Targeting gut microbiota: new therapeutic opportunities in multiple sclerosis

Figures & data

Figure 1. Contribution of genetic and environmental factors to development of MS.

Genetic and environmental factors, and their mutual interactions, are considered to play a significant contributing role in initiation and development of MS. The evidence of links between some of these factors and the gut microbiome supports the hypothesis of its relevance for the processes underlying MS background.

Table 1. Alterations of the gut microbiota in MS patients without specified treatment.

Altered bacteria	Identified in / Compared to	Reference
Clostridium perfringens type B↑	26 RRMS and 4 SPMS/31 HS	^Citation18
Akkermansia muciniphila↑, Acinetobacter calcoaceticus↑,Parabacteroides↓	71 RRMS/71 HS	^Citation19
Atopobium↑, Bifidobacterium↑, Bacteroidaceae↓	54 MS/HS (number of control not provided)	^Citation20
Bacteroides fragilis↓, Butyrivibrio↓, Clostridium↓, Coprococcus↓, Eubacterium rectale↓,Faecalibacterium prausnitzii↓, Lawsonella↑, Roseburia↓	129 RRMS/58 HS	^Citation21
Bacteroides↓, Faecalibacterium prausnitzii↓, Roseburia↓	25 RRMS/14 HS	^Citation22
Firmicutes/Bacteroides ratio↑, Prevotella↓, Streptococcus↑	19 RRMS/17 HS	^Citation23
Bacteroides coprocola↓, Bacteroides coprophilus↓, Bacteroides stercoris↓, Eggerthella lenta↑, Prevotella copri↓, Streptococcus thermophilus↑, Sutterella wadsworthensis↓	20 RRMS/40 HS	^Citation24
Bacteroides↓, Faecalibacterium↓, Ruminococcus↑	5 RRMS/8 HS	^Citation25
Bilophila↓, Blautia↑, Butyricicoccus↓, Clostridium XIVb↓, Dorea↓, Faecalibacterium↓, Flavonifractor↑,Gemella↓, Granulicatella↓, Haemophilus↓, Roseburia↓	22 RRMS/33 HS	^Citation26
Faecalibacterium↓	34 RRMS/165 HS	^Citation27
Akkermansia↑, Clostridium↑, Prevotella↓	40 RRMS, multi-ethnic ancestry/41 HS	^Citation28
Prevotella↓	13 RRMS/14 HS	^Citation29
Coprococcus↓, Lachnospira↓, Roseburia↓, Streptococcus↑	26 RRMS/38 HS	^Citation30
Akkermansia↑, Coprococcus↓, Roseburia↓	12 SPMS/38 HS	^Citation30
Akkermansia↑	34 twins pairs MS/HS	^Citation31
Akkermansia↑, Blautia wexlerae↓, Clostridium bolteae↑, Dorea formicigenerans↓, Erysipelotrichaceae CCMM↓, Ruthenibacterium lactatiformans↑	199 RRMS and 44 progressive MS/40 HS	^Citation32
Anaerococcus vaginalis↓, Blautia faecis ↓, Clostridium g24 FCEY↑, Dorea longicatena↓, Enterobacteriaceae↑, Ruminococcaceae FJ366134↑	44 progressive MS/199 RRMS and 40 HS	^Citation32
Akkermansia↑, Clostridium↑, Eubacterium↓, Lachnospiraceae↓, Megamonas↓, Streptococcus↑	62 RRMS/55 HS	^Citation33
Clostridium↑, Streptococcus↑	15 SPMS/55 HS	^Citation33
Acinetobacter calcoaceticus↑, Akkermansia muciniphila↑	64 MS/64 HS	^Citation34
Prevotella↓, Streptococcus↑	34 RRMS/34 NMOSD and 34 HS	^Citation35
Actinomyces↑, Clostridium III↑, Eggerthella↑, Faecalicoccus↑, Gemmiger↓, Lachnospiraceae↓, Sporobacter↓, Streptococcus↑	19 RRMS/21 RA and 20 CD and 19 UC and 23 HS	^Citation36
Gemmiger↑, Ruminococcus↑	15 PPMS/15 HS	^Citation37
Bacteroides↑, Clostridium↓, Coprococcus↓, Firmicutes↓, Methanobrevibacter↓, Paraprevotella↓, Proteobacteria↓, Ruminococcaceae↓	26 RRMS/39 HS	^Citation38

The alterations are indicated by arrows. Abbreviations: Crohn’s disease – CD, healthy subjects – HS, neuromyelitis optica spectrum disorder – NMOSD, rheumatoid arthritis – RA, RRMS – relapsing-remitting multiple sclerosis, SP – secondary progressive multiple sclerosis, PPMS – primary progressive multiple sclerosis, ulcerative colitis – UC.

