Probiotic and commensal gut microbial therapies in multiple sclerosis and its animal models: a comprehensive review

Figures & data

Table 1. Bradford Hill criteria numerical designations and descriptions

BHC	BHC #	Description
Temporal relationship	1	Does the exposure precede the outcome?
Strength of relationship	2	Level of evidence, ROB, study quality
Dose-response relationship	3	U-shaped, inverse U-shaped, etc.
Replication of findings	4	Across studies, across research groups, etc.
Biological plausibility	5	Do the findings make biological sense?
Cessation of exposure	6	Do the effects change after discontinuation?
Specificity of association	7	Does the exposure lead to the outcome?
Coherence between multiple approaches	8	How well do different lines of experimentation or observation support one another?

BHC, Bradford Hill criteria; ROB, risk of bias.

Table 2. Human studies of probiotic therapies: summary of study characteristics and major findings

Study	ROB	Sample	MS Type	Intervention	Timeline	Duration	Major Findings
Kouchaki et al.^Citation60	Low	18–55 yo n = 30/g	RRMS EDSS ≤ 4.5	T: Probiotic capsule, 2 × 10^9 CFU (L. acidophilus, L. casei, B. bifidum, L. fermentum) C: starch capsule	Thera	Biweekly for 12 wks	CD: ↓ EDSS, BDI, GHQ-28, DASS IM: ↓ hs-CRP, MDA; ↑ plasma NO MM: NA MC: NA
Rahimlou et al.^Citation63	Low	18–50 yo n = 35/g	RRMS EDSS ≤ 4.5	T: “Protexin”^a capsule, 2 × 10^9 CFU C: maltodextrin capsule	Thera	Daily for 6 mos	CD: – EDSS; ↓ BDI, GHQ-28, FSS & MPQ IM: ↓ IL-6; ↑ BDNF; – NGF MM: NA MC: NA
Salami et al.^Citation64	Low	20–60 yo n = 24/g	RRMS EDSS ≤ 4.5	T: Probiotic capsule, 2 × 10^9 CFU (L. plantarum, L. casei, L. reuteri, L. fermentum, B. lactis, B. infantis) C: maltodextrin capsule	Thera	16 wks (freq. not specified)	CD: ↓ EDSS, DASS; – BDI, GHQ-28 IM: ↓ IL-6, TNF-α, hs-CRP, MDA, 8-OHdG; ↑ IL-10, TAC, GSH, NO MM: NA MC: NA
Tamtaji et al.^Citation61	Low	18–55 yo n = 20/g	RRMS EDSS ≤ 4.5	T: Probiotic capsule, 2 × 10^9 CFU (L. acidophilus, L. casei, L. fermentum, B. bifidum) C: starch capsule	Thera	Daily for 12 wks	CD: – BMI; no relapses IM: ↓ IL-8, TNF-α; – IL-1, PPAR-γ, LDLR MM: NA MC: NA
Tankou et al.^Citation46	High	n = 7 MS, taking GA n = 2 MS, untreated n = 13 HC	RRMS	T: VSL3,^b 3.6 × 10^12 CFU/d HC: VSL3,^b 3.6 × 10^12 CFU/d	Thera	Daily for 2 mos	CD: NA IM: ↑ freq. IL-10+ Tregs; ↓ freq. intermediate & inflammatory monocytes, costimulatory marker CD80 on classical monocytes, MFI of HLA-DR on myeloid-derived DCs, rel freq. of TH1 & TH17 cells; ↓ freq. IL-10+ Tregs & ↑ freq. of inflammatory monocytes following cessation; – freq. B cells, NK cells, myeloid or plasmacytoid DCs, naïve CD4 or CD8 T cells, central memory CD4 or CD8 T cells, effector memory CD4 T cells MM: ↑ rel. abund. of Lactobacillus, Streptococcus, & Bifidobacterium, which returned to baseline following cessation MC: NA
Tankou et al.^Citation47	High	n = 7 MS, taking GA n = 2 MS, untreated n = 13 HC	RRMS EDSS = 1.4 ± 0.9	T: LBS,^c 3.6 × 10^12 CFU/d HC: LBS,^c 3.6 × 10^12 CFU/d	Thera	Daily for 2 mos	CD: NA IM: ↑ freq. IL-10+ Tregs; ↓ freq. intermediate & inflammatory monocytes, costimulatory marker CD80 on classical monocytes, MFI of HLA-DR on myeloid-derived DCs, rel freq. of TH1 & TH17 cells; ↓ freq. IL-10+ Tregs & ↑ freq. of inflammatory monocytes following cessation; – freq. B cells, NK cells, myeloid or plasmacytoid DCs, naïve CD4 or CD8 T cells, central memory CD4 or CD8 T cells, effector memory CD4 T cells MM: ↑ rel. abund. of Lactobacillus, Streptococcus, & Bifidobacterium; ↑ rel. abund. of Veillonellaceae family & Collinsela genus; ↓ rel. abund. of Akkermansia, Blautia, Dorea, B. adolescentis; microbiome changes returned to baseline following cessation & were associated with changes in stool metabolic profile MC: ↓ expression of MS risk allele HLA.DQA.1, & HLA.DPA1, ILGST, MALT1, LGALS3 in monocytes; ↑ expression of IL-10RA, LILRB2, CYBB; most returned to baseline following cessation.

All findings are reported with respect to control group(s) unless otherwise indicated.

^aProtexin = B. subtilis PXN 21, B. bifidum PXN 23, B. breve PXN 25, B. infantis PXN 27, B. longum PXN 30, L. acidophilus PXN 35, L. rhamnosus PXN 54, L. helveticus PXN 45, L. salivarius PXN 57, L. lactis ssp. lactis PXN 63, S. thermophilus PXN 66, L. casei PXN 37, L. delbrueckii ssp. bulgaricus PXN 39, L. plantarum PXN 47.

^bVSL3 = L. paracasei DSM 24732, L. plantarum DSM 24730, L. acidophilus DSM 24734, L. delbruckeii subsp. bulgaricus DSM 24734, B. longum DSM 24736, B. infantis DSM 24737, B. breve DSM 24732, S. thermophilus DSM 24731.

^cLBS = see ^bVSL3.

Key: ↓ decreased; ↑ increased; – no change or no difference compared to control; NA, not applicable to this study.

