Table 1 The effects and underlying mechanisms of probiotics on bone remodeling in animal models and population-based studies

From: Modulation of bone remodeling by the gut microbiota: a new therapy for osteoporosis

Genus

Species

Research models or population

Effects

Mechanisms

References

Lactobacillus

L. reuteri ATCC PTA 6475

OVX Balb/c mice

Femur and vertebrae BV/TV, BMD, BMC, Tb. N. ↑ ,

Tb spacing ↓

TRAP5 and RANKL mRNA expression ↓ ,

BM CD4+ T cells,

OC differentiation in vitro ↓ 

173

L. reuteri ATCC PTA 6475

Type 1 diabetic C57BL/6 mice

Tb. BV/TV, Tb. N., Tb. Th., BMD, BMC ↑ ,

Tb spacing ↓

MAR, OB surface, serum OCN, Wnt10b expression and Wnt10b+ cells in gut and bone ↑ , BM adipocyte area and size ↓

34

L. reuteri ATCC PTA 6475

BALB/c mice with OP

Femur and vertebrae BV/TV, BMD, BMC, Tb. N., MAR, serum OCN ↑ ,

Tb spacing, serum TRAP 5b ↓

Colon permeability, colon TNF-α/IL-10 ratio ↓

25

L. reuteri ATCC PTA 6475

Rag knockout C57BL/6 mice (deficient in mature T- and B- cells)

Femur BV/TV, BMC, Tb. Th. in WT mice ↑

IL-10, IFN-γ, TGF-β, osterix gene expression ↑ ,

L. reuteri requires lymphocytes to exert beneficial effects on bone.

181

L. rhamnosus GG

OP C57BL/6 J mice induced by leuprolide administration

Spine and femur BV/TV, serum OCN ↑ , serum CTX ↓ 

Intestinal barrier integrity ↑ ,

TNF-α, RANKL, IL-17 mRNA expression ↓

30

L. rhamnosus GG

Conventionally raised C57BL/6 mice

Femur BV/TV, Spine BV/TV ↑ , serum CTX ↓ 

MAR, P1NP,

Wnt10b expression in BM and CD8+ T cells, Foxp3+ T cells in BM, spleen, and PP ↑ 

33

L. acidophilus ATCC 4356

OVX Balb/c mice

Bone mass ↑ ,

Femur resorption pits/lacunae ↓

CD4+ Foxp3+ Treg cells, CD8+ Foxp3+ Treg cells, serum IL-10, IFN-γ ↑ ,

CD4+Rorγt+ Th17 cells, serum IL-17, TNF-α, RANKL ↓ 

174

L. sakei

RA DBA/1 J mice

Arthritis score, TRAP+-, RANK+-, RANKL+ -cells ↓

TNF-α, IL-1β, IL-6, IL-17 ↓

180

L. fermentum ZS40

OP Wistar rats

BV/TV, Tb. N., Tb. Th., BMD ↑, the number of OC, Tb spacing ↓

β-catenin, Wnt10b, Lrp5, Lrp6, Runx2, ALP, RANKL, OPG mRNA expression ↑ ,

DKK1, RANK, TRAP, CTSK mRNA expression ↓

175

L. Plantarum HFY15

OP Wistar rats

BV/TV, Tb. N., Tb. Th., BMD ↑, the number of OC, Tb spacing ↓

β-Catenin, Wnt10b, Lrp5, Lrp6, Runx2, ALP mRNA expression ↑ ,

DKK1, RANK, TRAP, CTSK mRNA expression ↓

176

L. helveticus ATCC 27558

OVX Sprague–Dawley rats

Femur BMD, breaking forces, serum OCN ↑ , serum CTX ↓ 

Runx2 and BMP2 mRNA expression ↑ ,

Lactobacillus enumeration in the feces ↑

177

L. curvatus Wikim 38

OVX C57BL/6 mice

BV/TV, BMD, Tb. Th. ↑

F-actin ring formation, bone resorption, osteoclastogenesis, RANKL/TRAF6/

NF-κB/MAPK gene expression ↓

178

L. paracasei DSM13434, or a mixture of L. paracasei DSM13434, L. plantarum DSM 15312 and DSM 15313

OVX C57BL/6 N mice

Cb. BMC., Cb. Area ↑

BM TNF-α, IL-1β, OPG ↑ 

179

L. reuteri ATCC PTA 6475

Postmenopausal women with osteopenia

The loss of total BMD ↓ 

 

189

L. casei Shirota

Elderly patients with an acute distal radius fracture

DASH (disabilities of the arm, shoulder, and hand) score, pain, complex regional pain syndrome score, wrist flexion, and grip strength of patients receiving probiotics exhibited a significantly faster pace of improvement.

