Table 2.
Summary of attempts exploring therapeutic effects of SCFA, MCFA and LCFA supplementation in MS animal models and patients
| Study | Subjects | FA | Dosage and time | Main results |
|---|---|---|---|---|
| Zhang et al. [180] |
Male Lewis rats MBP68–84 EAE |
SCFA (valproic acid) | 250 or 500 mg/kg per day for 19 days (preventive), 500 mg/kg per day for 12 days (therapeutic) | Preventive and therapeutic valproic acid treatment reduces EAE severity and CNS lesions by controlling CD4+T cells counts, inhibiting spinal cord inflammatory cytokines production while favoring a Th2 and Treg cytokine profile |
| Lv et al. [168] |
Female C57BL/6 mice MOG35–55 EAE |
SCFA (valproic acid) | 10–300 mg/kg per day until the end of study | Valproic acid supplementation attenuates EAE clinical symptoms, T lymphocytes peripheral population and CNS infiltration by inhibiting T cells proliferation, while inducing caspase-dependent apoptosis. In vitro experiments of PBMC from HC and MS patients support the regulatory role valproic acid in T lymphocytes |
| Pazhoohan et al. [169] |
Female Wistar rats Focal cortical EAE |
SCFA (valproic acid) | 300 mg/kg per day for 4 days (therapeutic) or 8 days (preventive) | Preventive valproic acid supplementation in a focal EAE model reduces severity, while a therapeutic treatment after EAE induction accelerates recovery. Overall, the valproic acid treatment enhances remyelination process measured by the ratio of myelin sheath thickness to axon diameter, with an increased recruitment of neural stem cells and oligodendrocyte progenitors to the lesion area |
| Haghikia et al. [54] |
Female C57BL/6 mice MOG35–55 EAE |
SCFA (propionic acid), MCFA (lauric acid) | 200 µl (150 mM) propionic acid per day, or diet containing 4.2% lauric acid | SCFA propionic acid-rich diet promotes intestinal Treg polarization and endows Treg a more protective phenotype by inhibiting p38/MAPK, ameliorating EAE clinical score and CNS autoimmunity. On the opposite, a diet rich in MCFAs, particularly lauric acid, induces the differentiation and proliferation, as well as the CNS migration of intestinal Th1, Th17 cells by activating p38/MAPK. Detrimental effects of MCFA on intestinal CD4+T cells can be transferred through feces gavage to GF recipient mice |
| Liu et al. [158] |
Male Lewis rats MBP EAE |
SCFA (valproic acid) | 250 or 500 mg/kg per day for 13 days | Valproic acid gavage alleviates EAE clinical scores, attenuates the local inflammation of optic nerves, by reducing pro-inflammatory cytokines expression and NF-κB pathway activity. Ultimately, valproic acid inhibits local microgliosis and caspase-dependent RGC apoptosis |
| Chevalier et al. [173] |
Female C57BL/6 mice MOG35–55 EAE |
SCFA (acetic acid) | 4 g/kg per day until the end of experiment in the form of glyceryl triacetate | Acetate supplementation prevents EAE symptom onset, presumably by providing materials for FAS, rescues the loss of spinal cord ethanolamine and choline glycerophospholipid, as well as the phosphatidylserine, thus preserving myelin structural characteristics. Moreover, acetate supplementation reduces cPLA2 level which would contribute to downwards proinflammatory lipid signaling |
| Mizuno et al. [106] |
C57BL/6 mice MOG35–55 EAE |
SCFA (acetic acid, butyric acid, propionic acid) | 200 mM in drinking water | High fiber diet or oral administration of SCFAs including acetic acid, butyric acid and propionate acid ameliorate EAE symptoms by upregulating Treg population. Ex vivo T cells from EAE after SCFAs supplementation reduces inflammatory cytokines production upon stimulation |
| Luu et al. [103] |
C57BL/6 mice MOG35–55 EAE |