Abbreviations: ROB, risk of bias; MS, multiple sclerosis; yo, y old; g, group; RRMS, relapsing-remitting multiple sclerosis; GA, glatiramer acetate; HC, healthy controls; EDSS, Expanded Disability Status Scale; T, treatment group; C, control; CFU, colony forming units; Thera, therapeutic; wks, weeks; mos, months; freq., frequency; CD, clinical disease; IM, immune/metabolic; MM, microbiome/metabolome; MC, mechanistic/correlative; BDI, Beck Depression Inventory; GHQ-28, General Health Questionnaire-28; DASS, Depression Anxiety Stress Scales; hs-CRP, high-sensitivity C-reactive protein; MDA, malondialdehyde; NO, nitric oxide; FSS, Fatigue Severity Scale; MPQ, McGill Pain Questionnaire; IL, interleukin; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; TNF-α, tumor necrosis factor alpha; 8-OHdG, 8-Oxo-2ʹ-deoxyguanosine; TAC, total antioxidant capacity; GSH, glutathione; BMI, body mass index; HLA-DR, human leukocyte antigen-antigen D related; DC, dendritic cell; rel. abund., relative abundance; NK, natural killer.

Table 3. Animal studies of probiotic therapies: summary of study characteristics and major findings

Study	ROB	Sample	MS Model	Intervention	Timeline	Duration	Major Findings
Maassen et al.^Citation59	UN	F SJL mice 8–12 wko n = 6/g	PLP-induced EAE	T1: L. reuteri ML1 T2: L. casei 393 T3: L. plantarum NCIB 8826 T4: L. murinus CNRZ Each 10^10 CFU o.g. C: NaCO3	Proph	Every other day for 5 admins	CD: ↑ CDB (T1), weak ↓ (T2), ↓ (T4), – (T3) IM: NA MM: NA MC: NA
Salehipour et al.^Citation50	Low	F C57BL6 mice 8–10 wko n = 8/g	MOG-induced EAE	T1: L. plantarum A7, 10^9 CFU o.g. T2: B. animalis PTCC 1631,10^9 CFU o.g. T3: T1+ T2 C: sterile saline	Thera	Daily for 22 d	CD: delayed EAE onset (T1-T3), T3 more pronounced; ↓ EAE CS, CDI, incidence, infiltration of MNCs, and demyelination (T1-T3), T3 more pronounced IM: ↓ ASP, IFN-γ, IL-6, IL-17 (T1-T3), T3 more pronounced; ↑ % CD4+ CD25+ Foxp3+ Tregs, IL-4, IL-10, TGF-β (T1-T3), T3 more pronounced MM: NA MC: ↑ expression of GATA3, FoxP3 and ↓ expression of Tbet, RORγt (T1-T3), T3 more pronounced
He et al.^Citation75	UN	F C57BL6 mice 10–12 wko n = 37–40/g	MOG-induced EAE	T: L. reuteri DSM 17938 100 µL of 10^8 CFU o.g. C1: 100 µL MRS media + EAE, o.g. C2: normal control	Thera	Daily for 20 d	CD: ↓ CDS, EAE incidence, maximum CS, inflammatory cell infiltration IM: ↓ CD3 + T cells & CD68+ macrophages in spinal cord, % and abs. # of TH1 and TH17 cells, IL-17, IFN-γ, ↓ % MOG35-55-specific splenocytes MM: reversed EAE rel. abund. changes (↑ Bacteriodetes, Proteobacteria, Deferribacteres); Bifidobacterium, Lactobacillus, Prevotella, & S24-7 = negative correlation w/ CS MC: NA
Goudarzvand et al.^Citation52	UN	M Wistar rats 8–10 wko n = 8/g	GID	T1: L. plantarum T2: Bifidobacterium B94 Each 1.5 × 10^8 CFU/mL orally C1: GID only C2: sterile saline, no GID	Thera	Daily for 28 d	CD: – traveled distance, escape latency, or swimming speed IM: NA MM: NA MC: NA
Consonni et al.^Citation53	Low	F Lewis rats 6–8 wko n = 6–9/g (T1-T4), n = 18/g (T5-T6)	gpMBP-induced EAE	T1: L. crispatus LMG P-23257 T2: L. rhamnosus ATCC 53103 T3: B. animalis subsp. lactis BB12 T4: B. animalis subsp. LMG S-28195 T5: T1+ T2 T6: T3+ T4 Each 2 × 10^9 CFU/300 µL orally C: vehicle	Proph & Thera	15 doses over 3 wks (5 doses pre-EAE)	CD: ↓ EAE incidence & median score at peak (T1-T6); ↓ myelin loss, astrocytosis, & spinal cord immune cell infiltration (T5/T6); delayed EAE onset (T1,T2, T5, T6); dose-response relationship observed with T5/T6 IM: ↓ proliferative response to MBP, IFN-γ, TNF-α, IL-17 (T5/T6); ↑ TGF-β, IL-16 (T5/T6) MM: NA MC: NA
Baken et al.^Citation73	UN	M Lewis rats 6–8 wko n = 8/g	gpSCH-induced EAE	T: L. casei strain Shirota, 1 mL of 1 × 10^9 CFU/mL C: 1 mL saline/peptone	Proph & Thera	Daily for 35 d (starting 8 d pre-EAE)	CD: ↓ body weight; ↑ EAE incidence, duration, CDS, & CDI; earlier EAE onset IM: NA MM: NA MC: NA
Gharehkhani Digehsara et al.^Citation71	UN	F C57BL6 mice 8–10 wko	Cuprizone (4 wks)	T1: L. casei 4 wks, cuprizone 4 wks T2: Cuprizone 4 wks, L. casei 4 wks T3: Cuprizone 4 wks, L. casei 4 wks w/ Vitamin D3 (20 IU/d) C1: L. casei 4 wks, 1 × 10^9 CFU/mL C2: Cuprizone 4 wks, 0.2% w/w All admin orally C3: normal control	Proph & Thera		CD: more normal & significant Y-maze alternation behavior (T1-T3) IM: ↓ IL-17 (T1-T3), T3 more pronounced; ↑ TGF-β (T1-T3) MM: NA MC: ↓ expression of IDO gene & miR-155 (T1-T3, C2); ↑ expression of miR-25 (C2), trending in T1-T3
