Compendium of the most significant studies with reference to properties, intake, effects.

Filippone A, Casili G, Scuderi SA, Mannino D, Lanza M, Campolo M, Paterniti I, Capra AP, Colarossi C, Bonasera A, Lombardo SP, Cuzzocrea S, Esposito E. Sodium Propionate Contributes to Tumor Cell Growth Inhibition through PPAR-γ Signaling. Cancers (Basel). 2022 Dec 29;15(1):217. doi: 10.3390/cancers15010217. 

Abstract. New therapeutic approaches are needed to improve the outcome of patients with glioblastoma (GBM). Propionate, a short-chain fatty acid (SCFA), has a potent antiproliferative effect on various tumor cell types. Peroxisome proliferator-activated receptor (PPAR) ligands possess anticancer properties. We aimed to investigate the PPAR-γ/SCFAs interaction in in vitro and in vivo models of GBM. The U87 cell line was used in the in vitro study and was treated with sodium propionate (SP). U87 cells were silenced by using PPAR-γ siRNA or Ctr siRNA. In the in vivo study, BALB/c nude mice were inoculated in the right flank with 3 × 106 U-87 cells. SP (doses of 30 and 100 mg/kg) and GW9662 (1 mg/kg) were administered. In vitro exposure of GBM to SP resulted in prominent apoptosis activation while the autophagy pathway was promoted by SP treatments by influencing autophagy-related proteins. Knockdown of PPAR-γ sensitized GBM cells and blocked the SP effect. In vivo, SP was able to decrease tumor growth and to resolve GBM tissue features. SP promoted apoptosis and autophagy pathways and tumor cell proliferation leading to cell cycle arrest through a PPAR-γ-dependent mechanism suggesting that the PPAR-γ/SCFAs axis could be targeted for the management of GBM.

Cook KJ, Coulter A, Keenan M, Greenway F, Losso JN. Sodium Propionate or Sodium Butyrate Promotes Fatty Acid Oxidation in HepG2 Cells Under Oxidative Stress. J Med Food. 2023 Jan;26(1):74-79. doi: 10.1089/jmf.2021.0120. 

Abstract. The beneficial effects of sodium butyrate (NaB) and sodium propionate (NaP) on fatty acid oxidation (FAO) genes and production of proinflammatory cytokines related to nonalcoholic fatty liver disease (NAFLD) were evaluated using HepG2 human liver hepatocellular carcinoma cells exposed to palmitate/oleate or lipopolysaccharides (LPSs) as a model. The results showed that NaP or NaB was able to promote FAO, regulate lipolysis, and reduce reactive oxygen species production by significantly increasing the mRNA expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), peroxisome proliferator-activated receptor alpha (PPARα), adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1 alpha (CPT1α), fibroblast growth factor 21 (FGF21), and uncoupling protein 2 (UCP2) in HepG2 cells. Together, NaP and NaB may produce greater effects by increasing CPT1α, PPARα, and UCP2 mRNA expression in LPS-treated HepG2 cells and by increasing CPT1α and ATGL mRNA expression in palmitate-/oleate-treated HepG2 cells. Only NaP treatment significantly increased FGF21 mRNA expression in palmitate-/oleate-treated HepG2 cells. The enzyme-linked immunosorbent assay results revealed that only pretreatment with LPSs and not palmitate/oleate significantly increased tumor necrosis factor alpha (TNF-α) expression in HepG2 cells. NaP alone or in combination with NaB significantly decreased TNF-α expression in LPS-induced HepG2 cells. The expression of interleukin-8 in both models showed no significant differences in all treatments. NaP and NaB show potential for in vivo studies on NAFLD.

Filippone A, Lanza M, Campolo M, Casili G, Paterniti I, Cuzzocrea S, Esposito E. The Anti-Inflammatory and Antioxidant Effects of Sodium Propionate. Int J Mol Sci. 2020 Apr 24;21(8):3026. doi: 10.3390/ijms21083026.

Abstract. The major end-products of dietary fiber fermentation by gut microbiota are the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate, which have been shown to modulate host metabolism via effects on metabolic pathways at different tissue sites. Several studies showed the inhibitory effects of sodium propionate (SP) on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. We carried out an in vitro model of inflammation on the J774-A1 cell line, by stimulation with lipopolysaccharide (LPS) and H2O2, followed by the pre-treatment with SP at 0.1, 1 mM and 10 mM. To evaluate the effect on acute inflammation and superoxide anion-induced pain, we performed a model of carrageenan (CAR)-induced rat paw inflammation and intraplantar injection of KO2 where rats received SP orally (10, 30, and 100 mg/kg). SP decreased in concentration-dependent-manner the expression of cicloxigenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) following LPS stimulation. SP was able to enhance anti-oxidant enzyme production such as manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1) following H2O2 stimulation. In in vivo models, SP (30 and 100 mg/kg) reduced paw inflammation and tissue damage after CAR and KO2 injection. Our results demonstrated the anti-inflammatory and anti-oxidant properties of SP; therefore, we propose that SP may be an effective strategy for the treatment of inflammatory diseases.

Marzocco S, Fazeli G, Di Micco L, Autore G, Adesso S, Dal Piaz F, Heidland A, Di Iorio B. Supplementation of Short-Chain Fatty Acid, Sodium Propionate, in Patients on Maintenance Hemodialysis: Beneficial Effects on Inflammatory Parameters and Gut-Derived Uremic Toxins, A Pilot Study (PLAN Study). J Clin Med. 2018 Sep 30;7(10):315. doi: 10.3390/jcm7100315. 