SCFA (valeric acid) | 150 mM in drinking water | Valeric acid, by promoting histone acetylation and mTOR activation, is able to enhance lymphocyte glucose oxidation. Valeric acid supplementation in EAE supports Breg immunomodulatory property while dampens Th17 function, succeeds in reversing an increase of EAE susceptibility prompted by detrimental gut bacteria colonization |
| Chen et al. [170] |
Male C57BL/6 mice Cuprizone-induced demyelination |
SCFA (butyric acid) | 200 mM in drinking water | In vivo butyric acid supplementation ameliorates cuprizone-inducing demyelination in a microglia-independent way. In vitro assays utilizing organotypic cerebellar slice cultures further verify the ability of butyric acid both in attenuating acute demyelination and enhancing afterwards remyelination process, by acting directly to promote OPC differentiation as HDACi |
| Duscha et al. [21] | RRMS, SPMS, PPMS patients | SCFA (propionic acid) | 500 mg twice daily | A reduced amount of propionic acid is found in MS patients’ serum and stool compared to HC. Two weeks of propionic acid supplementation as add-on therapy in MS patients rescues the imbalance of CD4+T cells differentiation and enhances Treg function by restoring mitochondrial respiration. Three years of supplementation significantly reduces MS ARR, disease progression and brain atrophy. The protective effect of propionic acid supplementation can be delivered by patients’ gut microbiota to an artificial murine gut culture system |
| Haase et al. [108] |
C57BL/6 mice MOG35–55 EAE |
SCFA (propionic acid) | 150 mM in drinking water | Propionic acid has a lower concentration in obese MS patients compared to non-obese MS patients. Propionic acid supplementation reverses the detrimental effects of lauric acid-enriched diet in EAE, involving the rise of clinical scores, CNS infiltration of macrophages and T lymphocytes. Mechanistically, in vitro studies show that propionic acid by reducing p38–MAPK phosphorylation, restores Treg–Th17 axis homeostasis both in animal models and in patients |
| Pompura et al. [111] | RRMS patients | LCFA (oleic acid) | (in vitro) | Oleic acid, as the most prevalent adipose FA, has a comparative low concentration in MS adipose tissue. Oleic acid by enhancing FAO, promotes Treg expression of FOXP4 and pSTAT5, thus inducing a more immunomodulatory phenotype of Treg cells. MS PBMC or adipose-resident Treg cells are transcriptionally similar to ARA-treated HC PBMC, instead of oleic acid-treated ones which resemble HC Treg cells. In vitro studies verify the therapeutic potential of oleic acid treatment in rescuing MS Treg immunosuppressive effects |
| Xie et al. [107] |
Male C57BL/6 mice MOG35–55 EAE |
SCFA (acetic acid) | 10, 30, or 100 mg/kg per day until the end of study in the form of methyl acetate | Methyl acetate reduces EAE severity, CNS T lymphocytes infiltration and demyelination by upregulating splenic expression of chemokines which attracts Th1 cells in the peripheral and blocks their central recruitment. Methyl acetate also attenuates intestinal inflammation by reducing local Th1, Th17 cells counts |
| Zhu et al. [174] |
Male C57BL/6 mice Cuprizone-induced demyelination |
SCFA (valproic acid) | 150 mg/kg per day | Valproic acid gavage mitigates cuprizone-induced myelin structure loss and anxiety-like behavior, by promoting hippocampal cholesterol biosynthesis |
ARR annual relapse rate, CNS central nervous system, cPLA2 cytosolic phospholipase A2, EAE experimental autoimmune encephalomyelitis, FAO fatty acid oxidation, FAS fatty acid synthesis, GF germ-free, HC healthy control, HDACi histone deacetylase inhibitor, LCFA long-chain fatty acid, MBP myelin basic protein, MCFA medium-chain fatty acid, MOG myelin oligodendrocyte glycoprotein, MS multiple sclerosis, OPC oligodendrocyte precursor cell, PBMC peripheral blood mononuclear cell, PPMS primary progressive multiple sclerosis, RRMS relapsing–remitting multiple sclerosis, SCFA short-chain fatty acid, SPMS secondary progressive multiple sclerosis