Table 1.
Applications of L. reuteri in diseases.
| Disease | Strains | Participants | Intervention | Mechanism of action | Outcomes | Ref |
|---|---|---|---|---|---|---|
| AD | ATCC 55730 | Children aged 4–10 years (n = 26) | 108 CFU/d, 8 weeks | Increased levels of IFN-γ and reduced levels of IL-4 in exhaled breath condensate | No changes in SCORD Index mean values | (106) |
| Fn041 | 7-week-old BALB/c mice during late gestation and lactation (n = 6), 3-week-old infant BALB/c mice (n = 8) | 109 CFU/d from 1 week before parturition to weaning | Reduced numbers of mast cells and eosinophils; increased numbers of Tregs cells; increased levels of IL-12; reduced levels of IL-4; reduced levels of IgE; enrichment of Lactobacillus and Akkermansia species; reduced numbers of Alloprevotella spp; increased numbers of Limosilactobacillus reuteri in breast milk | Reduced redness, swelling, and relative thickness of ear; decreased incidence of AD | (50) | |
| 7-week-old BALB/c mice during late gestation and lactation, infant (n = 6), 3-week-old infant BALB/c mice (n = 12) | Maternal mice with 109 CFU/d from day 3 before parturition to weaning, infant mice with 109 CFU/d for 10 days | Reduced levels of plasma OVA-specific IgG1/IgG2a; reduced levels of IL-4, IL-33, and TSLP; increased numbers of splenic Tregs; decreased numbers of eosinophils and mast cells; increased numbers of Limosilactobacillus, Faecalibacterium, and Akkermansia; activation of retinol metabolism and PPAR signaling pathway; downregulation of pathways associated with asthma, autoimmune thyroid disease, and SLE. | Reduced swelling and relative thickness of ear; increased height of ileal villi and ratio of ileal villus height to crypt depth; decreased incidence of AD | (107) | ||
| DYNDL22M62 | 6-week-old C57bl/6 mice (n = 6) | 109 CFU/d, 3 weeks | Reduced levels of IgE; reduced expression of TSLP, IL-4, and IL-5; reduced Th2 type responses; increase generation of ILA and IPA; increased numbers of Romboutsia and Ruminococcaceae NK4A214; reduced numbers of Dubosiella | Elevated tryptophan metabolism; reduced ear swelling and skin lesions; alleviated AD | (108) | |
| Asthma | Five-strain mixture including CCFM1072 (FSDLZ13M6),DYNDL2-16, CCFM1040 (YN-DL-1-3), GDLZ10-5, and FZJTZ20M3 | 4–5-week-old female BALB/c mice (n = 6–7) | (109 CFU)/strain/d, 1 week before the first sensitization until the end of the experiment, 6 weeks | Reduced levels of total IgE and HDM-IgG1; reduced levels of IL-5 and IL-13; enrichment of Lactobacillus and Enterococcus species; regulation of gut microbial function toward butyrate generation | Decreased airway inflammation score; decreased incidence of asthma | (88) |
| ATCC 23272 | 8–9-week-old male BALB/c and Toll-like receptor 9–deficient mice | 109 CFU/d, 9 days | Reduced numbers of eosinophils; reduce levels of TNF, MCP-1, IL-5, and IL-13; dependence on TLR9 and increased activity of indoleamine 2,3-dioxygenase | Reduced airway hyperresponsiveness; attenuated asthmatic response | (109) | |
| DSM 17938 | Children and adolescents aged 6–17 years with mild to moderate asthma (n = 14) | 108 CFU/d, 60 days | / | Increased ACT scores; reduced number of symptoms and wheezing | (110) | |
| Adults with mild allergic asthma, 8 women and 7 men , mean age of 27 years (n = 15) | 109 CFU/d, 4 weeks, followed by a second treatment period with 109 CFU/d for 4 weeks and then by 4–5 weeks of washout period | / | No differences in airway nerves, smooth muscle, sputum inflammatory cells, skin responses, or T-cell responses | (111) | ||