Abstract. Background: In end-stage renal disease (ESRD), gut-derived uremic toxins play a crucial role in the systemic inflammation and oxidative stress promoting the excess morbidity and mortality. The biochemical derangement is in part a consequence of an insufficient generation of short-chain fatty acids (SCFA) due to the dysbiosis of the gut and an insufficient consumption of the fermentable complex carbohydrates. Aim of the study: The primary end-point was to evaluate the potential efficacy of SCFA (specifically, sodium propionate (SP)) for patients on maintenance hemodialysis (MHD) on systemic inflammation. Secondary end-points included potential attenuation of oxidative stress markers, insulin resistance and production of gut-derived uremic toxins indoxyl sulfate and p-cresol sulfate, as well as health status after SP supplementation. Study design: We performed a single-center non-randomized pilot study in 20 MHD patients. They received the food additive SP with a daily intake of 2 × 500 mg in the form of capsules for 12 weeks. Pre-dialysis blood samples were taken at the beginning, after six weeks and at the end of the administration period, as well as four weeks after withdrawal of the treatment. Results: The subjects revealed a significant decline of inflammatory parameters C-reactive protein (-46%), interleukin IL-2 (-27%) and IL-17 (-15%). The inflammatory parameters IL-6 and IFN-gamma showed a mild non-significant reduction and the anti-inflammatory cytokine IL-10 increased significantly (+71%). While the concentration of bacterial endotoxins and TNF-α remained unchanged, the gut-derived uremic toxins, indoxyl sulfate (-30%) and p-cresyl sulfate (-50%), revealed a significant decline. The SP supplementation reduced the parameters of oxidative stress malondialdehyde (-32%) and glutathione peroxidase activity (-28%). The serum insulin levels dropped by 30% and the HOMA-index by 32%. The reduction of inflammatory parameters was associated with a lowering of ferritin and a significant increase in transferrin saturation (TSAT). Four weeks after the end of the treatment phase, all improved parameters deteriorated again. Evaluation of the psycho-physical performance with the short form 36 (SF-36) questionnaire showed an enhancement in the self-reported physical functioning, general health, vitality and mental health. The SP supplementation was well tolerated and without important side effects. No patient had left the study due to intolerance to the medication. The SP supplementation in MHD patients reduced pro-inflammatory parameters and oxidative stress and improved insulin resistance and iron metabolism. Furthermore, SP effectively lowered the important gut-derived uremic toxins indoxyl and p-cresol sulfate. These improvements were associated with a better quality of life. Further controlled studies are required in a larger cohort to evaluate the clinical outcome.

Ryu TY, Kim K, Son MY, Min JK, Kim J, Han TS, Kim DS, Cho HS. Downregulation of PRMT1, a histone arginine methyltransferase, by sodium propionate induces cell apoptosis in colon cancer. Oncol Rep. 2019 Mar;41(3):1691-1699. doi: 10.3892/or.2018.6938. 

Abstract. The microbiota and bacterial metabolites in the colon are regarded as alternative targets for colon cancer prevention and therapy. Among these metabolites, short-chain fatty acids (SCFAs) exhibit anticancer effects and suppress inflammation in the colon. However, the molecular mechanisms and target development of SCFAs require additional study. In the present study, using RNA-seq results from colon cancer samples derived from the Cancer Genome Atlas (TCGA) portal, overexpressed epigenetic modifiers were identified and RT-PCR and qRT-PCR analysis was performed to select target genes that responded to treatment with propionate in HCT116 cells. Downregulation of protein arginine methyltransferase 1 (PRMT1), a histone arginine methyltransferase, was observed after sodium propionate (SP) treatment. Moreover, phospho-array analysis demonstrated that the mTOR pathway was involved in propionate and siPRMT1 treatment, and regulation of this pathway was associated with apoptosis in HCT116 cells. The present study, to the best of our knowledge, was the first to demonstrate that PRMT1 levels were reduced by propionate treatment in HCT116 cells and that downregulation of PRMT1 induced cell apoptosis. Thus, this novel mechanism of sodium propionate treatment for colon cancer therapy may indicate more effective approaches, such as dietary therapy, for CRC patients.

Park T, Im J, Kim AR, Lee D, Jeong S, Yun CH, Han SH. Propionate Attenuates Growth of Oral Streptococci through Enhancing Methionine Biosynthesis. J Microbiol Biotechnol. 2022 Oct 28;32(10):1234-1244. doi: 10.4014/jmb.2205.05037. 

Abstract. Oral streptococci are considered as an opportunistic pathogen associated with initiation and progression of various oral diseases. However, since the currently-available treatments often accompany adverse effects, alternative strategy is demanded to control streptococci. In the current study, we investigated whether short-chain fatty acids (SCFAs), including sodium acetate (NaA), sodium propionate (NaP), and sodium butyrate (NaB), can inhibit the growth of oral streptococci. Among the tested SCFAs, NaP most potently inhibited the growth of laboratory and clinically isolated strains of Streptococcus gordonii under anaerobic culture conditions. However, the growth inhibitory effect of NaP on six different species of other oral streptococci was different depending on their culture conditions. Metabolic changes such as alteration of methionine biosynthesis can affect bacterial growth. Indeed, NaP enhanced intracellular methionine levels of oral streptococci as well as the mRNA expression level of methionine biosynthesis-related genes. Collectively, these results suggest that NaP has an inhibitory effect on the growth of oral streptococci, which might be due to alteration of methionine biosynthesis. Thus, NaP can be used an effective bacteriostatic agent for the prevention of oral infectious diseases caused by oral streptococci.