Table 2.

The studies on two-sided role of SCFA in host health via “gut-brain axis” establishing the connection between gut and brain.

Item	Model/subject	Administration route	Dose and duration	Outcomes	Effects type	Reference
–	30 autistic subjects from China, 20 healthy volunteers as controls	–	–	↓ Fecal acetate and butyrate, as well as butyrate-producing taxa in ASD subjects	Beneficial effect	Liu et al., 2019a, Liu et al., 2019b
Butyrate, SCFA-produced bacteria	C57BL/6J germ-free adult mice, sterile water as control	Oral gavage	Butyrate (1 g/kg body weight per day) for 3 d, Clostridium tyrobutyricum and Bacteroides thetaiotaomicron for 2 weeks	↓ Blood–brain barrier permeability; ↑ occludin expression in the frontal cortex and hippocampus	Beneficial effect	Braniste et al. (2014)
Acetate	C57BL/6 mice, saline as control	Intraperitoneal injection	500 mg/kg, 1, and 2 h	↓ Acute food intake; ↑ anorectic neuropeptide expression profile	Beneficial effect	Frost et al. (2014)
SCFA	C57BL/6J mice, saline as control	Intraperitoneal injection	Acetate (6 mmol/kg), propionate (6 mmol/kg), butyrate (6 mmol/kg) for 0.5, 1, and 3 h	↓ Food intake	Beneficial effect	Goswami et al. (2018)
SCFA	C57BL/6 mice SAE model, saline as control	Intragastrical administration before the model establishment	SCFA (acetate: propionate: butyrate at a ratio of 3:1:1) at 500 mg/kg body for 7 d	↓ Behavioral impairment and neuronal degeneration; ↓IL-1β and IL-6 levels in SAE mice brain	Beneficial effect	Liu et al. (2021)
–	Germ-free C57BL/6 mice	Fecal transplant gavage from aged or young male C57BL/6 mice into germ-free male mice at d 7, 14, 30, and 60	–	↓ Fecal acetate, propionate, and butyrate in aged mice with an aged microbiome	Beneficial effect	Lee et al. (2020a)
Butyrate	Sprague–Dawley rats cerebral ischemia model, saline as control	Intragastrical administration after ischemic modeling	Butyrate (30 mg/kg), 14 d	↓ Volume of the cerebral infarction; ↓ cerebral edema; ↓ intestinal integrity	Beneficial effect	Chen et al. (2019)
Butyrate	E3L.CETP mice received subdiaphragmatic vagotomy surgery, and sham surgery as controls	Intragastric gavage, intravenous injection after a recovery period of 1 week after the surgery	5% (wt/wt), 7 weeks	↓ Food intake; ↓ activity of orexigenic neurons for acute oral administration	Beneficial effect	Li et al. (2018)
SCFA	Human THP-1 cells with LPS (20 ng/mL) plus IFN-γ (100 U/mL)	SCFA were added to THP-1 cells 15 min before their stimulation with LPS plus IFN-γ, and then incubation 48 h	Acetate (5-500 μM), propionate (5-500 μM), butyrate (5-500 μM), formate (5-500 μM), and valerate (5-500 μM) for 48 h	↓ IL-1β, monocyte MCP-1, and TNF-α secretion	Beneficial effect	Wenzel et al. (2020)
–	Aged stroke mice	FTG from aged or young male C57BL/6 mice into aged stroke mice for 3 d	–	↑ SCFA-producers in young mice; ↓ poststroke neurological deficits, inflammation in aged stroke mice; ↑ gut, brain and plasma SCFA concentrations in aged stroke mice	Beneficial effect	Lee et al. (2020b)
Butyrate	N9 microglial cells, rat primary microglia	N9 cells incubated with LPS and butyrate simultaneously for 22 h, butyrate-pretreated (for 22 h) in rat primary microglia cultures and then incubated with 5 μg/mL LPS	Butyrate (0.6 mM) for N9 cells, butyrate (2.5 mM) for rat primary microglia	↑ LPS-induced IL-6 level in N9 cells; ↓ IL-6 level in rat primary microglia	Beneficial effect	Huuskonen et al. (2004)
–	Fifty-nine participants with insomnia symptoms (≥ 65 years)	Participants were divided into short and normal sleep duration phenotypes for a 2-week period	–	↑ Short sleep duration in insomnia is associated with an increase in SCFA	Pathological effect	Magzal et al. (2021)

ASD = autism spectrum disorder; SCFA = short chain fatty acids; SAE = sepsis-associated encephalopathy; IL-1β = interleukin-1β; IL-6 = interleukin-6; LPS = lipopolysaccharide; IFN-γ = interferon-γ; MCP-1 = monocyte chemoattractant protein-1; TNF-α = tumor necrosis factor-α; FTG = fecal transplant gavage. ↑ represents increase. ↓ represents decrease.