. 2021 Oct 21;13(1):1984104. doi: 10.1080/19490976.2021.1984104

Table 2.

The efficacy of A. muciniphila supplementation on metabolic diseases

Ref.	Bacterial status	Diet	Disease model	Dosage and period		study group	Treatment outcome
Animals
Everard et al (2013)¹⁹	Live A. muciniphila, heat-killed A. muciniphila	CT or HFD	HFD-fed obese mice	1. CT and HFD group mice orally administrated with 0.2 ml sterile anaerobic PBS containing a similar end concentration of glycerol (2.5% vol/vol) for 4 weeks.2. CT + AKK and HFD + AKK group mice orally administrated with 2 × 10⁸ CFU/0.2 ml A. muciniphila suspended in sterile anaerobic PBS.3. HFD + K-AKK group mice orally administrated with 2 × 10⁸ CFU/0.2 ml heat-killed A. muciniphila for 4 weeks.		1. Control diet (CT) (n = 10)2. HFD (n = 10)3. CT + AKK (n = 10)4. HFD + AKK (n = 10)5. HFD + K-AKK (n = 10)	A. muciniphila treatment reversed HFD including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. It also increased the intestinal levels of endocannabinoids and gut peptide secretion. And all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness.
Shin et al (2014)²²	Live A. muciniphila	NCD or HFD	HFD induced obese mice	1. HFD group treated with PBS for the 6 weeks.2. HFD + AKK group treated with 4.0 × 10⁸ CFU A. muciniphila for 6 weeks.		1. HFD (n = 6)2. HFD + AKK (n = 6)	Oral administration of A. muciniphila to HFD-fed mice significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by inducing Foxp3 regulatory T cells in the visceral adipose tissue.
Org et al (2015)⁷¹	HFD/high-sucrose diet (HSD) induced obesity	High-fat, high-sucrose (HF/HS) diet	(HF/HS) diet induced obese mice	1. HF/HS-AKK group was treated five times per week with A. muciniphila by oral gavage at a dose of 1.44 × 10⁹ CFU/0.2 mL for five weeks. 2. HF/HS group was treated with an oral gavage of an equivalent volume of heat-killed A. muciniphila for five weeks.	1. HF/HS-AKK (n = 5)2. HF/HS (n = 5)		Oral administration of A. muciniphila significantly reduced body weight and total body fat as well as improved metabolic parameters in HF/HS fed mice.
Plovier et al (2017)²¹	Live A. muciniphila, pasteurized A. muciniphila, and Amuc_1100	ND or HFD	HFD-induced obese mice	1. Control groups (ND and HFD) were treated with an oral gavage of an equivalent volume of sterile PBS containing 2.5% glycerol for 5 weeks. 2. HFD + AKK M group mice orally administered 2 × 10⁸ CFU/150 μl A. muciniphila grown on the mucus-based medium for 5 weeks.3. HFD + AKK S group mice orally administrated 2 × 10⁸ CFU/150 μl A. muciniphila grown on the synthetic medium for 5 weeks.4. HFD + AKK P group mice orally administrated 2 × 10⁸ CFU/150 μl pasteurized A. muciniphila for 5 weeks.5. Amuc_1100 group mice orally administrated 3 μg of the protein Amuc_1100 for 5 weeks.	1. ND (n = 10) 2. HFD (n = 9) 3. HFD + AKK M (mucus) (n = 9) 4. HFD + AKK S (synthetic) (n = 8) 5. HFD + AKK P (pasteurized) (n = 9) 6. Amuc_1100 (n = 9)		A. muciniphila retains its beneficial effects when grown on the synthetic medium. Pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. Amuc_1100 can interact with Toll-like receptor 2 and improve the gut barrier.
