In recent years, people’s dietary needs have expanded beyond subsistence level. Obesity has become another significant consequence of the affluence of material possessions. It is now one of the leading causes of health risks and a risk factor for many diseases, including T2DM, NAFLD, and CVD (52, 53), making obesity one of the most important public health problems of the 21st century (54). The regulation of intestinal microbiota has garnered widespread interest as an effective strategy to prevent or treat obesity. A. muciniphila, the only Verrucomicrobia (phylum) genus that can be cultured in vitro, has been repeatedly mentioned in the context of obesity. The objective regulations that exist between the two has been gradually revealed. In 2010, it was observed for the first time that the abundance of A. muciniphila was lower in overweight pregnant women than in normal-weight pregnant women (55). Similar findings were observed in the stool samples of obese or overweight preschool children (56). Furthermore, a study analyzing fecal microbiota in 17 lean weight (BMI 19-24.99 kg/m²) and 15 obese women (BMI>30 kg/m²) using real-time fluorescence quantification PCR (qPCR) method revealed that A. muciniphila was more abundant in lean individuals than in obese ones (57). To further investigate the relationship between A. muciniphila and obesity, researchers successfully induced an obese mouse model with a high-fat diet and collected cecal feces. Analysis of feces by qPCR showed a 100-fold decrease in the population of A. muciniphila in the obese model group compared to lean littermates. The ob/ob mice are homozygous Lepob mutant mice with an invisible gene on chromosome 6 that causes obesity and advanced diabetes. Similarly, analysis of their intestinal feces showed a 3300-fold reduction in A. muciniphila population in ob/ob mice compared to lean littermates (36). The substantial changes in A. muciniphila genus abundance indicate a possible association between A. muciniphila and obesity. However, a few studies contradicted the above findings. For instance, A. muciniphila was more abundant in obese than in normal-weight children (58). To comprehensively elaborate the regularity between the two, substantial human and animal studies were conducted, which conclusively demonstrated that A. muciniphila abundance was reduced in obese individuals or animals ( Table 1 ).

Based on the phenomenon of decreased A. muciniphila abundance due to obesity, researchers hypothesized that supplemental A. muciniphila could alleviate obesity or pathological features resulting from obesity. Amandine Everard et al. in 2013 investigated the beneficial effects of A. muciniphila on high-fat diet-induced obese mice (live and heat- killed at 121°C for 15 min). The results demonstrated that live A. muciniphila could alleviate fat-mass gain, insulin resistance, adipose tissue inflammation, and metabolic endotoxemia in obese mice, whereas heat-killed A. muciniphila had no such effects (36). In addition, numerous animal experiments have discovered that A. muciniphila supplementation also has physiological activities including reducing body weight, promoting metabolism, and enhancing intestinal barrier ( Table 2 ), However, A. muciniphila exacerbated intestinal inflammation in salmonella-infected gnotobiotic mice, which is a negative effect (78). Studies have shown that A. muciniphila extracellular vesicles reduce intestinal permeability (72). A. muciniphila also exacerbates depletion of the mucus layer by consuming mucin, which in turn leads to thinning of the mucus layer and increased inflammation. The application of A. muciniphila in humans has been relatively slow due to the uncertainty of its functional activity and the lack of complete understanding of its mechanism. Hubert Plovier et al. first introduced pasteurized (70°C, 30 min) A. muciniphila and unexpectedly observed that pasteurization enhanced the functional activity of A. muciniphila, which reduced fat-gain, insulin resistance and dyslipidemia in obese mice (6). This surprising discovery expands the potential of A. muciniphila as a next-generation probiotic for food applications. In a subsequent randomized, double-blind, placebo-controlled exploratory study, overweight or obese volunteers were supplemented with 10¹⁰ live or pasteurized A. muciniphila daily for three months. This study provided groundbreaking evidence that A. muciniphila is safe and tolerable. In addition, pasteurized A. muciniphila still retains the capacity to lower total plasma cholesterol and reduce body weight, body fat and hip circumference in humans (73). Toxicological experiments have also confirmed the safety of pasteurized A. muciniphila as a food ingredient (79). Although current research results are promising, there are limitations in the study subjects. Therefore, further studies are required to expand the scope of subjects and demonstrate the relationship between A. muciniphila supplementation and improving obesity metabolic parameters.