Figure 2. Methabolic pathways of bacterial fermentation resulting in the production of short chain fatty acid (SCFA) components.

Table 2. Mechanisms of action of bacterial fatty acid metabolites on events related to MS background.

Fatty acid metabolite(s)	Effect on	Proposed mechanism	Research model	Reference
Formate, acetate propionate, butyrate, pentanoate	Various tissues and mammalian cells	Activation of FFAR2 and FFAR3	In vitro	^Citation77
Acetate	Microglia	Upregulation of FFAR3 and suppression of the ERK/JNK/ NF-κB pathway	In vitro and in vivo	^Citation78
Acetate	Lipids	Increased acetyl-CoA metabolism alters fatty acid metabolism and gangliosides GD3 and GD1a content, prevents the loss of myelin and cholesterol (but not cholesteryl esters) and restores the level of cytosolic phospholipase A2 (cPLA2)	In vivo	^Citation79
Propionic acid	T cells	Suppressive capacity through IL-10 producing Tregs and elevated mitochondrial respiration	In vitro and ex vivo	^Citation63
Propionate	T cells	Induced HDAC inhibition increases IL-10 and FoxP3 expression in an FFAR2-dependent manner	In vivo	^Citation80
Propionate	BBB	Inhibition of pathways associated with nonspecific microbial infections via a CD14-dependent mechanism, suppression of expression of LRP-1 and protection of the BBB from oxidative stress via Nrf2 (NFE2L2) signaling	Ex vivo and in vitro	^Citation81
Butyrate	T cells	Induced expansion of Tregs by enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the FoxP3 locus	In vivo	^Citation82
Butyrate	T cells	Facilitation of TGF-β1-dependent generation of FoxP3+ Tregs, induction of expression of T-bet and IFN-γ as well as induction of H3 acetylation at tbx21 and Ifnγ locus during their differentiation, and promotion of Th1 polarization in an FFAR2, FFAR3 and SMCT1-independent manner	In vivo	^Citation83
Butyrate	Macrophages	Downregulation of pro-inflammatory mediators that included iNOS, IL-6 and IL-12 – effects mediated by inhibition of histone deacetylases	In vitro and in vivo	^Citation84
Butyrate	Oligodendrocytes	Induced suppression of demyelination and enhancement of remyelination; these effects were independent of microglia and were likely mediated by their activity as a HDAC inhibitor	In vivo	^Citation85
Butyrate, propionate and valerate	T cells	A boost in Tregs upon provision of butyrate due to potentiation of extrathymic differentiation of Tregs dependent on intronic enhancer of conserved non-coding sequence 1 and potentiated by propionate de novo Treg generation in the periphery, another SCFA capable of histone deacetylase inhibition	In vivo	^Citation86
Valerate/pentanoate	T cells and B cells	Elevated glucose oxidation mediated by pentanoate-triggered Akt/mTOR signaling pathway (increased IL-10 production by Bregs and effector T cells) along with its HDAC-inhibitory activity (reduced IL-17A expression)	In vivo	^Citation87
SCFAs	BBB permeability	Increased expression of the tight junction proteins occludin and claudin-5	In vivo	^Citation64
SCFAs	T cells	Expansion of gut Tregs by suppression of the JNK1 and p38-MAPK pathway	In vivo	^Citation62
SCFAs	T cells	Bidirectional regulatory potentials driven by: 1) induction of IL-10-producing T cells and 2) promotion the expression of IL-10 by conditioning CNS-resident APCs	In vitro and in vivo	^Citation88
SCFAs	Microglia	Downregulation of FFAR2 is responsible for microglia defects	In vivo	^Citation89
SCFAs	Microglia-like cells	Decreased secretion of IL-1β, MCP-1, TNF-α and cytotoxins (an effect not mediated by FFAR2/3) as well as reduced phagocytic activity and production of ROS	In vitro	^Citation90
SCFAs	BBB permeability	Reduced expression of the tight junction proteins occludin and claudin-5	In vivo	^Citation64
LCFAs	T cells	Enhanced differentiation and proliferation of Th1 and/or Th17 cells and their impaired intestinal sequestration via p38-MAPK pathway	In vivo	^Citation62

