Table 1.

Identified effects of SCFA in human interventional, observational, and animal studies.

SCFA	Study (Sample)	Study Design	Tissues Investigated	End-Point Measured	Observed Effects	Reference
Human interventional studies
C2	H (n =32)	Case-control	Peripheral blood	Immunopharmacological effects of Ringer’s acetate	Increased polyclonal antibody production and NK cell activity in healthy and cancer subjects	[141]
C3	H (n = 6)	Cross-over	Serum and stool	Blood lipids and glucose, stool bulk and microbiota	C3 supplementation lowers blood glucose. Lipid changes not significant; increase in stool bulk and Bifidobacteria after 1 week intervention	[142]
C4	H (n = 16)	Cross-over	Sigmoid colon biopsies and plasma	Oxidative stress markers in colon; CRP, calprotectin; histological inflammation	Rectal administration significantly reduced uric acid and increased GSH. No significant changes in other parameters	[143]
Human Observational studies
C2-C6	H (n = 232)	Observation	Stool	Levels of faecal SCFA and BCFA association with BMI and age	BCFA strongly correlated with age, but not with BMI; BCFA negatively associated with fibre consumption; BMI ≥ 40 showed significantly higher production of SCFA, total BCFA, isobutyrate, isovalerate and caproate SCFA production decreases with age	[131]
Animal (interventional) studies
C2, C3	M (n = 15)	Knock-out	Adipose tissue	Effects of GPCR43 activation	Reduction of lipolysis, reduced plasma free fatty acids levels without flushing associated with GPCR109A	[144]
C2, C3	M (n = 12)	Case-control	Adipose, gut, vascular and mesenchymal tissues	GPCR41 and GPCR43 mRNA expression	GPCR43 activation promoted adipose differentiation via PPARγ2. No effects on GPCR41	[145]
C2, C3, C4	S (n = 10)	Case-control	Portal and peripheral blood, liver	Food intake following SCFA infusions	Dose-dependent depression in food intake, explained by C3 content in portal vein, which resolved with portal plexus denervation	[146]
C3	R (n = 20) P (n = 12, 60)	Case-control	Portal blood and liver	Cholesterol synthesis and distribution	Supplemented C3 likely absorbed in the stomach Dose-dependent hypocholesterolemic effect likely due to redistribution of cholesterol from plasma to liver, as opposed to synthesis inhibition	[147,148]
C3	R (n = 74, 114)	Case-control	Brain, intracerebral ventricles	Behavioural, electrophysiological, neuropathological, and biochemical effects	C3 intraventricular infusion impaired social behaviours, similar to those seen in human ASD; induced neuroinflammation and oxidative stress; Alteration of brain phospholipid and acylcarnitine1 profiles	[149,150]
C4	R (n = 22)	Case-control	Duodenum, jejunum, cecum and distal colon	PYY and proglucagon gene expression in gut epithelial cells	Up-regulation of local peptide YY and proglucagon expression via colonocyte sensing following a RS diet in vivo, proved by in vitro incubation with butyrate	[151]
C4	M (n = 16–20)	Case-control	Whole-body autopsy	Insulin sensitivity and energy metabolism, mitochondrial function	C4 supplementation prevented diet-induced insulin resistance and reduced adiposity in high-fat model, without reducing food intake. Attributed to enhanced mitochondrial activity and thermogenesis	[152]
In Vitro Studies
C2-C6	M (n = 18)	N/A	mouse adipocyte cell line and adipose primary culture	Leptin expression	C2-C6 stimulate leptin expression via GPCR41 Acute administration of C3 increased leptin levels	[153]
C2, C4	R, B	N/A	Anterior pituitary, fat and liver aspirates	Leptin and leptin-receptor protein expression	C2 and C4 enhanced leptin expression in bovine pituitary and fat cells, however C4 inhibited leptin expression in rat anterior pituitary cells; while C4 suppressed leptin receptor expression in both rat and bovine pituitaries; probable species specific nutrient sensing	[154]
C2, C3, C4	R, H	N/A	Colonic stimulation	Effects on colon functions, inc. motility	C3 and C4 induced phasic and tonic contractions of circular muscle via GPCR41 and GPCR43 in mucosae, C2 did not	[155]
C2, C3, C4	M (n= 4) H (n= 3)	N/A	Human blood samples, colon cultures (colo320DM) and mice with colitis	Anti-inflammatory properties of SCFA	All SCFA decreased neutrophil TNF-α release without affecting IL-8; all decreased IL-6 release; all inhibited NF-κB activity in colon cells; C4 > C3 > C2	[156]
C3	H (n = 5–9)	N/A	Human umbilical vein endothelial cells (HUVEC)	Expression of endothelial leukocyte adhesion molecules and leukocyte recruitment by cytokine-stimulation	Significant inhibition of TNF-α and NF-κB, reducing expression of VCAM-1 and ICAM-1 in a time- and dose-dependent manner; significantly increased PPARα expression	[157]
C3	H (n = 28)	N/A	Omental and subcutaneous adipose tissue	Adipokine expression	Significant leptin induction and secretion; no effect on adiponectin; Reduction of resistin mRNA expression	[158]
C3	R, H (n = 1)	N/A	Human blood and rat mesenteric lymph nodes	T and B lymphocyte proliferation and metabolism	Inhibition of lipid synthesis as a possible mechanism leading to reduction of lymphocyte proliferation	[159]
C3	R (n = 9)	N/A	Isolated hepatocytes	Hepatic lipidogenesis	Inhibits hepatic cholesterol and fatty acid synthesis in a dose-dependent manner, possibly by competition with C2	[160]

ASD, autism spectrum disorder; B, bovine; H, human,; M, mice; P, pigs; R, rat; S, sheep; C2, acetate; C3, propionate; C4, butyrate; C5, valerate; C6, caproate; HUVEC, human umbilical vein endothelial cells; TNF-α, tumour necrosis factor alpha; VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intracellular adhesion molecule-1; RS, resistant starch; GSH, glutathione peroxidase; PYY, peptide YY; SCFA, short chain fatty acids; BCFA, branched-chain fatty acids; BMI, body mass index; GPCR, G-protein coupled receptor; TNF-α, tumour necrosis factor alpha; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells N/A, not applicable.