As the effects of A. muciniphila in alleviating obesity continue to be demonstrated, its underlying mechanisms are being explored. Obesity is a chronic metabolic disease caused by the excessive accumulation or abnormal distribution of organismal fat, mainly due to the imbalance between caloric intake and energy excretion of the body. When caloric intake exceeds energy excretion, excessive energy is stored as fat in adipocytes. Adipocytes are essential for fat synthesis and storage. Glycerol and fatty acids required for triglyceride synthesis are mainly provided by glucose metabolism. Glycerol is converted from dihydroxyacetone phosphate produced by glycolysis and fatty acids are synthesized from acetyl coenzyme A produced by the oxidative breakdown of glucose. Pasteurized A. muciniphila alleviates diet-induced obesity through increased energy expenditure and spontaneous physical activity. The energy expenditure is not associated with changes in thermogenic markers or white adipose tissue but with decreased expression of the lipid droplet-associated factor perilipin2 in brown and white fat. In addition, pasteurized A. muciniphila decreases carbohydrate absorption, increasing energy excretion in the feces (80). The treatment of 3T3-L1 cells with A. muciniphila cell lysate effectively diminished lipid accumulation and down-regulated mRNA expression of adipogenesis-associated proteins. A. muciniphila upregulates the expression of SERPINA3G in adipocytes and inhibits adipogenesis (81). Currently, the study of the molecular mechanism of A. muciniphila in alleviating obesity is still in the initial stage, additional studies are needed to further elucidate it.

Diabetes mellitus is a chronic metabolic disease caused by the deficiency in insulin secretion or the reduction in the body’s ability to utilize insulin. T2DM accounts for approximately 90% of diabetes mellitus cases worldwide. According to the 10th edition of the International Diabetes Federation, in 2021 there were 537 million adults (20-79 years old) with diabetes and more than 4 million deaths per year were caused by diabetes. Studies have demonstrated dramatic differences in the structure and composition of the gut microbiota in T2DM patients compared with healthy individuals, including A. muciniphila. In 2013, a study was conducted on normal, pre-diabetic and diabetic individuals using 16S rRNA sequencing of stool samples to quantify A. muciniphila. The results showed that A. muciniphila abundance was significantly lower in the pre-diabetic and diabetic groups compared to the normal group (82). Another study was conducted on the stool samples of patients with short-, medium- and long-term T2DM. The results indicated that the abundance of A. muciniphila in medium- and the long-term patient was significantly lower than that of short-term patients. The above studies strongly indicated a correlation between the pathological process and A. muciniphila abundance, and the longer the disease duration, the lower the A. muciniphila abundance. However, there are a few studies that contradict the above conclusion. Marion Régnier et al. induced a T2DM mouse model with a high-fat and high-sugar diet, collected feces, and analyzed them using 16S rRNA sequencing combined with qPCR. The results showed that A. muciniphila was more abundant in T2DM mice compared to normal mice (83). Another study showed that A. muciniphila was more abundant in T2DM patients than in healthy individuals (84). The inconsistency of the findings prompted a large number of studies to be conducted, which eventually concluded that there is a negative correlation between the two ( Table 1 ). This negative correlation property suggests that A. muciniphila supplementation may reverse the underlying physiological indices of T2DM. To test this hypothesis, researchers induced T2DM mice with a high-fat diet and gavaged them 2 x 10⁸ CFU/0.2 ml/day for four weeks. The results showed that A. muciniphila possessed the physiological activity to alleviate the elevated blood glucose induced by the high-fat diet (36). Meanwhile, Feifan Wu et al. reported that A.muciniphila could improve glucose tolerance, regulate intestinal microbiota destroyed by high-fat diets, promote acetate and propionate production, and enhance intestinal barrier function (22). Numerous subsequent studies confirmed these functional activities.