Kobayashi et al.^Citation68	UN	M & F Lewis rats 7 wko & 2 wko n = 8/g	gpSCH- or gpMBP-induced EAE	T1: L. casei strain Shirota in M rats (7 wko), 1–2 × 10^9 CFU o.g. T2: L. casei strain Shirota in F rats (7 wko), 1–2 × 10^9 CFU o.g. T3: L. casei strain Shirota in M & F rats (2 wko), 9.2–10.1 × 10^9 CFU o.g. T4: B. breve strain Yakult in M & F rats (2 wko), 5.0–6.9 × 10^9 CFU o.g. C: 0.5 mL saline/peptone	Proph & Thera	Daily T1-T2: 35 d (starting 7 d pre-EAE) T3-T4: 63 d (starting 5 wks pre-EAE)	CD: ↓ mortality in T1-T4 except T4 males (↑); – EAE onset, peak, mean CDS, infiltration of MNCs IM: – MBP IgG MM: NA MC: NA
Kobayashi et al.^Citation74	UN	F SJL & C57BL6 mice 7 wko n = 15/g	PLP-induced EAE (SJL) & MOG-induced EAE (C57BL6)	T: L. casei YIT 9029, 0.6–1.2 × 10^9 CFU o.g. C: 0.2 mL saline/peptone	Proph & Thera	Daily for 50 (SJL) or 29 (C57BL6) d (both starting 1 wk pre-EAE)	CD: ↓ EAE CS on ds 12, 29, & 30 (SJL); – EAE onset, peak score, MNC infiltration, white matter demyelination, or neutrophil infiltration (SJL & C57BL6) IM: ↓ % CD8 + T cells in spleen (SJL), ↑ IL-10, % Tregs in spleen, IL-17, IFN-γ (SJL) MM: NA MC: NA
Lavasani et al.^Citation48	UN	F C57BL6 (WT & IL-10-/-) mice 8–10 wko n = 3–18/g	MOG-induced EAE	T1: Proph L. paracasei DSM 13434 T2: Proph L. plantarum DSM 15312 T3: Proph L. plantarum DSM 15313 T4: Proph L. paracasei PCC 101 T5: Proph L. delbrueckii subsp. bulgaricus DSM 20081 Each 5 mL of 10^9 CFU orally until EAE, then 200 µL of 10^9 CFU o.g. T6: Thera T1 T7: Thera Lacto-mix (T1-T3) T8: HK T7 T9: T7 in IL-10-/- mice Each 200 µL of 10^9 CFU o.g. C: saline	Proph & Thera	Daily for 37 d (starting 12 d pre-EAE) or every other day for 20 d (starting 2 wks post-EAE onset)	CD: – EAE progression (T1-T5,T8); delayed EAE onset and ↓ CS (T1-T3, T7); therapeutic effects of Lacto-mix absent in T9 IM: ↓ T cell proliferation (T1-T3) ↓ CD4 + T cells (T1,T3),, ↓ IFN-γ, TNF-α (T1); ↑ IL-4, IL-10, TGF-β (T1); ↓ CNS inflammation, CD4 + T cell infiltration, IFN-γ, TNF-α, IL-17, and IL-17-producing CD4 + T cells (T7); ↑ IL-10, IL-10-producing CD4 + T cells, Tregs, Foxp3+ cells in brain, mLN, spleen (T7) MM: NA MC: EAE suppressed in recipient mice (mLN cells from T7) & depletion of CD4+ CD25 + T cells from mLN cells reverses suppression
Sanchez et al.^Citation49	UN	M & F C57BL6 (WT, CD45.1, CD45.2, GF, TLR-2-/-, & TLR-9-/-) mice & SJL mice 9–10 wko n ≥ 10/g	MOG-induced EAE (C57BL6) & PLP-induced EAE (SJL)	T1: Proph L. paracasei ATCC 27092 in C57BL6 mice T2: Proph HK T1 in C57BL6 mice T3: Proph L. paracasei DSM 2649 in C57BL6 mice T4: Proph L. paracasei ATCC 11582 in C57BL6 mice T5: Proph L. paracasei ATCC 334 in C57BL6 mice T6: Proph L. paracasei DSM 5622 in C57BL6 mice T7: T2 in CD45.1 C57BL6 donor mice AT into CD45.2 C57BL6 mice T8: T2 in TLR-2-/- C57BL6 mice T9: T2 in TLR-9-/- C57BL6 mice T10: T2 in WT C57BL6 mice GMT into GF C57BL6 mice T11: Thera T2 in SJL mice Each 10^9 CFU o.g. C: PBS, MRS medium, or T1-conditioned medium	Proph & Thera	Daily for 34–39 d (starting 2 wks pre-EAE) or daily for 39 d (starting 21 dpi) T10: daily for 28 d (starting 70 d pre-EAE) and GMT at 42 d pre-EAE	CD: ↓ EAE CS (T1-T6); ↓ EAE incidence (T1-T6); ↓ demyelination, infiltrating macrophages & lymphocytes in brain & spinal cord, and severity of subsequent relapses (T1-T2); ↑ EAE CS w/ T1-conditioned media; – BBB & BSCB permeability (T2) IM: – prop. CD4+ IFN-γ + T cells, CD4+ IL-17A+ T cells, or Tregs in CNS (T1-T2); ↓ CCL3, CCL4, CXCL5, CXCL13 (T2) MM: ↓ EAE incidence (T10); – EAE CS (T10) MC: EAE suppression and ↓ demyelination eliminated in TLR2-/- mice; – EAE incidence or severity in AT recipient mice of T2
Yamashita et al.^Citation67	UN	F SJL mice 5 wko n = 10/g	PLP-induced EAE	T: HK L. helveticus SBT2171, 1 mg i.p. C1: 1 mg PBS i.p. C2: PBS, no EAE (n = 3)	Proph & Thera	3×/wk for 3 wks (pre-EAE), daily for 42 dpi	CD: ↓ EAE incidence, CS, enlargement of inguinal LNs, infiltrating MNCs IM: ↓ # TH17, TH1, & CD4 + T cells in spinal cord, IL-17; ↓ IL-6, TGF-β, Foxp3+, IFN-γ in inguinal LNs; – IL-10 in inguinal LNs, – Ccl20 in spinal cord, CCR2, CCR4, & CCR6 on TH17 cells in dLNs MM: NA MC: NA
Libbey et al.^Citation54	UN	M C57BL6 mice 4 wko n = 15/g	MOG-induced EAE	T1: rE. coli Nissle 1917, 1.31 × 10^9 CFU o.g. single gavage day T2: rE. coli Nissle 1917, 1.19 × 10^9 CFU + 1.25 × 10^9 CFU o.g. double gavage C1: 70 µL PBS C2: rE. coli Nissle 1917, no EAE	Proph	1–2 admins 3 or 7 d pre-EAE Follow for 35–36 dpi	CD: ↓ survival & – CS, onset, incidence, CDS, maximal score, meningitis, demyelination, PVC (T1); ↓ CS, weight loss, PVC in T2; ↑ survival (T2); – EAE onset, incidence, CDS, maximal score, meningitis, demyelination (T2) IM: ↑ microglia, Tregs, IFN-γ, IL-27 (T1); ↓ CNS-derived cells, microglia, CD8 + T cells, CD4 + T cells, TH1 cells, Tregs in brain (T2); ↑ TH17 cells (T2) MM: NA MC: NA