Li et al (2016)²⁰	Live A. muciniphila, heat-killed A. muciniphila	NCD or WD	Western diet-induced atherosclerosis in Apoe^−/− mice on a C57BL background	1. WD + PBS group treated PBS for 8 weeks.2. WD + AKK group treated 5 × 10⁹ CFU live A. muciniphila for 8 weeks. 3. WD + hk-AKK group treated 5 × 10⁹ heat-killed A. muciniphila for 8 weeks.	1. NCD (n = 8–10)2. WD (n = 8–10)3. WD + AKK (n = 8–10)4. WD + hk-AKK (n = 8–10)5. WD + PBS (n = 8–10)		Oral gavage with A. muciniphila protected against WD-induced atherosclerotic lesion formation in Apoe^−/− mice. It also ameliorated both aortic and systemic inflammation, decreased intestinal permeability and reduced the penetration of gut-derived lipopolysaccharide into circulation in WD-fed Apoe^−/− mice.
Shen et al (2016)²³	Live A. muciniphila	CD	CREBH-null mice	1. WT + Veh and KO + Veh mice treated with PBS that included 25% (vol/vol) glycerol for 2 weeks. 2. WT + AKK and KO + AKK mice treated with AKK for 2 weeks. 3. KO + inactive-AKK mice treated with heat-inactivated AKK for 2 weeks.	1. WT + AKK (n = 6–12)2. WT + Veh (n = 6–12)3. KO (CREBH-null mice) + AKK (n = 6–12)4. KO + Veh (n = 6–12)5. KO + inactive-AKK (n = 6–12)		A. muciniphila administration protected mice from an acute fat load–induced hyperlipidemia compared with vehicle-treated mice. It also significantly ameliorated chronic hypertriglyceridemia, improved insulin sensitivity, and prevented overproduction of postprandial chylomicrons in CREBH-null mice. Treatment with A. muciniphila further improved hepatic endoplasmic reticulum stress and metabolic inflammation in CREBH-null mice.
Zhao et al (2017)²⁴	Live A. muciniphila	NCD	NCD induced obese mice	1. NCD + PBS group orally administrated sterile PBS (NCD + PBS) for five weeks. 2. NCD + AKK group orally administrated 2.0 × 10⁸ CFU/200 µl A. muciniphila every day for five weeks.	1. NCD + PBS (n = 10)2. NCD + AKK (n = 10)		A. muciniphila supplementation significantly alleviated body weight gain, reduced fat mass and improved glucose tolerance and insulin sensitivity when compared with the vehicle group. It also reduced gene expression related to fatty acid synthesis and transport in liver and muscle as well as alleviated the endoplasmic reticulum stress in liver and muscle. A. muciniphila decreased plasma levels of lipopolysaccharide (LPS)-binding protein (LBP) and leptin, inactivated LPS/LBP downstream signaling in liver and muscle as well as increased anti-inflammatory factors.
Gao et al (2017)²⁵	Live A. muciniphila	NCD or HFD	HFD induced metabolic syndrome in mice	1. The NCD + AKK and HFD + AKK groups mice were treated daily with oral doses of 1 × 10⁹ CFU/300 μl A. muciniphila for 14 weeks.2. NCD- and HFD-fed control mice received a gavage with the corresponding sterile culture medium for A. muciniphila for 14 weeks.	1. NCD (n = 6–8)2. HFD (n = 6–8)3. NCD + AKK (n = 6–8)4. HFD + AKK (n = 6–8)		A. muciniphila administration altered body composition and energy efficiency, promoted the browning of white fat tissue, and improved the lipid and glucose metabolism disorder in the HFD-fed mice.
Sheng et al (2018)²⁶	Live A. muciniphila	WD	WD induced obese mice	1. WD-fed WT mice + PBS group orally administrated PBS for 1 month.2. WD-fed WT mice + AKK group orally administrated A. muciniphila 10⁹ CFU/mouse per day for 1 month.	1. WD-fed WT mice + PBS (n = 3–4)2. WD-fed WT mice + AKK (n = 3–4)		Supplementation of A. muciniphila reduces body weight and regulates lipid metabolism.