Obesity is a crucial factor in the pathogenesis of T2DM, as evidenced by studies conducted on animal models induced with high-fat diets combined with streptozotocin. The primary pathological mechanisms of T2DM have been identified as: ① Insufficient insulin secretion. Obesity often leads to dyslipidemia and chronically elevated levels of free fatty acids (FFAs). FFAs are essential to maintain the function of islet cell (85). However, a high level of FFA stimulation can lead to a decline in islet cell function. In one study, when isolated islets were exposed to high levels of FFA, insulin secretion significantly decreased over time and eventually ceased, leading to non-insulin secretion (86). High levels of FFA oxidation in islet cells reduced the expression of glucose transporter receptor 2, glucokinase and insulin genes, which directly affected insulin synthesis and secretion (87). As the functional activity of A. muciniphila in modifying diabetes is further investigated ( Table 2 ), its intrinsic molecular mechanisms are being revealed. A. muciniphila has the function of reducing FFA levels by alleviating obesity. In addition, A. muciniphila improved the structure and composition of the intestinal microbiota and promoted the production of short-chain fatty acid (88). Acetic acid, propionic acid and butyric acid targeted G protein-coupled receptors 41 and 43 on the surface of intestinal L cells, which activated downstream molecular signaling and ultimately promoted the secretion of glucagon-like peptide-1(GLP-1) (89). Furthermore, A. muciniphila can secrete glucagon-like peptide-1-inducing protein P9. P9 bound to intercellular adhesion molecule 2 on the surface of L cells and activated downstream molecular pathways to stimulate the secretion of GLP-1 (90). GLP-1 is transported to the pancreas through blood vessels, and binds to its corresponding receptors to induce insulin secretion, ultimately achieving hypoglycemic effect. ② Insulin resistance. Obesity disrupts intestinal microbiota and elevated levels of lipopolysaccharides (LPS). High levels of LPS penetrate the intestinal barrier and activate the NF-κB/MAPKs signaling pathway, resulting in chronic low-grade inflammation (91). As chronic low-grade inflammation is generated, serine kinases (JNK, IKK) are activated and induce phosphorylation of insulin receptors, preventing insulin from binding properly to its receptors (92), leading to insulin resistance. LPS crossing the intestinal barrier is a central cause of chronic low-grade inflammation and is a key step in developing insulin resistance. The intestinal barrier function is maintained by two main factors: the thickness of the mucus layer and the degree of tight junctions between intestinal epithelial cells. The mucus primarily comprises water, inorganic salts and mucin, and mucin is its main functional component. The most abundant protein in the mucin complex is MUC2. The degree of tight junctions between intestinal epithelial cells is determined by the proliferation capacity of intestinal epithelial cells and the expression level of tight junction proteins. It has been reported that A. muciniphila upregulates MUC2, BIRC3 and TNFAIP3 (BIRC3 and TNFAIP3 are anti-apoptotic genes of intestinal epithelial cells involved in their proliferation process) via ADP-heptose-dependent activation of the ALPK1/TIFA pathway, which maintains intestinal barrier function and reduce its permeability (93). This subsequently inhibits chronic low-grade inflammation induced by LPS and insulin resistance. In addition, A. muciniphila promotes the expression of the tight junction proteins ZO-1, Occludin, and Claudin 3 (94). The outer membrane protein Amuc_1100 from A. muciniphila (95), and its extracellular vesicle (72) can enhance intestinal barrier function. In conclusion, A. muciniphila and its derivatives alleviate T2DM by promoting insulin secretion and reducing insulin resistance.