Secher et al.^Citation55	UN	M C57BL6 mice 8–12 wko n = 30–40/g	MOG-induced EAE	T1: E. coli Nissle 1917 T2: archetypal K12 E. coli MG1655 Each 10^8 CFU o.g. C: PBS	Proph & Thera	Daily for 37 d (starting 7 d pre-EAE)	CD: ↓ EAE CS, mortality, incidence, CDS, maximal score; – onset; ↓ colon & ileum permeability IM: ↓ total CD4+ and MOG-specific CD4 + T cells in spinal cord, IFN-γ, GM-CSF, IL-17, TNF-α, IL-6; ↑ total CD4+ and MOG-specific CD4 + T cells in LNs, IL-10, CD4+ Foxp3+ cells from draining LNs MM: NA MC: ↑ expression of Reg3g, Reg3b, Claudin-8, ZO-1
Mestre et al.^Citation43	UN	F SJL mice 5–8 wko n = 5–10/g	TMEV-IDD	T: TMEV-IDD w/ Vivomixx^b 100 µL of 3 × 10^8 CFU o.g. C1: Sham w/ Vivomixx^b C2: TMEV-IDD w/ vehicle C3: Sham w/ vehicle	Thera	3×/wk for 15 d (70–85 dpi)	CD: ↑ horizontal & vertical activity, latency to fall IM: ↓ CD4 + T cells, B cells, % Foxp3+ CD39+ and Foxp3-CD39 + T cells in spleen, IL-1B, IL-6; ↑ Bregs, IL-10; – TNF-α; microglia exhibited anti-inflammatory activation or ↓ proinflammatory activity MM: ↓ rel. abund. of Anaerostipes, Dorea, Oscillospira, Enterobacteraceae, Ruminococcus, Bilophila, ↑ rel. abund. of Bacteroides, Odoribacter, Lactobacillus, Sutterella; ↑ acetate & butyrate in plasma MC: NA
Calvo-Barreiro et al.^Citation44	Low	F C57BL6 OlaHsd mice 8 wko n = 17–20/g	MOG-induced EAE	T1: Lactibiane iki^c, 1.6 × 10^9 CFU o.g. once daily T2: T1 twice daily T3: Vivomixx^b, 9 × 10^9 CFU o.g. once daily T4: T3 twice daily C1/C2: water o.g. once or twice daily C3: untreated EAE C4: normal control	Thera	1–2× daily for 18–22 d (13–16 or 12–15 dpi)	CD: ↓ CS w/ T1/T2 but not T3/T4 (dose-response observed); ↓ % demyelination, T cell inflammatory infiltrate density, & axonal damage (T1-T4); – intestinal permeability or microglia or astrocyte reactivity; improved motor coordination IM: ↓ ASP w/ T1/T2 but not T3/T4, % peripheral plasma cells (T1/T2); ↑ Tregs (T1/T2) MM: – alpha or beta diversity; ↑ rel. abund. of Lachnoclostridium and Bifidobacterium (T1/T2), Streptococcus (T3/T4); Atopobiacaeae & Bifidobacterium assoc. with ↓ accumulated EAE scores MC: 4x↓ expression of Th17 txn factor RORγt in spinal cord T1/T2
Kwon et al.^Citation69	UN	C57BL6 mice 6–8 wko n = 10/g	MOG-induced EAE	T1: Proph IRT5^d T2: Thera IRT5^d Each 5 × 10^8 CFU o.g. C: PBS	Proph & Thera	Daily for 3 wks (pre-EAE) or 16 d (starting 12 dpi)	CD: ↓ EAE incidence, CS, lymphocytes, Gr1+ and CD11b+ monocytes, and CD4 + T cells in spinal cord (T1); delayed EAE onset & ↓ EAE CS (T2) IM: ↓ ASP, IFN-γ, TNF-α, IL-17; ↑ IL-4, IL-10, CD4+ Foxp3+ Tregs from spinal cord MM: NA MC: NA
McMurran et al.^Citation45	Low	F C57BL6 mice 13 mo n = 3–5/g	Cuprizone (5 wks)	T: VSL#3^e, 1.35 × 10^9 CFU o.g. C: autoclaved water	Proph & Thera	Daily for 7 wks (starting 4 wks pre-lysolecithin injection)	CD: – remyelination IM: ↑ SCFAs in feces & serum, inflammatory response at 5 dpi, density of CD68+ activated microglia & infiltrating macrophages, # of ODCs at 5 dpi; – ODC response at 14 dpi, inflammatory response at 14 dpi MM: NA MC: NA
Ezendam et al.^Citation51	UN	M & F Lewis rats 2 wko n = 4–8/g	gpMBP-induced EAE	T: B. animalis w/ EAE, 200 µL of 1 × 10^9 CFU o.g. C1: B. animalis w/ no EAE C2: 200 µL saline w/ EAE C3: 200 µL saline w/ no EAE	Proph & Thera	Daily for ~60 d (starting 5 wks pre-EAE)	CD: ↑ weight gain for M; shorter EAE duration for M; – EAE onset, duration, or CDI for F; – EAE onset or CDI for M IM: NA MM: NA MC: NA
Ezendam & van Loveren^Citation72	High	M & F Lewis rats 2 wko n = 4–8/g	gpMBP-induced EAE	T; L. casei strain Shirota, 500 µL of 1–2 × 10^9 CFU o.g. C: 500 µL saline/peptone	Proph & Thera	Daily for ~9 wks (starting 5 wks pre-EAE)	CD: – EAE onset, CS, CDI for M & F; slightly longer duration for F; ↑ EAE incidence IM: NA MM: NA MC: NA
Johanson et al.^Citation76	UN	F C57BL6 mice 8 wko n = 10/g	MOG-induced EAE	T: L. reuteri ATCC 2327 ad libitum C: MRS broth	Thera	Daily for 20 d	CD: ↓ average CS, – weight loss IM: NA MM: ↑ Lactobacillus 16S V3-V4 amplicon abundance MC: NA
Abdurasulova et al.^Citation66	UN	F Wistar rats 3 mo n = 26–35/g	homologous SCH-induced EAE	T1: E. faecium LMG P-27496 L3 probe, 0.5 mL o.g. T2: Glatiramer acetate, 0.2 mL s.c. C1: saline, 0.5 mL o.g. C2: saline, 0.2 mL s.c.	Thera	Daily for 15 d (starting 2 dpi)	CD: ↓ prevalence, CDS, CS, mortality (T1/T2); delayed onset and shorter duration (T1/T2); T1 outperformed T2 in prevalence, duration, and CDS IM: ↓ CD4+ CD25+ Foxp3+ Tregs during peak and recovery phases, CD4 + T cells during peak; ↑ CD4+ Tcells during inductive, CD4+ CD25+ Foxp3- Tregs during peak, CD8 + T cells during peak & recovery MM: NA MC: NA