Lee et al (2018)²⁷	AmEVs	HFD	Six-week-old mice were fed a HFD for 39 weeks to induce metabolic disorders, including obesity and T2DM.	1. HFD + PBS mice were orally administrated PBS for 5 weeks.2. HFD + AmEVs were orally administrated 20 µg AmEVs daily for 5 weeks.	1. HFD + PBS (n = 4) 2. HFD + AmEVs (n = 3)		AmEVs significantly decreased the body weight gain, when compared with HFD-fed group. The total cholesterol level in the AmEVs-fed group was lower than that in the HFD-fed group. The epididymal fat pad weight in the AmEVs-fed group was lower than that in the NC group, albeit not significantly so.
Bodogai et al (2018)⁴⁰	Live A. muciniphila	/	Young (10 to 12 weeks) and aged (18 to 24 months) female C57BL/6 mice (n = 400)	1. Young and aged group mice orally administrated vehicle every second day for 20 days.2. Aged mice + AKK group orally administrated 1 × 10⁸ A. muciniphila every second day for 20 days.	1. Young (n = 7)2. Aged (n = 7)3. Aged mice+AKK (n = 7)		Supplementation with A. muciniphila could restore normal insulin response in aged mice and macaques.
Chelakkot et al (2018)⁴¹	AmEVs	NCD or HFD	HFD induced a diabetic phenotype	1. NCD and HFD groups treated with PBS for 2 weeks.2. NCD+AmEVs and HFD+AmEVs groups EVs were orally administered for 2 weeks.	1. NCD (n = 5–7)2. NCD + AmEVs (n = 5–7)3. HFD (n = 5–7)4. HFD + AmEVs (n = 5–7)		AmEVs improved body weight and glucose tolerance in diabetic mice. It also reduced HFD-induced barrier permeability.
Hänninen et al (2018)²⁸	Live A. muciniphila	/	Non-obese diabetic (NOD) mice	1. Vehicle control group treated with PBS three times a week for 7 weeks.2. A. muciniphila group treated with 2 × 10⁸ CFU of A. muciniphila three times a week for 7 weeks.	1. Vehicle control (n = 25)2. A. muciniphila (n = 24)		Oral gavage of female NOD/Jax mice with A. muciniphila delayed diabetes significantly as compared with gavage with vehicle only.
Shin et al (2019)³⁹	Live A. muciniphila	HFD	HFD induced obese mice	1. HFD group orally administrated with 25% glycerol in sterile PBS for 4 weeks.2. HFD + AKK mucin (+) group orally administrated with A. muciniphila (1.0 × 10⁸ CFU/day) grown on mucus-based for 4 weeks.3. HFD + AKK mucin (-) group orally administrated with A. muciniphila (1.0 × 10⁸ CFU/day) grown on mucus-depleted medium for 4 weeks.	1. HFD group (n = 4–5) 2. HFD + AKK mucin (+) group (n = 4–5) 3. HFD + AKK mucin (-) group (n = 4–5)		Administration of A. muciniphila grown under mucin-depleted conditions to high-fat diet-induced diabetic mice reduced obesity and improved intestinal barrier integrity more efficiently than administration of A. muciniphila grown under mucin-containing conditions.
Ashrafian et al (2019)²⁹	Live A. muciniphila, AmEVs	ND or HFD	HFD-induced obese mice	1. ND or HFD-fed mice treated with 200 μl PBS for 5 weeks.2. HFD + Live A. muciniphila and ND + Live A. muciniphila groups treated with 10⁹ CFU/200 μl live A. muciniphila.3. HFD + AmEVs and ND + AmEVs groups treated with 10 μg protein/200 μl AmEVs.	1. HFD + PBS (HPBS) (n = 5)2. HFD + Live A. muciniphila (n = 5)3. HFD + AmEVs (n = 5)4. ND + PBS (NPBS) (n = 5)5. ND + Live A. muciniphila (n = 5)6. ND + AmEVs (n = 5)		A. muciniphila and AmEVs reduced food intake and body weight gain. They can also alleviate adipose Inflammation, ameliorate HFD-induced intestinal barrier dysfunction, regulate inflammation and energy homeostasis in the colon of obese mice, and regulate gene expression involved in FA oxidation and energy metabolism of adipose tissues.