Abbreviations: Akt – serine/threonine protein kinase, APC – antigen presenting cell, BBB – blood–brain barrier, CNS – central nervous system, cPLA₂ – cytosolic phospholipase A₂, ERK – extracellular signal-regulated kinase, FFAR – free fatty acid receptor, HDAC – histone deacetylase, iNOS – induced nitric oxide synthase, JNK – Jun N-terminal kinase, LCFA – long chain fatty acid, MAPK – mitogen-activated protein kinase, MCP-1 – monocyte chemoattractant protein 1, mTOR – mammalian target of rapamycin, NFE2L2 –nuclear factor erythroid‐derived 2‐like 2, NFκB – nuclear factor kappa light chain enhancer of activated B cells, Nrf2 – nuclear factor erythroid 2-related factor 2, ROS – reactive oxygen species, SCFA – short chain fatty acid, SMCT1 – sodium-coupled monocarboxylate transporter 1.

Figure 3. Tryptophan metabolic pathways.

Only tryptophan catabolism via the indole and kynureine pathways have been shown; serotonic pathway has been excluded. Indole pathway takes place in gut lumen via gut microbiome although tryptophan could be also converted to kyneurine in the host via indolamine 2,3-dioxygenase (IDO-1).

Table 3. Mechanisms of action of tryptophan metabolites on events related to MS background.

Tryptophan metabolite(s)	Effect on	Proposed mechanism	Research model	Reference
I3C, indole, I3S, indirubin, kynurenine	AhR ligands	Decreased levels of circulating AhR ligands in RRMS compared to active MS or benign MS	Ex vivo	^Citation96
IPA, I3C	T cells	Dietary tryptophan mediated disease protection via microbiota-dependent impairment of autoreactive T cells	In vivo	^Citation97
IAld	T cells	Suppression of Th17 polarization and IL17 production	In vivo	^Citation98
IAld	Mucosal surface	Induction of mucosal IL-22 via AhR	In vivo	^Citation99
IPA	Mucosal surface	Regulation of mucosal integrity via PXR dependent manner and TLR4 signaling	In vivo	^Citation100
I3S, IPA and IAld	Astrocytes	I3S, IPA and IAId mediated limitation production of Il-6, TNF-α, CCL2 and iNOS in astrocytes via AhR signaling, resulting in MS amelioration	In vivo	^Citation101
I3S	Microglia and astrocytes	Dietary tryptophan metabolites control microglial activation and TGF-α and VEGF-B production and modulation astrocyte activities via AhR	In vivo and in vitro	^Citation102
Kynurenine metabolites	BBB	Basolateral secretion of kynurenine (by BBB endothelial cells) further metabolized to quinolinic acid, leading to neurotoxic effect	In vitro	^Citation103
Kynurenine metabolites	T cells	Suppressive effect of T cell mediated by IDO-1 resulting in more chronic form of kynurenine pathway activation, leading to MS progression by production of excitotoxic quinolinic acid and increased quinolinic acid/kynurenic acid ratio by infiltrating macrophages	Ex vivo	^Citation104
Quinolinic acid	Microglia	Detectable amount of quinolinic acid production by microglia, lack of production of quinolinic acid by neurons	In vitro	^Citation105
Laquinimod	Astrocytes	Amelioration of the disease via AhR activation in astrocytes by laquinimod	In vivo	^Citation106

Abbreviations: AhR – aryl hydrocarbon receptor, BBB – blood-brain barrier, CCL2–chemokine (C-C motif) ligand 2, I3C – indole-3-carbinol, I3S – indole-3-sulfate, IAld – indole-3-aldehyde, IDO-1–indolamine 2,3-dioxygenase, iNOS – induced nitric oxide synthase, IPA – indole-3-propionic acid, PXR – pregnane X receptor, RRMS – relapsing-remitting multiple sclerosis, TLR – toll-like receptor, VEGF-B – vascular endothelial growth factor B.