All findings are reported with respect to control group(s) unless otherwise indicated.

^bVivomixx = L. paracasei DSM 24734, L. plantarum DSM 24730, L. acidophilus DSM 24735, L. delbrueckii subsp. bulgaricus DSM 24734, B. longum DSM 24736, B. infantis DSM 24737, B. breve DSM 24732, S. thermophilus DSM 24731.

^cLactibiane iki = B. lactis LA 304, L. acidophilus LA 201, L. salivarius LA 302.

^dIRT5 = L. casei, L. acidophilus, L. reuteri, B. bifidum, S. thermophilus.

^eVSL#3 = see ^bVivomixx.

Key: ↓ decreased; ↑ increased; – no change or no difference compared to control; NA, not applicable to this study.

Abbreviations: ROB, risk of bias; MS, multiple sclerosis; UN, uncertain; M, male; F, female; wk/wks/wko, week/weeks/weeks old; mo/mos, month/months; g, group; WT, wild-type; IL, interleukin; GF, germ-free; TLR, toll-like receptor; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein; MBP, myelin basic protein; gp, guinea pig; SCH, spinal cord homogenate; GID, gliotoxin-induced demyelination; TMEV-IDD, Theiler’s murine encephalomyelitis virus-induced demyelinating disease; CFU, colony-forming units; T, treatment group; C, control; o.g., oral gavage; IU, international units; w/w, weight/weight; HK, heat-killed; -/-, deficient; AT, adoptive transfer; GMT, gut microbiome transfer; i.p., intraperitoneally; PBS, phosphate-buffered saline; Proph, prophylactic; Thera, therapeutic; admins, administrations; dpi, days post immunization; CD, clinical disease; IM, immune/metabolic; MM, microbiome/metabolome; MC, mechanistic/correlative; CDB, clinical disease burden; CS, clinical score; CDI, clinical disease index; MNC, mononuclear cell; IgG, immunoglobulin G; ASP, antigen-specific proliferation; IFN-γ, interferon gamma; TGF-β, transforming growth factor beta; CDS, cumulative disease score; rel. abund., relative abundance; TNF-α, tumor necrosis factor alpha; CNS, central nervous system; LN, lymph node; BBB, blood–brain barrier; BSCB, blood spinal cord barrier; PVC, perivascular cuffing; GM-CSF, granulocyte monocyte colony-stimulating factor; txn, transcription; SCFA, short-chain fatty acid; ODC, oligodendrocyte; abs., absolute

Table 4. Animal studies of commensal therapies: summary of study characteristics and major findings

