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Short-chain fatty acids (SCFAs), mainly acetate, propionate, and butyrate, produced by microbial fermentation of undigested food substances are believed to play a beneficial role in human gut health. Short-chain fatty acids influence colonic health through various mechanisms. In vitro and ex vivo studies show that SCFAs have anti-inflammatory and anticarcinogenic effects, play an important role in maintaining metabolic homeostasis in colonocytes, and protect colonocytes from external harm. Animal studies have found substantial positive effects of SCFAs or dietary fiber on colonic disease, but convincing evidence in humans is lacking. Most human intervention trials have been conducted in the context of inflammatory bowel disease. Only a limited number of those trials are of high quality, showing little or no favorable effect of SCFA treatment over placebo. Opportunities for future research include exploring the use of combination therapies with anti-inflammatory drugs, prebiotics, or probiotics; the use of prodrugs in the setting of carcinogenesis; or the direct application of SCFAs to improve mucosal healing after colonic surgery.

Background: Short-chain fatty acids (SCFAs), fermentation products of undigested fibers, are considered beneficial for colonic health. High plasma concentrations are potentially harmful; therefore, information about systemic SCFA clearance is needed before therapeutic use of prebiotics or colonic SCFA administration. Objective: The aim of this study was to investigate the effect of rectal butyrate administration on SCFA interorgan exchange. Methods: Twelve patients (7 men; age: 66.4 6 2.0 y; BMI 24.5 6 1.4 kg/m 2 ) undergoing upper abdominal surgery participated in this randomized placebo-controlled trial. During surgery, 1 group received a butyrate enema (100 mmol sodium butyrate/L; 60 mL; n = 7), and the other group a placebo (140 mmol 0.9% NaCl/L; 60 mL; n = 5). Before and 5, 15, and 30 min after administration, blood samples were taken from the radial artery, hepatic vein, and portal vein. Plasma SCFA concentrations were analyzed, and fluxes from portal-drained viscera, liver, and splanchnic area were calculated and used for the calculation of the incremental area under the curve (iAUC) over a 30-min period. Results: Rectal butyrate administration led to higher portal butyrate concentrations at 5 min compared with placebo (92.2 6 27.0 mmol/L vs. 14.3 6 3.4 mmol/L, respectively; P < 0.01). In the butyrate-treated group, iAUCs of gut release (282.8 6 133.8 mmol/kg BW 0.5 h) and liver uptake (2293.7 6 136.0 mmol/kg BW 0.5 h) of butyrate were greater than in the placebo group [216.6 6 13.4 mmol/kg BW 0.5 h (gut release) and 16.0 6 13.8 mmol/kg BW 0.5 h (liver uptake); P = 0.01 and P < 0.05, respectively]. As a result, splanchnic butyrate release did not differ between groups. Conclusion: After colonic butyrate administration, splanchnic butyrate release was prevented in patients undergoing upper abdominal surgery. These observations imply that therapeutic colonic SCFA administration at this dose is safe. The trial was registered at clinicaltrials.gov as NCT02271802. JN utr2015;145:2019‐24.

Background and aims: Gut derived short-chain fatty acids (SOFA), formed by microbial fermentation of dietary fibers, are believed to be involved in the etiology of obesity and diabetes. Previous data from our group showed that colonic infusions of physiologically relevant SOFA mixtures attenuated whole-body lipolysis in overweight men. To further study potential mechanisms involved in the antilipolytic properties of SOFA, we aimed to investigate the in vitro effects of SOFA incubations on intracellular lipolysis and signaling using a human white adipocyte model, the human multipotent adipose tissue-derived stem (hMADS) cells. Methods: hMADS adipocytes were incubated with mixtures of acetate, propionate, and butyrate or single SOFA (acetate, propionate and butyrate) in concentrations ranging between 1 mu mol/L and 1 mmol/L. Glycerol release and lipase activation was investigated during basal conditions and following p-adrenergic stimulation. Results: SOFA mixtures high in acetate and propionate decreased basal glycerol release, when compared to control (P < 0.05), while mixtures high in butyrate had no effect. Also, p-adrenergic receptor mediated glycerol release was not significantly altered following incubation with SOFA mixtures. Incubation with only acetate decreased basal (1 mu mol/L) and p-adrenergically (1 mmol/L and 1 mmol/L) mediated glycerol release when compared with control (P < 0.05). In contrast, butyrate (1 mu mol/L) slightly increased basal and p-adrenergically mediated glycerol release compared with control (P < 0.05), while propionate had no effect on lipolysis. The antilipolytic effect of acetate was accompanied by a reduced phosphorylation of hormone-sensitive lipase (HSL) at serine residue 650. In addition, inhibition of Gi G proteins following pertussis toxin treatment prevented the antilipolytic effect of acetate. Conclusion: The present data demonstrated that acetate was mainly responsible for the antilipolytic effects of SOFA and acts via attenuation of HSL phosphorylation in a Gi coupled manner in hMADS adipocytes. Therefore, the modulation of colonic and circulating acetate may be an important target to modulate human adipose tissue lipid metabolism.

The gut microbiota has been implicated in obesity and cardiometabolic diseases, although evidence in humans is scarce. We investigated how gut microbiota manipulation by antibiotics (7-day administration of amoxicillin, vancomycin, or placebo) affects host metabolism in 57 obese, prediabetic men. Vancomycin, but not amoxicillin, decreased bacterial diversity and reduced Firmicutes involved in short-chain fatty acid and bile acid metabolism, concomitant with altered plasma and/or fecal metabolite concentrations. Adipose tissue gene expression of oxidative pathways was upregulated by antibiotics, whereas immune-related pathways were downregulated by vancomycin. Antibiotics did not affect tissue-specific insulin sensitivity, energy/substrate metabolism, postprandial hormones and metabolites, systemic inflammation, gut permeability, and adipocyte size. Importantly, energy harvest, adipocyte size, and whole-body insulin sensitivity were not altered at 8-week follow-up, despite a still considerably altered microbial composition, indicating that interference with adult microbiota by 7-day antibiotic treatment has no clinically relevant impact on metabolic health in obese humans.