Everard et al (2019)³⁰	Live A. muciniphila	ND or HFD	Napepld^∆IEC mice fed with ND or HFD	1. WT ND, WT HFD and Napepld^∆IEC HFD group mice treated daily with 150 μl PBS.2. WT ND AKK and Napepld^∆IEC HFD AKK groups mice treated daily with an oral gavage of either 2.0 × 10⁸ CFU of Akkermansia muciniphila.	1. WT ND (n = 8–10)2. WT ND AKK (n = 8–10)3. WT HFD (n = 8–10)4. Napepld^∆IE^C HFD (n = 8–10)5. Napepld ^∆IEC HFD AKK (n = 8–10)		Napepld^∆IEC mice are hyperphagic upon first HFD exposure, and develop exacerbated obesity and steatosis. A. muciniphila administration partly counteracts the gene deletion effects.
Van der Lugt et al (2019)³¹	Live A. muciniphila	An ad libitum purified diet	Aging Ercc1 ^−/Δ7 mice	1. The control group simultaneously received oral gavages PBS. 2. Ercc1^−/Δ7 + AKK group mice were supplemented with Akkermansia muciniphila by oral gavage at a dose of 2 × 10⁸ CFU/200 μL, three times a week, for a total of 10 weeks. Oral gavages were given in the morning.	1. Control group (n = 18)2. Ercc1^−/Δ7 + AKK (n = 18)		Supplementation with A. muciniphila prevented the age-related decline in thickness of the colonic mucus layer and attenuated inflammation and immune-related processes at old age.
Wu et al (2020)⁷²	An Akkermansia muciniphila subtype (A. muciniphila^sub)	NCD or HFD	HFD-induced obesity and diabetes	1. The mice in the HFD + PBS and NCD + PBS groups were administered the PBS vehicle.2. The mice in the HFD + AKK^sub and NCD + AKK^sub groups were orally administered AKK^sub daily at a dose of 10⁹ CFU/200 μl.	1. HFD + PBS (n = 10)2. HFD + AKK^sub (n = 10)3. NCD + PBS (n = 10)4. NCD + AKK^sub (n = 10)		A. muciniphila^sub reduced body weight and food consumption, improved blood glucose control, and prevented memory decay but not depression induced by high fat diet. A. muciniphila^sub can also decrease systemic inflammation and improve tryptophan metabolism in mice fed HFD, produce high concentrations of acetic acid, propionic acid and isovaleric acid, and restore gut microbiota altered by HFD.
Depommier et al (2020)³²	Pasteurized A. muciniphila	HFD	HFD-induced obesity	1. ND and HFD groups treated with 180 µl of vehicle solution (PBS containing 2.5% glycerol) for 5 weeks.2. HFD pasteurized A. muciniphila group mice were treated daily with an oral gavage of either 2 × 10⁸ CFU/180 µl of pasteurized A. muciniphila.	1. ND (n = 7)2. HFD (n = 7)3. HFD pasteurized A. muciniphila (n = 7)		Daily oral administration of pasteurized A. muciniphila alleviated diet-induced obesity and decreased food energy efficiency. This effect was associated with an increase in energy expenditure and spontaneous physical activity.
Huo et al (2020)³³	Live A. muciniphila	ND or HFD	HFD induced obesity	1. The mice in the HFD group treated with 0.9% saline solution for 9 weeks.2. The mice in the HFD + AKK group treated with 10⁹ CFU/kg per day for 9 weeks.	1. ND (n = 6)2. HFD (n = 6)3. HFD + AKK (n = 6)		A. muciniphila decreased body weight, relative fat weight, and serum LPS. It can also increase lipid catabolism in epididymal adipose tissues.
Deng et al (2020)⁴²	A. muciniphila I (Amuc_GP01), A. muciniphila II (Amuc_GP25)	NCD or HFD	HFD induced obese mice	1. HFD + PBS and NCD + PBS groups mice orally gavaged with 200 µL sterile PBS daily for 16 weeks.2. The remaining groups orally gavaged with A muciniphila (5 × 10⁹ CFU/mL) in 200 µL sterile PBS for 16 weeks.	1. HFD + A. muciniphila I (n = 10)2. HFD + A. muciniphila II (n = 10)3. HFD + PBS group (n = 10)4. NCD + A. muciniphila I (n = 10)5. NCD + A. muciniphila II (n = 10)6. NCD + PBS group (n = 10)		A. muciniphila I and II exert different impacts on blood glucose and lipid metabolism. Both A. muciniphila I and II could alleviate brown adipose tissue inflammation and whitening induced by HFD, which were regulated much better under A. muciniphila I intervention; A. muciniphila I could alleviate endotoxemia in HFD mice while II could not.