 

190

L. paracasei DSM 13434, DSM 15312, and DSM 15313

Postmenopausal women with osteopenia

Lumbar spine bone loss ↓

 

188

Bifidobacterium

B. longum

OVX Sprague-Dawley rats

Serum OCN, femur BMD, Tb. Th., femur strength ↑ ,

Serum CTX ↓ 

Sparc and BMP2 mRNA expression ↑ ,

Total Bifidobacteria in the feces ↑

184

B. longum 35624

OC precursors from C57BL/6 N mice

OC differentiation ↓

Surface exopolysaccharide of B. longum 35624 mediated inhibition of osteoclast formation is TLR2-dependent.

186

B. adolescentis

Fractured C57BL/6 mice

Serum P1NP, callus cartilage remodeling ↑ , post-traumatic bone loss ↓

Tight junction protein ↑ ,

Systemic inflammation ↓

187

B. pseudocatenulatum CECT 7765

Obesity C57BL/6 mice

Tb. N., Serum OCN ↑ ,

Tb spacing, Serum CTX ↓ ;

Canonical Wnt/β-catenin pathway ↑

185

VSL#3 (B. breve,

B. longum, B. infantis,

L. acidophilus,

L. plantarum,

L. paracasei,

L. bulgaricus,

and Streptococcus thermophilus)

OP C57BL6/J mice induced by leuprolide administration

Femur BV/TV, Cb. V., serum OCN ↑ 

Intestinal tight junction ↑

30

Akkermansia

A. muciniphila

OVX C57BL/6 mice

BMD, Tb. BV/TV., Tb. N., serum OCN, MAR ↑ ,

Tb spacing, the number and size of OC ↓ 

EVs are required for the A. muciniphila‐induced bone protective effects.

159

A. muciniphila

C57/BL6 mice with experimental periodontitis

Alveolar bone loss ↓

M2 macrophages, IL-10 gene expression ↑

201

A. muciniphila

Fractured C57BL/6 mice

BV/TV, tissue mineral density of callus, femoral ultimate load, serum OCN, bone fracture healing ↑

Type H vessel formation in callus ↑,

inflammatory responses in fracture healing, intestinal permeability, and inflammation ↓

203

  1. ↑: up-regulated or increased compared to those mice without treatment
  2. ↓: down-regulated or decreased compared to those mice without treatment
  3. ALP Alkaline phosphatase, BM Bone marrow, BMC Bone mineral content, BMD Bone mineral density, BMP2 Bone morphogenetic protein 2, BV/TV The ratio of bone volume to total volume, Cb Cortical bone, CTSK Cathepsin K, CTX-I C-terminal telopeptides of type I collagen, DKK1 Dickkopf-related protein 1, EVs Extracellular vesicles, IFN-γ Interferon-γ, IL Interleukin, LRP Low-density lipoprotein receptor-related protein, MAPK Mitogen-activated protein kinase, MAR Mineral apposition rate, OB Osteoblasts, OC Osteoclasts, OCN Osteocalcin, OP Osteoporosis, OPG Osteoprotegerin, OVX Ovariectomized, P1NP Procollagen type I N-terminal propeptide, PPs Peyer’s patches, RA Rheumatoid arthritis, RANKL Receptor activator of nuclear factor kappa-B ligand, Tb. N. Trabecular bone number, Tb. Th. Trabecular bone thickness, Tb Trabecular bone, TGF-β Transforming growth factor-β, TLR Toll-like receptor, TNF-α Tumor necrosis factor-α, TRAF6 Tumor necrosis factor receptor associated factor 6, TRAP Tartrate-resistant acid phosphatase, WT Wild-type