Figure 4. Polyamine metabolism.

Abbreviations: Arg-1 – arginase 1, ODC-1 – ornithine decarboxylase 1, SAT-1 – spermidine/spermine N1 acetyltransferase 1.

Table 4. Mechanisms of action of polyamine metabolites on events related to MS background.

Polyamine metabolite(s)	Effect on	Proposed mechanism	Research model	Reference
Putrescine	T cells	Suppression of ODC1 or SAT1 restricts Th17 function in a putrescine-dependent manner	In vitro	^Citation110
Spermidine	T cells	Shift of polarization of Th17 cells toward FoxP3+ Treg differentiation in a TGF-β dependent manner	In vitro and in vivo	^Citation111
Spermidine	Macrophages and T cells	Synergistic mode of action on activation and proliferation of T cells by: i) suppression of expression of pro-inflammatory cytokines IL-1β, IL-12 and co-stimulatory molecules CD80 and CD86 in macrophages through downregulation of activity of NF-κB pathway and ii) upregulation of expression of Arg-1 in macrophages, both causing a shift to M2 phenotype	In vivo	^Citation112
Spermidine	Astrocytes	Suppression of astrocyte-derived chemokines (MIP-1α, MCP-1, RANTES)	In vivo	^Citation113
Spermidine, spermine	T cells	Suppression of LFA-1 expression on human T lymphocytes	Ex vivo and in vitro	^Citation114

Abbreviations: Arg-1 – arginase 1, LFA-1 – lymphocyte function associated antigen 1, MCP-1 – monocyte chemoattractant protein-1, MIP-1α – macrophage inflammatory protein-1α, NFκB – nuclear factor kappa light chain enhancer of activated B cells, ODC-1 – ornithine decarboxylase 1, RANTES – regulated on activation, normal T cell expressed and secreted, SAT-1 – spermidine/spermine N1 acetyltransferase 1.

Table 5. Mechanisms of action of urolithin metabolites on events related to MS background.

Urolithins metabolite(s)	Effect on	Proposed mechanism	Research model	Reference
Urolithin A	T cells	Suppression of T cell activation and proliferation by modulating calcium machinery (downregulation of Orai1/STIM1/2 expression) in a miR-10a-5p-dependent manner	In vivo	^Citation115
Urolithin A	T cells, DCs, and microglia	Reduced levels of CD80, CD86 and MHC-II on DCs, lower numbers of M1 type microglia, activated DCs as well as reduced infiltration of Th1/Th17 cells and monocytes by targeting AhR and modulating the signaling pathways	In vitro and in vivo	^Citation116
Urolithin A	Gut barrier integrity	Upregulation of epithelial tight junction proteins through AhR and Nrf2 dependent pathways	In vitro and in vivo	^Citation117
Urolithin A	Neurons	Neuroprotection and anti-inflammatory effect by activation/phosphorylation of the AMPK, p65NFκB, p38MAPK and BACE1 signaling pathways	In vivo	^Citation118
Urolithin A and urolithin B	Microglia and neurons	Decreased secretion of pro-inflammatory markers (NO, IL-6, prostaglandin E2, TNF-α), mitigated apoptosis and caspase 3/7 and 9 release	In vitro	^Citation119
Urolithin A and urolithin B	Oligodendrocytes	Prevention of myelin associated sphingolipid loss by stimulation of synthesis of ceramide	In vitro and in vivo	^Citation120
Urolithin B	Neurons	Neuroprotection by suppression of c-JNK activation and cytochrome c release as well as activation of ERK and PI3K pathway along with Akt and p44/42 MAPK phosphorylation and activation	In vivo	^Citation121

Abbreviations: AhR – aryl hydrocarbon receptor, Akt – serine/threonine protein kinase, AMPK – adenosine monophosphate-activated protein kinase, BACE1 – β-site amyloid precursor protein cleaving enzyme 1, DC – dendritic cell, ERK – extracellular signal-regulated kinase, JNK – Jun N-terminal kinase, MAPK – mitogen-activated protein kinase, MHC-II – major histocompatibility complex class II, NFκB – nuclear factor kappa light chain enhancer of activated B cells, Nrf2 – nuclear factor erythroid 2-related factor 2, Orai1 – calcium release-activated calcium modulator 1, PI3K – phosphoinositide 3-kinase, STIM – stromal cell interaction molecule.