Kim et al (2020)³⁴	Live A. muciniphila	NCD or HFD (45% fat diet)	HFD induced obesity in mice	1. The NC + PBS and HFD + PBS groups mice are daily treated with 10⁸ to 10⁹ CFU/ml A. muciniphila by oral gavage for 10 weeks.2. Mice in the ND + PBS and HFD + PBS groups were fed with the same volume of PBS by oral gavage for 10 weeks.	1. NC + PBS (n = 4)2. NC + AKK (n = 4)3. HFD + PBS (n = 4)4. HFD + AKK (n = 4)		A. muciniphila treatment prevented fatty liver disease in obese mice.
Katiraei et al (2020)³⁵	Live A. muciniphila	Atherogenic Western‐type diet containing 1% cholesterol and 0.05% cholate	Hyperlipidemic APOE*3‐Leiden (E3L). CETP mice	1. The AKK group mice are daily treated with 2 × 10⁸ CFU A. muciniphila by oral gavage for 4 weeks.2. The Control mice orally gavaged daily for 4 weeks with anaerobic PBS.	1. Control (n = 8)2. AKK (n = 8)		A. muciniphila administration decreased body weight as well as plasma TC and TG levels.
Yoon et al (2021)³⁶	P9	HFD	HFD induced obese mice	1. HFD group mice treated with 200 μl anaerobic PBS.2. HFD + Am group mice treated with 4.0 × 10⁸ CFU/200 μl A. muciniphila.3. HFD + P9 group mice treated with 100 μg per mouse for 8 weeks.	1. HFD (n = 7–10)2. HFD + A. muciniphila (Am) (n = 7–10)3. HFD + P9 (n = 7)		A. muciniphila increases thermogenesis and glucagon-like peptide-1 (GLP-1) secretion in HFD-induced C57BL/6 J mice by induction of uncoupling protein 1 in brown adipose tissue and systemic GLP-1 secretion. Purified P9 alone is sufficient to induce GLP-1 secretion and brown adipose tissue thermogenesis.
Human
Depommier et al (2019)³⁷	Live A. muciniphila, pasteurized A. muciniphila	/	Overweight/obese insulin resistant	1. Placebo group received placebo per day for 3 months. 2. Alive group received 10¹⁰ CFU alive A. muciniphila per day for 3 months.3. Pasteurized group received 10¹⁰ pasteurized A. muciniphila per day for 3 months.	1. Placebo (n = 11)2. Pasteurized (n = 12)3. Alive (n = 9)		The supplemention of A. muciniphila was safe and well-tolerated, it can reduce the levels of relevant blood markers of liver dysfunction and inflammation while the overall gut microbiome structure was unaffected.
Perraudeau et al (2021)³⁸	Live A. muciniphila	/	T2DM	1. Placebo group received colloidal silicon dioxide for 12 weeks.2. WBF-010 group received WBF-010 (which contains inulin, Clostridium beijerinckii, Clostridium butyricum and Bifidobacterium infantis).3. WBF-011 group received WBF-011 (which contains inulin, Akkermansia muciniphila, Clostridium beijerinckii, Clostridium butyricum, Bifidobacterium infantis and Anaerobutyricum hallii).	1. Placebo (n = 26)2. WBF-010 (n = 27)3. WBF-011 (n = 23)		Compared with placebo, a statistically significant decrease in total glucose AUC_{0-180 min} was observed in WBF-011 group. Incremental glucose AUC_{0-180 min} was also lower in WBF-011 group. The validated measure of long-term glucose control, A1c, was reduced by 0.6 in WBF-011 group when compared with placebo.