Study	ROB	Sample	MS Model	Intervention	Timeline	Duration	Major Findings
Montgomery et al.^Citation37	Low	M & F C57BL6 & PWD mice 4 wko	2× MOG-induced EAE	T: L. reuteri isolated from PWD cecal contents (100 µL of 10^9 CFU o.g.) w/ 100 µL cryopreserved C57BL6 cecal microbiota C: 200 µL cryopreserved C57BL6 cecal microbiota	Proph	4 wks (one initial admin)	CD: ↑ CDS & freq. of infiltrating CD4 + T cells in spinal cord; – freq. of infiltrating CD8 + T cells in spinal cord IM: ↑ freq. of GM-CSF- and IFN-γ- producing CD4+ & CD8 + T cells MM: NA MC: NA
Chen et al.^Citation65	UN	F C57BL6 mice 3–4 wko n = 8/g	2× MOG-induced EAE	T1: C. butyricum GDBIO1501, 5 × 10^6 CFU/mL o.g. T2: norfloxacin, 5 mg/kg o.g. C1: PBS w/ EAE C2: normal control	Proph	Daily for 3 wks pre-EAE	CD: ↓ daily CS, lymphocyte infiltration, demyelinating plaques in lumbar spinal cord IM: ↓ TH17 cells in CNS, LN, colon, spleen, & small intestine, IFN-γ-producing CD4 + T cells in spleen; – IL-17A+IFN-γ+ CD4 + T cells; ↑ differentiation of Tregs MM: ↑ # of OTUs, abundance, diversity, and rel. abund. of Prevotella, Bacteriodetes; ↓ rel. abund. of Firmicutes, Desulfovibroneceae, Ruminococcus MC: ↓ phosphorylation of p38 MAPK, ERK1/2, and JNK in lumbar spinal cord
Mangalam et al.^Citation56	UN	M & F HLA-DR3.DQ8 transgenic mice 8–12 wko n = 5–11/g	PLP-induced EAE	T1: Proph P. histicola, 10^8 CFU/mL o.g. T2: Proph P. melaninogenica, 10^8 CFU/mL o.g. T3: Proph C. sputigena, 10^8 CFU/mL o.g. All isolated from duodenum of celiac disease patients T4: Proph mouse-specific E. coli, 10^8 CFU/mL o.g. T5: T1 w/ Abx-depleted flora T6: Thera T1 T7: HK T6 T8: T6 cell-free supernatant T9: T6 10^7 CFU T10: T6 10^9 CFU C: medium	Proph & Thera	Every other day for 2 wks (starting 7 d pre-EAE or 7 dpi) Abx depletion for 3 wks AT at 5 dpi	CD: ↓ EAE incidence, CDS, regions of brain & spinal cord inflammation and demyelination, BBB permeability, CNS cellular infiltration (T1); earlier onset (T1); T1 restored gut permeability IM: ↓ IL-23, IL-12, IFN-γ, IL-17, CD4 + T cells, IFN-γ- and IL-17-expressing CD4 + T cells (T1); ↑ IL-10, TGF-β, CD4+ CD25+ Foxp3+ Tregs (T1); ↑ IL-10 (T2) MM: ↑ rel. abund. of Prevotella, Lactobacillus, Sutterella (T1), resembling pre-EAE states MC: Milder EAE (T5); ↑ EAE incidence (T7/T8); ↑ EAE suppression (T6 vs T9/T10); ↓ EAE incidence in AT recipient mice of T1
Shahi et al.^Citation57	UN	M & F HLA-DR3.DQ8 double transgenic mice & C57BL6 mice 8–12 wko n ≥ 7/g	PLP-induced EAE (HLA) and MOG-induced EAE (C57BL6)	T1: Proph P. histicola, 10^8 CFU o.g. in HLA mice T2: Proph Copaxone, 2 mg s.c. in HLA mice T3: T1+ T2 T4: T1 in C57BL6 mice T5: T2 in C57BL6 mice T6: T3 in C57BL6 mice T7: Thera T1 T8: Thera T2 T9: Thera T3 C: PBS or TSB media	Proph & Thera	Every other day for 2 wks (starting 7 d pre-EAE or 7 dpi) T3, T6, T9 = T1 & T2 on alternating days	CD: ↓ average daily scores & CDS (T2,T3,T4-T6,T7-T9); delayed EAE onset (T9); ↓ inflammation, demyelination (T1-T3); effects of T3/T6/T9 not more pronounced IM: ↓ IL-17+ CD4+ & IFN-γ+ CD4 + T cells in brain & spinal cord (T1,T3); ↑ CD4+ Foxp3+ Tregs in splenocytes and GALT (T1,T3); – IL-10-producing CD4 + T cells (T1-T3) MM: ↑ rel. abund. Lactobacillus (T1,C), ↓ (T2,T3) MC: NA
Shahi et al.^Citation58	UN	M & F HLA-DR3.DQ8 double transgenic mice 8–12 wko n ≥ 12/g	PLP-induced EAE	T1: Proph P. histicola, 10^8 CFU o.g T2: Proph IFNβ, 10,000 IU T3: Proph T1+ T2 T4: Thera T1 T5: Thera T2 T6: Thera T3 C: TSB media	Proph & Thera	Every other day for 2 wks pre-EAE (7 doses) or starting 7 dpi (7 doses)	CD: ↓ average daily score & CDS (T4-T6), inflammatory cellular infiltration into brain & spinal cord (T4,T6), spinal cord tissue and meningeal/stratum regions of brain (T4-T6); no additive effects for T6 vs T4/T5 IM: ↓ Iba-1+ microglia & GFAP+ astrocytes in brain & spinal cord white matter, CD4+ IL-17+ & CD4+ IFN-γ + T cells (T1-T3); ↑ CD4+ Foxp3+ Tregs, IL-10-producing CD4 + T cells (T1,T3) MM: NA MC: NA
Takata et al.^Citation70	UN	F C57BL6 mice & SJL mice 6 wko n = 17/g	MOG-induced EAE (C57BL6) and PLP-induced EAE (SJL)	T1: HK P. acidilactici R037 in C57BL6 mice, 20 mg/mL o.g. T2: HK P. acidilactici R037 in water in SJL mice, 0.8 mg/mL orally C1: PBS, o.g. C2: PBS in water, orally	Proph & Thera	Daily for 36 d (starting 2 wks pre-EAE)	CD: ↓ CS (T1,T2); ↓ infiltrating MNCs (T1); delayed EAE onset (T2) IM: ↓ IL-17 & IFN-γ in splenocytes & draining LNs; ↑ IL-10 & CD4+ IL-10 + T cells in mesenteric LNs and splenocytes MM: NA MC: NA
Miyauchi et al.^Citation38	Low	F GF C57BL6 mice 5–7 wko n = 5–10/g	MOG-induced EAE	T1: OTU0001 (L. reuteri, 100% 16S rRNA match to strains H4 & LMG 18238) T2: OTU0002 (Allobaculum) Both isolated from small intestine of specific PF mice and o.g. at 5–7 wko for stable colonization. T3: T1 + T2 co-colonized T4: T3 with urvA-deficient L. reuteri C: naïve GF	Proph	One admin at 5–7 wko	CD: ↑ CS (T2,T3); – CS (T1); ↓ CS, EAE incidence (T4); ↑ demyelination, spinal cord infiltration, EAE incidence (T3) IM: ↑ IL-17A, TH17 cells in lamina propria of small intestine & splenocytes (T2); ↑ Tregs in small intestine (T2); ↑ TH17 cells (T3); – IL-17A, TH17 cells, Tregs in small intestine (T2/T3); – TH17 cells in small intestine (T1/T4) MM: – rel. abund. in small intestine (T2/T3); – rel. abund. in small intestine (T1/T4) MC: ↑ expression of Saa1, Saa2, Il23a, Il12b, Csf2, Il23r in small intestine (T2); – expression of Saa1, Saa2, Il23a in small intestine (T2/T3)
Ochoa-Reparaz et al.^Citation62	UN	F SJL mice 6 wko n = 6–8/g	PLP-induced EAE	T1: 1 wk Abx, recolonize w/ WT B. fragilis NCTC 9343 T2: 1 wk Abx, recolonize w/ PSA-deficient B. fragilis Both at 10^10 CFU in 200 µL sterile PBS o.g. C1: 1 wk Abx only C2: sham (no Abx, receive PBS)	Proph	30 d (one initial admin)	CD: ↓ CS, CDS (T1,C1); delayed EAE onset (T1,C1); – EAE incidence IM: ↓ Tbet (C1), IFN-γ (C1), RORγt (T1,C1), IL-17 (T1,C1); ↑ GATA-3 (T1,C1), IL-10 (T1,C1), SMAD-3 (T1), IL-13 (C1), freq. Foxp3+ CD25+ CD4 + T cells in cervical LNs (C1); ↑ IL-17, RORγt, Tbet and ↓ GATA-3, IL-10, IL-13 (T2); ↓ conversion of CD103+ DCs to Foxp3+ Tregs (T2) MM: # of detectable bacteria after Abx restored (T1,T2) (colonization confirmed) MC: Depletion of CD25 + T cells eliminated protective effects (C1,T1); ↓ CS & ↑ IL-10 in AT recipient mice (T1 only)
Liu et al.^Citation35	UN	F C57BL6 mice 6–8 wko n = 23–28/g	MOG-induced EAE	T1: Akkermansia muciniphila ATCC BAA-835 T2: E. coli K-12 Strain #7296 C: medium	Thera	Daily for 7 d (starting 11 dpi)	CD: ↓ CS, demyelination, axonal loss (T1) IM: ↑ MOG-specific Foxp3+ Tregs and total Tregs in spleen (T1); ↑ Foxp3+ Tregs from DCs (T1); – direct Foxp3+ Treg induction (T1 vs T2); ↓ IL-6, IL-1b expression in DCs (T1), – TGF-β expression (T1/T2) MM: NA MC: NA