Table 6. Modulation of the gut microbiota in MS patients after specified disease-modifying treatment.

Observations noted	Identified in/Compared to	Treatment	Reference
Differences in: Bacteroidaceae, Clostridium, other Clostridiales, Faecalibacterium, Lactobacillaceae, Ruminococcus	5 RRMS DMT treated / 2 RRMS untreated	5 RRMS GA treated, 2 RRMS untreated	^Citation25
Bifidobacterium↓, Faecalibacterium↑	36 RRMS DMT treated / 165 HS	27 RRMS DMF treated, 3 RRMS GA treated, 3 RRMS peginterferon-β1a treated, 2 RRMS IFN-β1b treated, 1 RRMS IFN-β1a treated	^Citation27
Alistipes↑, Anaerotruncus↑, Butyricicoccus↓, Clostridium cluster IV↑, Gemminger↓,Intestinibacter↓, Lactobacillus↑, Methanobrevibacter↑, Olsenella↑, Parabacteroides↑, Roseburia↓, Ruminococcus↑, Sporobacter↑	98 MS (including 26 PPMS, 20 benign MS, 24 active untreated RRMS, 24 RRMS DMT treated, 4 RRMS in relapse / 120 HS	24 RRMS IFN-β treated	^Citation39
Butyricicoccus↓	26 PPMS / 72 MS (including 20 benign MS, 24 active untreated RRMS, 24 RRMS DMT treated, 4 RRMS in relapse)	24 RRMS IFN-β treated	^Citation39
Akkermansia muciniphila↑, Bacteroides finegoldii↓, Blautia↓, Eisenbergiella tayi↑, Faecalibacterium prausnitzii↓, Hungatella hathewayi↑,Roseburia faecis↓, Ruthenibacterium lactatiformans↑	576 MS (367 DMT treated, 209 MS untreated) / 576 household HS	71 MS FTY720 treated, 86 MS DMF treated, 68 MS GA treated, 87 MS IFN treated 28 MS anti-CD20 antibody treated, 27 MS NZ treated, 209 MS untreated	^Citation41
Adlercreutzia↓, Blautia↑, Collinsella↓, Dorea↑, Haemophilus↑, Lactobacillus↓,Mycoplana↑, Parabacteroides↓, Prevotella↓, Pseudomonas↑	31 RRMS (20 RRMS DMT treated, 11 RRMS untreated) / 36 HS	14 IFN-β treated, 1 GA treated, 5 NZ treated 11 untreated	^Citation66
Akkermansia↑, Butyricimonas↓, Methanobrevibacter↑	60 RRMS patients (32 RRMS DMT treated, 28 RRMS untreated) / 43 HS	14 RRMS GA treated, 18 RRMS IFN-β treated, 28 RRMS untreated	^Citation67
Prevotella↑, Sarcina↓, Sutterella↑	32 RRMS DMT treated / 28 RRMS untreated	14 RRMS GA treated, 18 RRMS IFN-β treated, 28 RRMS untreated	^Citation67
Absence of Fusobacteria phylum	17 RRMS (9 RRMS DMT treated, 8 RRMS untreated)	5 RRMS GA treated, 3 RRMS IFN-β treated, 1 RRMS NZ treated, 8 RRMS untreated	^Citation71
Differences in: Actinobacteria, Firmicutes, Lentisphaerae, Proteobacteria, Prevotella copri in untreated MS vs. HS↓, Prevotella copri in treated MS vs. untreated↑	30 RRMS / 14 HS	15 RRMS IFN-β treated, 15 RRMS untreated	^Citation122
Clostridiales↓, Firmicutes↓, Fusobacteria↓, Lachnospiraceae↑, Veillonellaceae↑	93 RRMS DMT treated / 75 RRMS untreated	33 RRMS DMF treated, 60 RRMS GA treated	^Citation123
Atypical E. coli↑, Enterobacter sp.↑, Normal E. coli↓	34 RRMS DMT treated	17 RRMS GA treated, 17 RRMS FTY720 treated	^Citation124
Bacteroidaceae↓, Bacteroides fragilis↓, Bifidobacterium↑, Bilophila↑, Butyricimonas↓, Christensenellaceae↑, Desulfovibrio↑, Faecalibacterium↓, Lachnospiraceae↓, Methanobrevibacter↑, Ruminococcaceae↓	18 RRMS (9 RRMS DMT treated, 9 RRMS untreated) / 17 HS	3 IFN-β treated, 5 GA treated, 1 NZ treated 9 untreated	^Citation125
Several associations between immune markers and certain gut microbiota including Bacteroidetes and Actinobacteria were observed	15 RRMS (7 RRMS DMT treated, 8 RRMS untreated) / 9 HS	2 RRMS IFN-β treated, 5 RRMS GA treated, 8 RRMS untreated	^Citation126