| CCFM1040 | Adults aged 18–60 years with at least a 1-year-long history of rhinitis or asthma or both (n = 4) | 109 CFU/d , 8 weeks | Decreased numbers of Proteobacteria phylum, Escherichia_Shigella genus, and Intestinibacter order; promotion of mineral absorption and apoptosis; inhibition of novobiocin biosynthesis; altered biological pathways associated with the metabolism of carbohydrates, energy, lipids, cofactors, and vitamins, xenobiotic biodegradation and metabolism, and immune system | Decreased TSS, RQLQ, 3 nasal scores in TSS (nasal congestion,watery eyes, and rhinorrhea) and mean sneezing score; improved sleep and non-nose/eye symptoms; increased ACT score; enhanced control in patients with asthma | (112) | |
| NEC | DSM 17938 | 5-day-old newborn C57BL/6J (WT) mice and B6.129-TLR2tm1kir/J (TLR2-/-) mice | NEC-induced+LR 17938-fed (WT: n = 21; TLR2-/-: n = 12), 106 CFU/g body/d/pup, 4 d | Reduced numbers of activated effector CD4+ T-cells; increased numbers of Foxp3+ Tregs; activated tolerogenic DCs by TLR2; decreased levels of IL-1β and IFN-γ | Decreased incidence and severity of NEC | (49) |
| Preterm infants of ≤32 weeks gestational age and birth weight ≤1500 g (n = 400) | 108 CFU/d, from first feeding to discharge | / | No effect in incidence and mortality of NEC; reduced frequency of proven sepsis, rates of feeding intolerance, and duration of hospital stay | (113) | ||
| Infant Sprague-Dawley rats | NEC+17938 (n = 38), NEC+4659 (n = 36), formula+17938 (n = 22), formula+4659 (n = 17), 106 CFU/g body/d, 3 days | Downregulated levels of TLR1, TLR4, IL-1β, IL-6, TNF-α, and nfrκb; upregulated levels of IL-10 and Nfκbib; inhibited MAPK8IP3; inhibited LPS-induced IκB phosphorylation | Increased survival rate; decreased incidence and severity of NEC | (114) | ||
| ATCC PTA 4659 | Downregulated levels of TLR1, TLR4, IL-1β, IL-6, TNF-α, and nfrκb; upregulated levels of IL-10 and Nfκbib; inhibited production of myelin and lymphocyte protein; inhibited LPS-induced IκB phosphorylation | |||||
| SLE | Unknown | TLR7.1 Tg C57BL/6 mice and WT B6 mice | Gavage daily | Translocation depending on TLR7; increased abundance and translocation of Lactobacilli; increased numbers of pDCs and leukocyte recruitment; increased IFN signaling | Increased splenomegaly and hepatomegaly; worsened IMQ-induced anemia and gut permeability; increased lupus-related pathogenesis and systemic autoimmunity | (115) |
| GMNL-263 | 16-week-old BWF1 mice (n = 5) | 108 cells/mL/d, up to week 28 | Reduced number of TUNEL-positive cells; decreased levels of TNF-R1, FADD, MMP-9; increased levels of p-AKT | Decreased cardiac apoptosis and fibrosis | (116) | |
| GMNL-89 | 6-week-old BWF1 mice | 109 CFU/d, 12 weeks | Reduced levels of hepatic MMP-9, CRP, and iNOS; reduced levels of IL-1β, IL-6, and TNF-α; suppressed MAPK and NF-κB; reduced hepatic lymphocyte infiltration; reduced numbers of TUNEL-positive cells and levels of cleaved caspase-3; Reduced ratios of p-ERK:ERK, p-P38:P38, and p-JNK:JNK; reduced expression of IKK and NF-κB | Decreased hepatic apoptosis and inflammation | (117) | |
| DSM 17509 | 4-week-old female BWF1 mice (n = 6–11) | 108 CFU/biw, 10 months | Increased levels of IL-10 and IL-12 | Delayed lupus onset; increased survival | (60) | |
| RA | CCFM 8631 and CCFM 14 | 6-week-old female Wistar rats | 2.5 × 108 CFU/d, 2 weeks before CIA induction and continued for another 7 week |