All findings are reported with respect to control group(s) unless otherwise indicated.

Key: ↓ decreased; ↑ increased; – no change or no difference compared to control; NA, not applicable to this study.

Abbreviations: ROB, risk of bias; MS, multiple sclerosis; UN, uncertain; M, male; F, female; wk/wks/wko, week/weeks/weeks old; g, group; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein; T, treatment group; C, control; CFU, colony-forming units; o.g., oral gavage; PBS, phosphate-buffered saline; s.c., subcutaneous; Abx, antibiotics; HK, heat-killed; IFNβ, interferon beta; IU, international unit; OTU, operational taxonomic unit; PF, pathogen-free; GF, germ-free; WT, wild-type; PSA, polysaccharide A; Thera, therapeutic; Proph, prophylactic; admin; administration; dpi, days post immunization; CD, clinical disease; IM, immune/metabolic; MM, microbiome/metabolome; MC, mechanistic/correlative; CDS, cumulative disease score; freq., frequency; GM-CSF, granulocyte monocyte colony-stimulating factor; IFN-γ, interferon gamma; CS, clinical score; CNS, central nervous system; LN, lymph node; IL, interleukin; rel. abund., relative abundance; BBB, blood–brain barrier; AT, adoptive transfer; GALT, gut-associated lymphoid tissue; DC, dendritic cell; TGF-β, transforming growth factor beta; MNC, mononuclear cell.