The alterations are indicated by arrows. Abbreviations: DMF – dimethyl fumarate, FTY720 – fingolimod, GA – glatiramer acetate, healthy subjects – HS, NZ – natalizumab, PPMS – primary progressive multiple sclerosis, RRMS – relapsing-remitting multiple sclerosis.

Figure 5. Effects of dietary intervention upon the gut dysbiosis and processes involved in MS pathology.

SCFAs, tryptophan, polyamines and urolithin, derived from diet components, are the most relevant metabolites which can interact with immune and nervous system.

Gut bacteria are known to produce major SCFAs (acetate, propionate and butyrate), spermidine (the end product of L-arginine metabolism) and urolithins, as well as increase tryptophan metabolites (ILA, IAA, IAld).

SCFAs modulate Tregs in the systemic circulation by promoting transcription of genes encoding IL-10 and FoxP3, by inhibition of HDAC, and stimulate production of IL-10 via FFAR2-dependent manner. ILA and urolithin A inhibit Th17 polarization and reduce production of IL-17 via AhR. Spermidine inhibits the expression of pro-inflammatory cytokines and co-stimulatory molecules in macrophages through downregulating the activity of NF-κB pathway, as well as upregulates expression of Arg-1 in macrophages.

SCFAs cross the BBB to enter CNS by difusion or via MCT1. They can increase BBB integrity by restoring tight junction proteins (occludin and claudin 5) expression and by preventing ROS production in the endothelial cells.

In the CNS, SCFAs inhibit production of TNF-α, IL-1β, IL-6, IL-12 and iNOS by pro-inflammatory microglia M1 and limit their proliferation. Urolitin A decreases secretion of pro-inflammatory markers (TNF-α, IL-1β, NO, PGE₂). Tryptophan metabolites (I3S, IPA and IAld) inhibit TNF-α, IL-6 and CCL2 production from astrocytes in an AhR dependent manner, whereas spermidine supresses astrocyte-derived chemokines (MIP-1α, MCP-1, RANTES).

Abbreviations: AhR – aryl hydrocarbon receptor, Arg-1 – arginase 1, CCL2 – chemokine (C-C motif) ligand 2, CNS – central nervous system, FFAR2 – free fatty acid receptors 2, FoxP3 – forkhead box P3, HDAC – histone deacetylase, I3S – indole-3-sulfate, IAA – indole-3-acetic acid, IAld – indole-3-aldehyde, IL – interleukin, ILA – indole-3-lactic acid, iNOS – inducible nitric oxide synthase, IPA – indole-3-propionic acid, MCP-1 – monocyte chemoattractant protein-1, MCT1 – proton-dependent monocarboxylate transporter 1, MIP-1α – macrophage inflammatory protein-1α, NO – nitric oxide, PGE₂ – prostaglandin E₂, RANTES – regulated upon activation, normal T cell expressed and secreted, ROS – reactive oxygen species, SCFAs – short chain fatty acids, Th – T helper, TNF-α – tumor necrosis factor alpha, Treg – regulatory T cell.

