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Frontiers of Medicine

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Front. Med.    2022, Vol. 16 Issue (5) : 667-685    https://doi.org/10.1007/s11684-022-0960-z
REVIEW
Role of Akkermansia muciniphila in the development of nonalcoholic fatty liver disease: current knowledge and perspectives
Yuqiu Han1, Lanjuan Li1,2,3, Baohong Wang1,2,3()
1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
2. Research Units of Infectious disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
3. Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, China
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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and a common cause of liver cirrhosis and cancer. Akkermansia muciniphila (A. muciniphila) is a next-generation probiotic that has been reported to improve metabolic disorders. Emerging evidence indicates the therapeutic potential of A. muciniphila for NAFLD, especially in the inflammatory stage, nonalcoholic steatohepatitis. Here, the current knowledge on the role of A. muciniphila in the progression of NAFLD was summarized. A. muciniphila abundancy is decreased in animals and humans with NAFLD. The recovery of A. muciniphila presented benefits in preventing hepatic fat accumulation and inflammation in NAFLD. The details of how microbes regulate hepatic immunity and lipid accumulation in NAFLD were further discussed. The modulation mechanisms by which A. muciniphila acts to improve hepatic inflammation are mainly attributed to the alleviation of inflammatory cytokines and LPS signals and the downregulation of microbiota-related innate immune cells (such as macrophages). This review provides insights into the roles of A. muciniphila in NAFLD, thereby providing a blueprint to facilitate clinical therapeutic applications.
Keywords Akkermansia muciniphila      NAFLD      NASH      steatosis      inflammation     
Corresponding Author(s): Baohong Wang   
Just Accepted Date: 23 September 2022   Online First Date: 27 October 2022    Issue Date: 18 November 2022
 Cite this article:   
Yuqiu Han,Lanjuan Li,Baohong Wang. Role of Akkermansia muciniphila in the development of nonalcoholic fatty liver disease: current knowledge and perspectives[J]. Front. Med., 2022, 16(5): 667-685.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0960-z
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I5/667
Fig.1  A. muciniphila protects intestinal barrier function. A. muciniphila enhances intestinal barrier function by regulating mucosal (turnover of mucin), microbial (production of antibacterial peptide), epithelial (tight junction protein), metabolic (e.g., SCFAs, tryptophan metabolites, and BAs), and immunological (e.g., adaptive immune T cells) components. Abbreviations: AhR, aryl hydrocarbon receptor; BAs, bile acids; CTLs, cytotoxic T lymphocytes; DC, dendritic cell; FXR, farnesoid X receptor; GPR43/41, G protein-coupled receptors 41/43; IgA, immunoglobulin A; ISCs, intestinal stem cells; LPS, lipopolysaccharide; SCFAs, short-chain fatty acids.
Reference Subjects/diets Severity of NAFLD Study group Sample type (detection method) Changes in Akkermansia muciniphila or Akkermansia
Animals 　
Kim et al. (2020) [21] Male C57BL/6N mice, HFD, 10 weeks NAFL (H&E staining; serum ALT and AST↑) 1. Normal diet (ND + PBS, n = 5); 2. HFD + PBS (n = 5); 3. ND + A. muciniphila (n = 5); 4. HFD + A. muciniphila (n = 5) Cecal contents (16S rRNA gene sequencing) ↓