Reduced levels of serum anti-CII IgG and anti-CII IgG2b; attenuated increase in the levels of IL-6 and TNF-α; decreased levels of IL-1β, IFN-γ, and IL-12; downregulated levels of IL-10; enriched Verrucomicrobia and Bifidobacterium species; restored decrease in numbers of Clostridium species. increased levels of SCFAs; enriched microbial metabolic functions | Decreased ankle swelling; attenuated arthritis | (118) |
| MM2-3 (ATCC PTA 4659) | 6–8-week-old female DBA/1J mice (n ≥ 6) | Gavage at days 7–21 or days 21–35, 14 days | Reduced levels of serum CII-specific IgG, IL-6, and CXCL1; increased levels of IL-10; increased levels of Tregs, CD4+IL-10+ cells, CD103+ dendritic cells, and α4β7+ Tregs; promoted peripheral migration of Tregs | Decreased incidence, severity, and progression of arthritis | (53) | |
| MS | Unknown | GFAP-AHR deficient mice | / | Conversion of dietary Trp into AHR agonists via TnAse dependent and independent pathways | Regulated astrocyte function | (119) |
| Unknown | 10-week-old female WT C57BL/6 mice | 108 CFU/d, 20 days | Reduced numbers of CD3+ T-cells, CD68+ macrophages, Th1, and Th17 cells; reduced levels of IL-17 and IFN-γ; restored diversity of gut microbiota; decreased splenocyte proliferation; reduced numbers of Proteobacteria and Deferribacteres; reduced numbers of Anaeroplasma and Rikenellaceae; increased numbers of Bacteroidetes; increased numbers of Prevotella and S24-7 | Decreased severity of EAE. regulated microbial dysbiosis | (120) | |
| H4 and LMG 18238 | 5–7-week-old female GF C57BL/6 mice | Colonization | Cooperation with OTU0002 (Erysipelotrichaceae); upregulated expression of UvrA; cross-reaction with and activation of Ki67+ proliferating CD4+ T-cells; activation of antigen-specific Th17 cells | Aggravated inflammation in spinal cord | (58) |
"/" indicates that the study does not have information on the mechanism of action or Intervention. OVA, ovalbumin; TSLP, thymic stromal lymphopoietin; PPAR, Peroxisome Proliferator Activated Receptor; ZO-1, zonula occludens-1; ILA, indole lactic acid; IPA, indole propionic acid; MCP-1, Monocyte Chemoattractant Protein-1; TLR9, Toll-like receptor 9; DCs, dendritic cells; Tem, Effector memory T; nfrκb, nuclear factor related to κB-binding protein; Nfκbib, NF- κB inhibitor-β; MAPK8IP3, mitogen-activated protein kinase 8 interacting protein 3; IκB, inhibitor of NF-κB; pDCs, Plasmacytoid Dendritic Cells; TNF-R1, tumor necrosis factor receptor 1; FADD, Fas-associated protein with death domain; MMP-9, matrix metalloprotein-9; p-AKT, phospho-AKT; CRP, C reactive protein; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; p-ERK, phosphorylated extracellular signal-regulated kinase; p-JNK, phosphorylated c-Jun N-terminal kinase; p-P38, phosphorylated P38; IKK, IκB kinase; SCFAs, short chain fatty acids; Trp, Tryptophan; GFAP, glial fibrillary acidic protein; AHR, Aryl Hydrocarbon Receptor; TnAse , tryptophanase; GM-CSF, granulocyte macrophagecolony stimulating factor; UvrA , UvrABC system protein A; ArAT, aromatic amino acid aminotransferases; fldH, D-lactate dehydrogenase; AmiE, aliphatic amidase E; SCORAD, Severity scoring of atopic dermatitis; ACT, the Asthma Control and Test; FEV, Forced Expiratory Volume; TSS, total symptom score; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; IMQ, Imiquimod ; EAE, Experimental autoimmune encephakmyelitis ; CNS, Central Nervous System.