Table 7. Experimental and clinical studies on gut commensal-based therapies and dietary interventions affecting gut microbiome in MS.

Intervention	Research model	Impact on the gut microbiome	Other effects	Reference
Probiotics	Experimental: rhMOG-induced EAE Marmoset twin pairs Yogurt-based (YBS) vs. water-based supplement	YBS – fed twins after immunization: Bifidobacteria↑, Bacteroides barnesiae↓, Blautia stercoris↓, M. formatexigens↓	Frequency of EAE induction from 100% to 75%↓, demyelination of the spinal cord ↓, expression of Callitrichine herpesvirus 3↓	^Citation133
	Experimental: TMEV-IDD SJL/J mice Vivomixx-probiotic cocktail	Bacteroidetes↑, Actinobacteria↑, Tenericutes↑, TM7↑	Improvement in motor disability, microgliosis↓, astrogliosis↓, leukocyte infiltration↓, IL-10 gene expression↑, plasma levels of butyrate and acetate↑	^Citation134
	Clinical: 9 pwMS/13 HS Probiotic – VSL3	Lactobacillus↑, Bifidobacterium↑, Streptococcus↑, Akkermansia↓, Blautia↓	Frequency of inflammatory monocytes↓, expression of CD80 on monocytes↓, expression of HLA on dendritic cells↓, alterations of microbial metabolic pathways associated with e. g. methane metabolism	^Citation140
Prebiotics	Experimental: Spontaneous EAE – OSE and wild-type C57BL/6 mice Non-fermentable fiber (cellulose) rich diet vs. control diet	Significantly altered Beta-diversity Decreased OTU richness in Alpha-diversity analysis Ruminococcaceae↑, Helicobacteraceae↑, Enterococcaceae↑, Sutterellaceae↓, Lactobacillaceae↓, Coriobacteriaceae↓	IFN-γ-producing Th1 cells in intestinal lamina propria↓, levels of IL-4 and IL-5 produced by Th2 cells↑, butyric acid↓, LCFAs↑	^Citation160
SCFAs	Experimental: MOG35–55-induced EAE C57BL/6 mice Propionic acid (PA) intake vs. lauric acid (LA) intake vs control diet	EAE did not change microbiome composition LA intake: shift toward Prevotellaceae↓ and Bacteroidetes↓	LA intake: more severe course of the disease, Th17 cells in the CNS↑, Th1 and Th17 cells in the spleen↑, LCFAs↑, SCFAs (particularly PA) in feces↓ PA intake: restoring the altered balance between Tregs and effector T cells	^Citation62
PUFAs	Experimental: Spontaneous EAE -OSE IgH^MOGxTCR^MOG mice Conjugated linoleic acid (CLA) intake vs. control diet	Profound changes in the overall composition of the microbiome (principal component analysis) Porphyromondaceae↑, Lachnospiraceae↑, Bacteroides↑, Lactobacillus↑, Akkermansia↑	Ameliorated disease course, infiltration of immune cells in the spinal cord and the intestinal lamina propria↓, MDSC-like cells in the intestinal lamina propria↑, pro-inflammatory T cell responses↓	^Citation165
NaCl	Experimental: MOG35–55-induced EAE FVB/N mice High salt diet (HSD) vs normal salt diet	Lack of obvious pattern in overall microbial composition (based on OTUs) HSD: Lactobacillus↓, Oscillibacter↓, Pseudoflavonifractor↓, Clostridium XIVa↑, Johnsonella↑, Rothia Parasutterella↑	Altered level of fecal central carbon and nitrogen metabolites	^Citation98
Vitamin D	Clinical: 7 pwMS (5 GA-treated and 2 non-treated) vs. HS (both with vitamin D deficiency) Vitamin D3 5000 IU/d	After vitamin D supplementation: Faecalibacterium↑, Enterobacteriaceae↑, Ruminococcus↓ Non-treated pwMS: Akkermansia↑, Faecalibacterium↑, Coprococcus↑ GA-treated pwMS: Janthinobacterium↑ Eubacterium↓, Ruminococcus↓		^Citation25