Shi et al. (2021) [44] Female C57BL/6 mice, saccharin or sucralose, 11 weeks NASH (histopathological changes) 1. Control (n = 10); 2. neohesperidin dihydrochalcone (NHDC, n = 10); 3. saccharin (n = 10); 4. sucralose (n = 10) Cecal contents (16S rRNA gene sequencing, metagenomic sequencing) ↓
Natividad et al. (2018) [48] Male C57BL/6J mice, HFD, 9 weeks NAFL (H&E staining; serum ALT and AST↑) 1. Control diet (CD, n = 10); 2. HFD (n = 10); 3. CD + B. wadsworthia (n = 10); 4. HFD + B. wadsworthia (n = 10) Feces (16S rRNA gene sequencing) ↓
Hussain et al. (2016) [49] Male C57BL/6 mice, HFD, 12 weeks NAFL (Oil Red O staining) 1. Normal chow diet (NCR, n = 7); 2. HFD (n = 7); 3. HFD + orilistat (ORL, n = 7); 4. HFD + daesiho-tang (DSHT, n = 7) Feces (qPCR) ↓ (tendency)
Lee et al. (2018) [50] Male C57BL/6 mice, HFD, 12 weeks NAFL (H&E staining) 1. ND (n = 5); 2. HFD (n = 5); 3. HFD-fed mice treated with a mixture of two L. plantarum strains (DSR, n = 5) Cecal contents (16S rRNA gene sequencing, qPCR) ↓
Wang et al. (2019) [51] Male C57BL/6 mice, HFD, 13 weeks NAFL (H&E and Oil Red O staining; serum ALT ↑) 1. Normal control (NC, n = 6); 2. HFD (n = 6); 3. NC + puerarin (NC + PUE) (n = 6); 4. HFD + PUE (n = 6) Feces (16S rRNA gene sequencing) ↓
Schneeberger et al. (2015) [52] Male C57BL/6 mice, HFD, 16 weeks Unknown 1. CT diet (CT, n = 6); 2. HFD (n = 6) Cecal contents (qPCR) Negative correlation with age and HFD feeding
Ye et al. (2018) [53] Male C57BL/6 mice, methionine-choline-deficient (MCD) diet, 4 weeks NASH (histopathological changes) 1. Control (n = 6); 2. MCD (n = 6) Feces (16S rRNA gene sequencing) ↓
Moreira et al. (2018) [72] Male C57BL/6 mice, HFD, 10 weeks NASH (histopathological changes) 1. Control group (C); 2. C + liraglutide (C + L); 3. HFD; 4. HFD + liraglutide (HFD + L) Feces (16S rRNA gene sequencing) Liraglutide increased its abundance in HFD mice
Du et al. (2021) [73] Kunming female mice, HFD, 23 weeks NAFL (Oil Red O staining; serum ALT and AST ↑) 1. Normal chow (Chow, n = 6); 2. HFD (n = 6); 3. chow + betaine (Chow + B) (n = 6); 4. HFD + B (n = 6) Feces (16S rRNA gene sequencing) ↓
Zhang et al. (2022) [74] Male C57BL/6 mice, HFD, 12 weeks NASH (histopathological changes; serum ALT/AST ↑) 1. Control group (Con, n = 5); 2. HFD (n = 5); 3. HFD + purified MDG (MDG-1. n = 5); 4. HFD + coarse MDG (MDG-C, n = 5); 5. HFD + inulin (Inu, n = 5); 6. HFD + antibiotics (Anti, n = 5) Feces (metagenomic sequencing) ↓, negative correlation with most NAFLD parameters
Wang et al. (2021) [75] Male C57BL/6J mice, HFD, 30 weeks NASH (hepatic steatosis; hepatic TNFα, MCP-1, IL-6 and ROS ↑; serum ALT, AST, ALP, and γ-GT ↑; hepatic fibrosis) 1. NCD-fed mice (Control); 2. HFD-fed mice (Model); 3. HFD + metformin (Metf); 4. HFD + 100 mg/kg/day of PYOs (PYOs-L); 5. HFD + 300 mg/kg/d of PYOs (PYOs-H) Cecal contents (16S rRNA gene sequencing) Negative correlation with the development of NAFLD
Han et al. (2021) [76] Male C57BL/6 mice, high fat/high sucrose (HFHS), 16 weeks NAFL (H&E and Oil Red O staining; serum ALT and AST ↑) 1. Control group (Con, n = 5); 2. HFHS (n = 5); 3. HFHS + low-dose SMF (SMF-L, n = 5); 4. HFHS + high-dose SMF (SMF-H, n = 5) Cecal contents (16S rRNA gene sequencing) ↑ (tendency)
Bao et al. (2021) [79] Male C57BL/6J mice, HFD, 14 weeks NASH (NAS scores ↑; hepatic IL-1β, IL-18, IL-6 and TNF-α ↑; hepatic macrophages ↑) 1. ND (n = 5); 2. HFD (n = 5); 3. ND + inulin (ND-INU, n = 5); 4. HFD + inulin (HFD-INU, n = 5) Feces (16S rRNA gene sequencing) ↓
