Table 5.

Therapeutic approaches for Alzheimer’s disease: focusing on microbiota and gram-negative bacteria-derived molecules

Therapeutic methods	Treatment or drug	Subject or model	Target (or antibiotic range)	Effects or trial phase	References
Antibiotics	Doxycycline	APP/PS1 mice	Gram-positive bacteria Gram-negative bacteria	Cognitive dysfunction↓ Neuroinflammation↓	[187]
	Gentamicin, Vancomycin, Metronidazole, Neomycin, Ampicillin, Kanamycin, Colistin, and Cefaperazone	APP/PS1 mice	Gram-positive bacteria Gram-negative bacteria	Aβ deposition↓ Soluble Aβ↓ Neuronal loss↓ Gliosis↓	[188]
	Rifampicin	AD patients	Gram-positive bacteria Gram-negative bacteria	Phase 2	NCT03856359
	Doxycycline Rifampicin	AD patients	Gram-positive bacteria Gram-negative bacteria	Phase 3	NCT00439166
	Doxycycline Rifampicin	AD patients	Gram-positive bacteria Gram-negative bacteria	Phase 3	NCT00715858
	Minocycline	AD patients	Gram-positive bacteria Gram-negative bacteria	Phase 2	NCT01463384
	Doxycycline Rifampicin	AD patients	Gram-positive bacteria Gram-negative bacteria	Dysfunctional behavior↓ Cognitive dysfunction↓	[189]
Gingipain inhibitor	COR271 COR286 COR388	BALB/c mice	Gingipain	Aβ deposition↓ TNF-α↓ Neuronal loss↓	[59]
	COR388	AD patients	Gingipain	Phase 2/3	NCT03823404
Probiotics	Lactobacillus acidophilus Bifidobacterium bifidum Bifidobacterium longum	Aβ-administered rats	Intestinal microbiota	Cognitive dysfunction↓ LTP↑	[190]
	Bifidobacterium longum Lactobacillus acidophilus	APP/PS1 mice	Intestinal microbiota	Cognitive dysfunction↓ Aβ deposition↓	[191]
	Lactobacillus plantarum MTCC1325	D-galactose-induced AD albino rats	Intestinal microbiota	Aβ deposition↓ NFT↓ Cognitive dysfunction↓ Acetylcholine level↑	[192]
	Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, Lactobacillus fermentum	AD patients	Intestinal microbiota	MMSE score↑	[193]
	Lactobacillus casei W56, Lactococcus lactis W19, Lactobacillus acidophilus W22, Bifidobacterium lactis W52, Lactobacillus paracasei W20, Lactobacillus plantarum W62, Bifidobacterium lactis W51, Bifidobacterium bifidum W23, Lactobacillus salivarius W24	AD patients	Intestinal microbiota	Systemic inflammation↓	[194]
	Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium longum	AD patients	Intestinal microbiota	MMSE score↑	[195]
	Lactobacillus fermentum, Lactobacillus plantarum, Bifidobacterium lactis Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium longum	AD patients	Intestinal microbiota	Cognitive dysfunction-	[196]
Intestinal microbiota reconstruction	Mediterranean-style diet	MCI patients	Non-specific bacteria	Changes of the microbiota	[157]
	Mediterranean-style diet	MCI patients	Non-specific bacteria	Changes of the microbiota	[197]
	Curcumin	APP/PS1 mice	Non-specific bacteria	Cognitive impairment↓ Aβ deposition↓ Changes of the microbiota	[198]
	Folate and vitamin B-12	Aβ-administered rats	Non-specific bacteria	Changes of the microbiota	[199]
	Ginsenoside Rg1	Tree shrew model of AD	Non-specific bacteria	Aβ deposition↓ Phosphorylated tau↓ Pro-apoptotic factor↓ Changes of the microbiota	[200]
	Streptococcus thermophilus, Bifidobacteria longum, Bifidobacteria breve, Bifidobacteria infantis, Lactobacillus acidophilus, Lactobacillus plantarum,Lactobacillus paracasei, Lactobacillus delbrueckii subsp, Bulgaricus, Lactobacillus brevis	3xTg mice	Intestinal microbiota	Cognitive impairment↓ Aβ deposition↓ Neuronal loss↓	[201]
	NK46 (Bifidobacterium longum) oral administration	5xFAD mice	Gram-negative bacteria	Pro-inflammatory cytokines↓ LPS↓ Gliosis↓ Neuronal loss↓ Aβ↓ Cognitive dysfunction↓	[23]
	Fecal microbiota transplant	ADLPAPT mice	Microbiota dysbiosis	Aβ deposition↓ NFT↓ Neuroinflammation↓ Cognitive dysfunction↓	[202]
	Fecal microbiota transplant	AD patients	Microbiota dysbiosis	MMSE score↑	[203]
	Fecal microbiota transplant	AD patients	Microbiota dysbiosis	Phase 1	NCT03998423

Ach Acetylcholine, AD Alzheimer’s disease, Aβ Amyloid-β, LPS lipopolysaccharides, LTP long-term potentiation, MCI mild cognitive impairment, MMSE mini-mental state examination, NFT neurofibrillary tangles, NF-kB nuclear factor-κB, SADAScog standardized Alzheimer’s disease assessment scale cognitive subscale