified) in Desbonnet et al. (2014).• Postweaning bacterial colonization mitigated the avoidance of social situations by GF mice (Desbonnet et al., 2014).
Foley et al. (2015)Rats• Pregnant P0 rats were treated with the bacterial metabolite, PPA (500 mg/ kg b.wt. s.c. on GDs 12–16) or the LPS (50 mg/ kg b.wt. s.c. on GD 15 or 16). Control pregnant P0 rats received vehicle control on GDs 12–16 or 15 to 16.• F1 male and female offspring derived from the treated rats showed impairments in olfactory-mediated social recognition, persistence in examining a novel object, hyperlocomotion, and disruptions in social behaviors.
Foley et al. (2014a, b)Rats• Pregnant P0 rats were treated with the bacterial metabolite, PPA (500 mg/ kg b.wt. s.c. on GDs 12–16) or the LPS (50 mg/ kg b.wt. s.c. on GD 12 or GDs 15 to 16), and these treatments were continued during the postnatal period. Control pregnant P0 rats received vehicle control on GDs 12, 12–16, or 15 to 16.• F1 males subjected to prenatal LPS treatment were hypersensitive in acoustic startle testing.
• F1 females exposed to pre- and postnatal PPA (double hit) were sensitized in this test.
• F1 females exposed to PPA during the prenatal period had reduced prepulse inhibition, but similar effects were not observed in males.
• F1 males and females exposed to prenatal PPA treatment spent less time in the center of the open field maze, suggestive of increased anxiety-like behaviors.
• Anxiogenic behaviors were also exhibited by F1 females exposed to PPA pre- and postnatally when tested in the EPM.
• The double-hit female group also engaged in more repetitive behaviors in the open-field tests.
Thomas et al. (2012)Rats• Rats (47–49 days of age) were exposed twice daily to intraventricular injection of PPA (4.0 μl of a 0.26 M solution) for an acute period (8 days).• Treated rats exhibited hyperlocomotion and architectural changes in the brain.
Shultz et al. (2008)Male rats• Adult male rats were assigned to one of four treatments:• PPA-treated rats demonstrated social behavioral deficits evidenced by increased mean distance apart and less time spent in proximity to other animals, reduced playful bouts, and altered response to playful intentions from companions.
1. PPA (4 μl of 0.26 M solution)• Another SCFA, sodium acetate, induced similar impairments but no effects were detected with PROP (alcohol analog of PPA).
2. SA (4 μl of 0.26 M solution)• Reactive astrogliosis (neuroinflammation) occurred in the brains of PPA-treated rats.
3. PROP (4 μl of 0.26 M solution)
4. PBS vehicle control (4 μl of 0.1 M solution)
Shultz et al. (2015)Seizure-prone (FAST) and seizure-resistant (SLOW) male rats• Nine week old male rats were assigned to one of four groups:• PPA induced social abnormalities in FAST and SLOW rat strains.
1. FAST + PPA (4μl, 0.26 M)• PPA treatment resulted in neuroinflammation (astrogliosis) in the corpus callosum and cerebral cortex.
2. SLOW + PPA (n = 14)• Neuroinflammatory effects were more prominent in FAST compared with SLOW rats.
3. FAST + PBS vehicle control (4μl)
4. SLOW + PBS
Shultz et al. (2009)Male rats• Adult male rats were assigned to one of five treatment groups:• PPA-treated rats showed impairments in spatial acquisition and reversal training in the water maze test and beam task.
1. PPA-5 (4 μl of 0.26 M solution)• Neuroinflammation was increased in the brains of PPA-treated rats.
2. PPA-3 (4 μl of 0.26 M solution)
3. SA (4 μl of 0.26 M solution)
4. PROP (4 μl of 0.26 M solution)
5. PBS (4 μl)
de Theije et al. (2014)Mice• Pregnant P0 mice were treated on GD 11 with VPA (600 mg/kg b.wt. s.c.) or PBS (controls).• F1 VPA-treated offspring demonstrated social behavioral deficits.
• The composition of SCFAs was changed in the F1-treated offspring.
• Gut dysbiosis with changes in the Bacteroidetes and Firmicutes phyla and Desulfovibrionales resulted in F1 exposed offspring.
• F1-exposed male offspring had alterations in Alistipes, Enterohaabdus, Mollicutes, and Erysipelotrichalis genera.
• Gut microbiome disturbances were more pronounced in F1 male than female offspring.
Hsiao et al. (2013)MIA mouse model and wild-type (naive) mice• Pregnant P0 mice were treated on GD 12.5 with saline (control) or the immunostimulant Poly I:C acid, 20 mg/kg b.wt. via i.p. injection). This latter treatment results in MIA offspring.• MIA offspring demonstrated disruption of the intestinal barrier.
• MIA offspring were orally treated with B. fragilis (ATCC 9343) or vehicle every other day for 6 days at weaning. 1 × 1010 CFUs of freshly grown B. fragilis or 1.5% sodium bicarbonate was administered in sugar-free applesauce.• Approximately 8% of bacterial metabolites were altered in MIA offspring with a leaky gut.
• Wild-type mice were treated with the bacterial metabolite (4-EPS, 30 mg/kg b.wt. via i.p. injection from 3 to 6 weeks of age).• MIA offspring exhibited communication deficits, and stereotypic, anxiety-like, and sensorimotor behaviors.
• Supplementation of MIA offspring with B. fragilis restored the intestinal barrier and mitigated the gut dysbiosis, metabolomics changes (including for 4-EPS), and behavioral changes.
• Wild-type mice treated with 4-EPS exhibited anxiety-like behaviors similar to those observed in other ASD animal models.
  • ACTH, adrenocorticotropic hormone; CFU, colony forming unit; EPM, elevated plus maze; GD, gestational day; PBS, phosphate-buffered saline; Poly I:C, polyinosinic:polycytidylic; PROP, 1-propanol; SA, sodium acetate.