Cui et al. (2020) [80] Male Sprague–Dawley rats, HFD, 12 weeks NASH (histopathological changes; serum ALT/AST ↑) 1. Control (n = 10); 2. HFD (model, n = 10); 3. HFD + metformin (positive control, n = 10); 4. HFD + Da-Chai-Hu (DCH, n = 10) Feces (16S rRNA gene sequencing) ↓
Nakano et al. (2020) [81] Male C57BL/6J mice, Western diet, 12 weeks NAFL (Oil Red O staining; serum ALT ↑) 1. ND (n = 4); 2. ND + 2% BA group (NDBA, n = 2); 3. Western diet (WD, n = 4); 4. WD + 2% BA (WDBA, n = 4) Feces (16S rRNA gene sequencing) AST and ALT were positively correlated with family Verrucomicrobiaceae
Mu et al. (2020) [82] Male C57BL/6J mice, HFD/F (high fat + 10% fructose solution), 8 weeks NAFL (H&E staining; serum ALT, AST, AKP and hepatic ROS ↑) 1. Normal group (Normal); 2. HFD (Model); 3. L-carnitine; 4. HFD + low-concentration L. fermentum CQPC06 (LCQPC06); 5. HFD + high-concentration L. fermentum CQPC06 (HCQPC06); 6. HFD + Lactobacillus delbrueckii subsp. Bulgaricus (LDSB) Feces (16S rRNA gene sequencing) ↓
Xie et al. (2020) [83] Male C57BL/6J mice, Western diet, 12 weeks NAFL (H&E staining; serum ALT and AST ↑) 1. ND (n = 4); 2. ND + 1% vine tea polyphenols (ND + 1% VTP, n = 4); 3. WD (n = 4); 4. WD + 0.5% VTP (n = 4); 5. WD + 1% VTP (n = 4); 6. WD + 2% VTP (n = 4) Feces (16S rRNA gene sequencing) ↓
Nishiyama et al. (2020) [84] Male ob/ob mice, standard diet, 4 weeks NASH (histopathological changes; serum ALT/AST ↑) 1. C57BL/6J mice fed standard diet (WILD, n = 6); 2. ob/ob mice fed with standard diet (CONT, n = 6); 3. ob/ob mice fed with standard diet containing 5% bofutsushosan (BTS) (n = 6) Feces (16S rRNA gene sequencing, qPCR) Negative correlation with suppression of body weight gain
Li et al. (2020) [85] Male C57BL/6J mice, HFD, 18 weeks NASH (histopathological changes; serum ALT and AST ↑) 1. Normal chow diet (NCD, n = 8); 2. HFD (n = 8); 3. HFD + fed with 0.5% carboxymethylcellulose sodium (CMC-Na) (n = 8); 4. HFD + Sil (100 mg/kg, HFD + Sil group 1, n = 8); 5. HFD + Sil (300 mg/kg, HFD + Sil group 2, n = 8) Cecal contents (16S rRNA gene sequencing) ↓
Régnier et al. (2020) [87] Male C57BL/6J mice, high-fat and high-sucrose diet (HFHS), 8 weeks NAFL (hepatic triglycerides ↑) 1. Control diet (CTRL, n = 10); 2. HFHS (n = 10); 3. HFHS + 0.3% (g/g) of rhubarb (RHUB, n = 10) Feces (16S rRNA gene sequencing, qPCR) Rhubarb promotes its growth in HFHS-fed mice
Juárez-Fernández et al. (2022) [88] Wistar rats, HFD, 9 weeks NAL (histopathological changes; serum ALT and AST ↑) 1. Control group (C) (n = 7); 2. HFD (n = 7); 3. C + quercetin (n = 7); 4. C + A. muciniphila; 5. HFD + quercetin (n = 7); 6. HFD + A. muciniphila (n = 8); 7. C + quercetin + A. muciniphila (n = 8); 8. HFD + quercetin + A. muciniphila (n = 8) Feces (16S rRNA gene sequencing) The colonization with Akkermansia muciniphila was associated with less body fat
Human 　
Hoyles et al. (2018) [59] Morbidly obese women NAFL (diagnosed by histology) 1. No liver steatosis (n = 10); 2. liver steatosis 1 (n = 22); 3. liver steatosis 2 (n = 14); 4. liver steatosis 3 (n = 10) Feces (metagenomic sequencing) Increased trend in women with obesity. Verrucomicrobia and Akkermansia were significantly correlated with liver steatosis
Nistal et al. (2019) [60] Adults with obesity NAFLD (diagnosed by clinical, analytical and ultrasonographic data) 1. Twenty healthy adults (n = 20); 2. obese patients with NAFLD (n = 36); 3. obese patients without NAFLD (n = 17) Feces (16S rRNA gene sequencing) Reduced trend in patients with obesity with NAFLD