Table 5. Bradford Hill criteria evaluation of probiotic and commensal therapies

Therapy	Study	Study Type	ROB	Strain Used	Treatment Effect	BH Score
VSL#3/ Vivomixx/ LBS	Mestre et al.^Citation43	Animal TMEV-IDD Thera	UN	L. paracasei DSM 24734, L. plantarum DSM 24730, L. acidophilus DSM 24735, L. delbrueckii ssp. bulgaricus DSM 24734, B. longum DSM 24736, B. infantis DSM 24737, B. breve DSM 24732, S. thermophilus DSM 24731	Improved	9
	Calvo-Barreiro et al.^Citation44	Animal EAE Thera	Low		Improved
	McMurran et al.^Citation45	Animal Cuprizone Proph & Thera	Low		No change
	Tankou et al.^Citation46	Human Prospective Cohort	High		Improved (immunologically)
	Tankou et al.^Citation47	Human Prospective Cohort	High		Improved (immunologically & microbiologically)
L. paracasei	Lavasani et al.^Citation48	Animal EAE Proph & Thera	UN	DSM 13434, PCC 101	Improved	7
	Sanchez et al.^Citation49	Animal EAE Proph & Thera	UN	ATCC 27092 (live & heat-killed), ATCC 11582, DSM 2649, DSM 5622, ATCC 334	Improved
B. animalis	Salehipour et al.^Citation50	Animal EAE Thera	Low	PTCC 1631	Improved	7
	Ezendam et al.^Citation51	Animal EAE Proph & Thera	UN	Not specified	No change
	Goudarzvand et al.^Citation52	Animal GID Thera	UN	Susbp. lactis B94	No change
	Consonni et al.^Citation53	Animal EAE Proph & Thera	Low	Subsp. lactis BB12	Slightly improved
	Consonni et al.^Citation53	Animal EAE Proph & Thera	Low	Subsp. lactis LMG S-28195	Slightly improved
E. coli	Libbey et al.^Citation54	Animal EAE Proph	UN	Nissle 1917 recombinant strain for ampicillin resistance (pGEN-MCS)	Improved	7
	Secher et al.^Citation55	Animal EAE Proph & Thera	UN	Nissle 1917	Improved
P. histicola	Mangalam et al.^Citation56	Animal EAE Proph & Thera	UN	Isolated from duodenum of celiac disease patients	Improved	7
	Shahi et al.^Citation57	Animal EAE Proph & Thera	UN	Isolated from duodenum of celiac disease patients	Improved
	Shahi et al.^Citation58	Animal EAE Proph & Thera	UN	Isolated from duodenum of celiac disease patients	Improved
L. plantarum	Lavasani et al.^Citation48	Animal EAE Proph & Thera	UN	DSM 15312, DSM 15313	Improved	6
	Salehipour et al.^Citation50	Animal EAE Thera	Low	A7	Improved
	Goudarzvand et al.^Citation52	Animal GID Thera	UN	Not specified	No change
	Maassen et al.^Citation59	Animal EAE Proph	UN	NCIB 8826, 14917	No change
Lacto-mix	Lavasani et al.^Citation48	Animal EAE Proph & Thera	UN	L. plantarum DSM 15312, L. plantarum DSM 15313, L. paracasei DSM 13434	Improved	6
L. crispatus & L. rhamnosus	Consonni et al.^Citation53	Animal EAE Proph & Thera	Low	L. crispatus LMG P-23257 & L. rhamnosus ATCC 53103	Improved	6
B. animalis & B. animalis	Consonni et al.^Citation53	Animal EAE Proph & Thera	Low	B. animalis subsp. lactis BB12 & B. animalis subsp. lactis LMG S-28195	Improved	6
L. acidophilus, L. casei, L. fermentum, & B. bifidum	Kouchaki et al.^Citation60	Human RCT	Low	Not specified	Improved	5
	Tamtaji et al.^Citation61	Human RCT	Low	Not specified	Slightly improved (immunologically)
B. fragilis	Ochoa-Reparaz et al.^Citation62	Animal EAE Proph	UN	NCTC 9343	Improved	5
L. crispatus	Consonni et al.^Citation53	Animal EAE Proph & Thera	Low	LMG P-23257	Improved	4
L. rhamnosus	Consonni et al.^Citation53	Animal EAE Proph & Thera	Low	ATCC 53103	Improved	4
Lactibiane iki	Calvo-Barreiro et al.^Citation44	Animal EAE Thera	Low	B. lactis LA 304, L. acidophilus LA 201, L. salivarius LA 302	Improved	4
Protexin	Rahimlou et al.^Citation63	Human RCT	Low	B. subtilis PXN 21, B. bifidum PXN 23, B. breve PXN 25, B. infantis PXN 27, B. longum PXN 30, L. acidophilus PXN 35, L. rhamnosus PXN 54, L. helveticus PXN 45, L. salivarius PXN 57, L. lactis ssp. lactis PXN 63, S. thermophilus PXN 66, L. casei PXN 37, L. delbrueckii ssp. bulgaricus PXN 39, L. plantarum PXN 47	Slightly improved	4
L. plantarum, L. casei, L. reuteri, L. fermentum, B. infantis, & B. lactis	Salami et al.^Citation64	Human RCT	Low	Not specified	Improved	4
L. plantarum & B. animalis	Salehipour et al.^Citation50	Animal EAE Thera	Low	L. plantarum A7, B. animalis PTCC 1631	Improved	4
C. butyricum	Chen et al.^Citation65	Animal EAE Proph	UN	GDBIO1501	Improved	4
Allobaculum	Miyauchi et al.^Citation38	Animal EAE Proph	Low	Isolated from content of small intestines of specific PF mice	Slightly worsened	4
L. murinus	Maassen et al.^Citation59	Animal EAE Proph	UN	CNRZ	Improved	3
E. faecium	Abdurasulova et al.^Citation66	Animal EAE Thera	UN	LMG P-27496	Improved	3
L. helveticus	Yamashita et al.^Citation67	Animal EAE Proph & Thera	UN	SBT2171	Improved	2
B. breve	Kobayashi et al.^Citation68	Animal EAE Proph & Thera	UN	Yakult	Slightly improved (F) Worsened (M)	2
IRT5	Kwon et al.^Citation69	Animal EAE Proph & Thera	UN	L. casei, L. acidophilus, L. reuteri, B. bifidum, S. thermophilus	Improved	2
P. acidilactici	Takata et al.^Citation70	Animal EAE Proph & Thera	UN	R037	Improved	2
A. muciniphila	Liu et al.^Citation35	Animal EAE Thera	UN	ATCC BAA-835	Improved	2
L. casei	Maassen et al.^Citation59	Animal EAE Proph	UN	393	Slightly improved	1
	Gharehkhani Digehsara et al.^Citation71	Animal Cuprizone Proph & Thera	UN	Not specified	Improved
	Ezendam & van Loveren^Citation72	Animal EAE Proph & Thera	High	Shirota	Slightly worsened
	Baken et al.^Citation73	Animal EAE Proph & Thera	UN	Shirota	Worsened
	Kobayashi et al.^Citation68	Animal EAE Proph & Thera	UN	Shirota	No change
	Kobayashi et al.^Citation74	Animal EAE Proph & Thera	UN	YIT 9029	No change
L. reuteri	He et al.^Citation75	Animal EAE Thera	UN	DSM 17938	Improved	1
	Johanson et al.^Citation76	Animal EAE Thera	UN	ATCC 2327	Improved
	Maassen et al.^Citation59	Animal EAE Proph	UN	ML1	Worsened
	Miyauchi et al.^Citation38	Animal EAE Proph	Low	Isolated from content of small intestines of specific PF mice 100% 16S rRNA match to strains H4 & LMG 18238 Also uvrA-deficient L. reuteri	Slightly worsened
	Montgomery et al.^Citation37	Animal EAE Proph	Low	Isolated from PWD cecal contents	Worsened
L. delbrueckii subsp. bulgaricus	Lavasani et al.^Citation48	Animal EAE Proph & Thera	UN	DSM 20081	No change	1

Abbreviations: ROB, risk of bias; BH, Bradford Hill; EAE, experimental autoimmune encephalomyelitis; Proph, prophylactic; Thera, therapeutic; RCT, randomized controlled trial; GID, gliotoxin-induced demyelination; TMEV-IDD, Theiler’s murine encephalomyelitis virus-induced demyelinating disease; UN, uncertain.

Table 6. Bradford Hill criteria (BHC) warranting most attention for future probiotic and commensal therapy studies

	Probiotic Therapy	Commensal Therapy
BHC #	1. Temporal relationship	2. Strength of relationship
	4. Replication of findings	3. Dose–response relationship
	6. Cessation of exposure	4. Replication of findings
	7. Specificity of association	6. Cessation of exposure
		8. Coherence between multiple approaches

Abbreviation: BHC, Bradford Hill criteria.

Figure 1. Search strategies, selection criteria, and inclusion of articles. Articles from four separate databases were identified and screened for inclusion. Note that helminth therapy studies were included in the search strategy but manually removed during the eligibility stage of the second search

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