Intermittent fasting	Experimental: Induced EAE model, -C57BL/6 mice Fasting every other day vs. normal diet	Overall increased gut bacteria richness, Lactobacillaceae↑, Bacteroidaceae↑, Prevotellaceae↑	Th17 cells↓, Tregs↑, inflammatory cells infiltration and demyelination in spinal cord↓, antioxidative microbial metabolic pathways↑, synthesis and degradation of ketone bodies↑, glutathione metabolism↑, lipopolysaccharide biosynthesis↓, leptin↓, adiponectin↑	^Citation189
	Clinical: 16 pwMS IER vs. free caloric intake	Faecalibacterium↑, Lachnospiracea incertae sedis↑, Blautia↑ Faecalibacterium abundance correlated with adiponectin level	Plasma B cells↓	^Citation189
Ketogenic diet	Clinical: 25 pwMS (ketogenic vs. normal diet), 14 HS	Roseburia↓, Bacteroides↓, Faecalibacterium prausnitzii↓		^Citation22
Other dietary regimens	Clinical: 24 untreated pwMS and 25 controls Balanced diet (intake of basic types of food)	Faecalibacterium↓, Prevotella↓, Lachnospiraceae↓, Anaerostipes↓ (OTU relative abundance) Correlation between microbiota and level of disability B. thetaiotaomicron↓ correlating with consumption of meat	Th17cells↑, abundance of meat-associated blood metabolites – associated with consumption of meat↑	^Citation191
	Clinical: 20 pwMS High-vegetable/low-protein diet (HV/LP) vs. “Western Diet”	HV/LP subgroup: Lachnospiraceae↑	IL −17 producing T cells↓, relapse rate↓, disability level↓	^Citation192
FMT	Experimental: MOG35–55-induced EAE C57BL/6 mice FMT-treated vs. non-treated immunized mice vs. normal controls	Increased Shannon index for α-diversity after FMT FMT-treated EAE mice: Bacteroidetes↑ Firmicutes↓, Tenericutes↓, Cyanobacteria↓ (shift toward the levels typical for normal controls) EAE severity scores: Lachnoclostridium, Lachnospiraceae - negative correlation, Mollicutes_RF9, Ruminococcaceae, Turicibacter, Thalassospira - positive correlation	Activation of microglia and astrocytes↓, improvement of BBB integrity	^Citation200
	Experimental: Germ-free RR SJL/J mice FMT from pairs of human twins discordant for MS	FMT from healthy twin: Adlercreutzia↑, Tannerella↑, Ruminococcus↓ FMT from MS twin: Sutterella↓ FMT from healthy twin: Adlercreutzia↑, Tannerella↑, Ruminococcus↓	IL-10 production↓	^Citation31
	Clinical: Single MS patient, 2 FMT 12-months of follow-up	Increased microbial richness Firmicutes-to-Bacteroidetes↑, Prevotellaceae-to-Bacteroidaceae↑, Faecalibacterium prausnitzii↑	Concentration of acetate, propionate and butyrate in feces↑, SCFA genomic pathways↑, serum level of BDNF↑, improved measures of gait	^Citation202
	Clinical: 9 pwMS Monthly FMTs for up to 6 months	At baseline: Bacteroides↑, Blautia faecis↑, Bacteroides uniformis↑, Prevotella↓, Paraprevotella↓ No significant change in microbiota diversity following repeated FMTs	Partial normalization of elevated intestinal permeability, pro- or anti-inflammatory markers unchanged	^Citation203

The alterations are indicated by arrows. Abbreviations: BDNF – brain derived neurotrophic factor, EAE – experimental autoimmune encephalomyelitis, FMT – fecal microbiota transplantation, GA – glatiramer acetate, HLA – human leukocyte antigen, IER – intermittent energy restriction, OSE – spontaneous opticospinal encephalomyelitis, OTU – operational taxonomic unit, PUFAs – polyunsaturated fatty acids, pwMS – people with multiple sclerosis, (rh) MOG – recombinant human myelin, oligodendrocyte glycoprotein, SCFAs – short chain fatty acids, TMEV-IDD – Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease.

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Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.