Tsai et al. (2021) [61] Patients with T2DM NAFLD (diagnosed by ultrasonographic data) 1. Patients with T2DM with no or mild NAFLD (n = 80); 2. patients with T2DM with moderate or severe NAFLD (n = 83) Feces (qPCR) Decreased trend in patients with T2DM with moderate/severe NAFLD
Lee et al. (2021) [62] Patients with NAFLD NAFLD (diagnosed by abdominal ultrasound or computed tomography with elevated liver enzyme) 1. Healthy controls (n = 37); 2. NAFLD (n = 57) Feces (16S rRNA gene sequencing) ↓
Özkul et al. (2017) [63] Patients with NASH NASH (diagnosed by histology) 1. Healthy controls (n = 38); 2. NAFLD (n = 46) Feces (qPCR) ↓
Chierico et al. (2017) [64] Children and adolescents NAFL and NASH (diagnosed by liver ultrasound and percutaneous liver biopsy) 1. NAFL (n = 27); 2. NASH (n = 26); 3. obesity (n = 8) 4. case-controls (CTRLs, n = 54) Feces (16S rRNA gene sequencing) Decreased trend in pediatric patients with NAFLD
Pan et al. (2021) [65] Children with obesity NAFL (diagnosed by ultrasonography) and NASH (unknown diagnostic criterion) 1. NAFL (n = 25); 2. NASH (n = 25); 3. obese without NAFLD (n = 25) Feces (16S rRNA gene sequencing) ↓
Schwimmer et al. (2019) [66] Children who are overweight/obese NAFLD (diagnosed by liver biopsy) 1. Overweight/obese children without NAFLD (n = 37); 2. children with NAFLD (n = 86, including 38 NAFL, 37 borderline NASH, and 11 NASH) Feces (16S rRNA gene sequencing, metagenomic sequencing) Decreased in children with NASH or moderate/severe fibrosis
Ponziani et al. (2019) [67] Patients with NAFLD NAFLD with cirrhosis (diagnosed by histological and/or clinical findings) and HCC (diagnosed by histology) 1. Patients with NAFLD-related cirrhosis and HCC (n = 21); 2. NAFLD-related cirrhosis without HCC (n = 20); 3. healthy controls (n = 20) Feces (16S rRNA gene sequencing) Decreased in NAFLD patients with cirrhosis
Dao et al. (2016) [58] Adults who are overweight and obese Unknown 1. Lower A. muciniphila abundance in baseline (Akk LO, n = 24); 2. higher A. muciniphila abundance in baseline (Akk HI, n = 25) Feces (qPCR) Akk HI group had lower AST and GGT and greatest benefits from dietary intervention
Liu et al. (2017) [68] Patients with obesity Obesity with elevation of serum ALT, AST, ALP, and GGT levels 1. Lean controls (n = 79); 2. individuals with obesity (n = 72) Feces (metagenomic sequencing) Enriched in lean controls; positive correlation with the concentration of circulating adiponectin
Kordy et al. (2021) [70] Children and adolescents NASH (diagnosed by liver biopsy) 1. NASH (n = 20); 2. control subjects (n = 20) Feces (metagenomic sequencing) ↓
Tab.1  Alteration of Akkermansia muciniphila in NAFLD models and patients
Reference Diet Subjects Diseases Dosages Time Colonization (detection method) Study group Efficiency of treatment
Animals 　 　 　 　 　 　 　
Kim et al. (2020) [21] HFD Male C57BL/6N mice NAFL (H&E staining; serum ALT and AST levels ↑) Live, 108–109 CFU/mL 10 weeks Obviously increased abundance (16S rRNA gene sequencing) 1. Normal diet (ND + PBS, n = 5); 2. HFD + PBS (n = 5); 3. ND + A. muciniphila (n = 5); 4. HFD + A. muciniphila (n = 5) Serum TG and ALT levels↓; the gene expression of hepatic TG synthesis and inflammatory factor IL-6↓
Rao et al. (2021) [38] High-fat and high-cholesterol (HFC) diet Male C57BL/6J mice NASH (histopathological changes) Live, 1 × 108 CFU/ mL, 200 μL, every other day 6 weeks Increased by 20-fold (qPCR) 1. HFC (n = 5–8); 2. HFC + A. muciniphila (n = 5–8) Hepatic steatosis/ inflammatory (indicated by HE staining) ↓, serum ALT/AST/ALP↓, and hepatic genes expression related to steatosis and inflammation↓
Higarza et al. (2021) [92] High-fat, high cholesterol diet (HFHC) Male Sprague–Dawley rats NASH-induced cognitive damage Live, 109 CFU, 100 μL, daily 4 weeks No differences (16S rRNA gene sequencing and qPCR) 1. NC group (n = 8); 2. HFHC + PBS (n = 8); 3. HFHC + Lacticaseibacillus rhamnosus GG (HFHC + LGG, n = 8); 4. HFHC + A. muciniphila CIP107961(HFHC + AKK, n = 8) HFHC-induced cognitive dysfunction (including impaired spatial working memory and novel object recognition) ↓
Human 　 　 　 　 　 　 　 　
Depommier et al. (2019) [18] / / Overweight/obese insulin-resistant volunteers Live (1010 or 109 CFU per day) or pasteurized A. muciniphila (1010 CFU per day) 3 months Unknown 1. Placebo group (n = 11); 2. pasteurized bacteria group (n = 12); 3. live bacteria group (n = 9) Blood markers for liver dysfunction including γ-glutamyltransferase (GGT) and AST↓
Other liver diseases 　 　 　 　 　 　
Grander et al. (2018) [22] Lieber-De-Carli diet containing 1–5 vol.% Female WT mice Alcoholic liver disease (ALD) Live, 1.5 × 109 CFU, 200 μL, every other day 2 day or 15 days or 6 days Obviously increased abundance (qPCR) 1. Pair fed (Ctrl); 2. Pair fed + A. muciniphila (Ctrl + A.muc); 3. ethanol fed (EtOH); 4. ethanol fed + A. muciniphila (EtOH + A.muc) Acute ethanol-induced hepatic injury and inflammation↓; chronic ethanol-induced hepatic inflammation and steatosis↓
Keshavarz et al. (2021) [23] HFD (+ CCl4 injection) Male C57BL/6 mice Liver injury (liver fabrosis) 109 CFU/200 μL live or pasteurized A. muciniphila, 50 mg/200 μL Evs, daily 4 weeks Obviously increased abundance (qPCR) 1. Healthy control animals (ND, n = 5); 2. HFD/CCl4 + PBS (PBS, n = 5); 3. HFD/CCl4 + live A. muciniphila (Am) (n = 5); 4. HFD/CCl4 + pasteurized A. muciniphila (Pam, n = 5); 5. HFD/CCl4 + EV (EV, n = 5) Serum liver enzymes↓; hepatic inflammation and fibrosis markers↓
Wu et al. (2017) [25] Normal chow diets (+ concanavalin A injection) Male C57BL/6 mice Liver injury (resembling autoimmune liver diseases and virus hepatitis) Live, 3 × 109 CFU, 200 μL, daily 14 days Obviously increased abundance (16S rRNA gene sequencing) 1. A. muciniphila + Con A (Akk, n = 7); 2. PBS + Con A (Control, n = 7); 3. PBS + PBS (Normal, n = 8) Serum ALT and AST↓; liver histopathological damage↓
Tab.2  Efficacy of Akkermansia muciniphila in treating NAFLD and other liver injuries
Fig.2  Potential mechanism by which A. muciniphila alleviates hepatic fat accumulation in NAFLD. Live or pasteurized A. muciniphila and its active ingredient (Amuc_1100, P9 and AmEVs) alleviate steatosis and its related insulin resistance. Abbreviations: AKK, A. muciniphila; AmEVs, A. muciniphila-derived extracellular vesicles; GLP-1, glucagon-like peptide-1; IR, insulin resistance; LPS, lipopolysaccharide; TMAO, trimetly-lamine oxide.
Fig.3  Potential mechanism by which A. muciniphila prevents hepatic inflammation in NAFLD. A. muciniphila regulates hepatic inflammation and the immune response in NAFLD via multiple potential mechanisms. The current focus on the mechanisms of A. muciniphila in improving hepatic inflammation mainly centers on the production of inflammatory factors, LPS signals, and macrophages. Abbreviations: AKK, A. muciniphila; AhR, aryl hydrocarbon receptor; LPS, lipopolysaccharide; M1/2 cells; macrophage type 1/2; TLR4, toll-like receptor 4.
Fig.4  Perspectives on the regulation of NAFLD by A. muciniphila.
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