Metformin, as a first-line treatment for type 2 diabetes, has a good safety profile, but its exact mechanism of action is currently unclear. While traditionally thought to lower blood sugar levels by activating the hepatic AMPK pathway, thereby reducing hepatic glucose output (96–101), recent findings suggest metformin may also influence intestinal pathways (102, 103). Metformin can rapidly change the composition and structure of the intestinal microbial flora, mainly by reducing the diversity of the bacterial flora in mice and promoting the abundance of A. muciniphila and various short-chain fatty acid-producing microbial flora in the human intestine, including Butyrivibrio, Bifidobacterium bifidum, Megasphaera, and an operational taxonomic unit of Prevotella (104, 105). Metformin’s positive regulation of intestinal flora is beneficial to increase the production of short-chain fatty acids. Short-chain fatty acids can promote the proliferation of intestinal mucosal epithelial cells and enhance the expression of tight junction proteins, thereby improving intestinal barrier function (106). Strengthening the intestinal barrier effectively suppresses inflammation triggered by lipopolysaccharide penetration. Additionally, short-chain fatty acids bind to G-protein-coupled receptors, prompting intestinal L cells to release PYY and GLP-1. PYY curbs appetite and slows gastrointestinal motility, aiding in obesity management (107), while GLP-1 stimulates insulin release by binding to pancreatic islet B cell receptors, thereby regulating blood sugar levels (108). In summary, metformin’s modulation of intestinal flora is intricately linked to its anti-inflammatory, anti-obesity, and hypoglycemic effects.

During the modulation of gut microbiota, the impact of metformin on the levels of A. muciniphila is consistently highlighted. C57BL/6 mice were fed a high-fat diet (60% fat) for 28 weeks to induce metabolic disorders (obesity and T2D), and then treated with metformin at a dose of 300 mg/kg/day for 10 weeks to observe the effect of metformin on the intestinal microbiota. The findings indicated a notable increase in the abundance of A. muciniphila and Clostridium cocleatum in mice receiving metformin post high-fat diet (109). In an experiment using metformin to treat ulcerative colitis, the ability of metformin to increase the relative abundance of Lactobacillus and Akkermansia, reduce Clostridium erysipelvis at the genus level, and alter the composition of the intestinal microbiota was similarly demonstrated (110). Presently, there’s no evidence to suggest direct stimulation of A. muciniphila production by metformin; however, studies have noted a significant rise in goblet cell count in mouse intestines post-metformin treatment. This increase in mucin secretion by goblet cells directly correlates with the elevated abundance of A. muciniphila (69). In summary, metformin achieves the effect of alleviating T2DM by regulating the abundance of intes tinal flora, especially A. muciniphila.

CVD is the leading cause of mortality worldwide (111). According to the World Health Organization, approximately 17.9 million people died from CVD in 2019, accounting for 32% of all deaths worldwide. There are significant differences between the intestinal microbiota of CVD patients and healthy individuals. A survey of patients with major adverse cardiovascular and cerebrovascular events (MACCE) showed that Eubacterium eligens, A. muciniphila, Prevotella stercorea, and Eubacterium rectale were less abundant in MACCE patients than in the no-MACCE group (112) ( Table 1 ). Notably the amount of A. muciniphila in the intestine of abdominal aortic aneurysms patients or mice was nearly depleted. This predicts that A. muciniphila may play a crucial role in their pathological process. A. muciniphila supplementation has been found to reverse Western diet-induced atherosclerosis, which is a major pathological process in CVD. In addition, A. muciniphila (2 × 10⁸ CFU/180µl) improved cardiovascular disease in mouse models by altering the intestinal microbiota and immune system (113). A. muciniphila had also been demonstrated to improve cold-associated atrial fibrillation by inhibiting the formation trimethylamine (TMA)/trimethylamine N-oxide (TMAO) in a mouse model of cold-associated atrial fibrillation (114). Currently, the physiological activity of A. muciniphila for CVD has been validated to a certain extent. However, relevant studies and clinical data are still relatively scarce. Therefore, further studies need to be conducted.

Atherosclerosis, the leading cause of CVD (115), is manifested as atheromatous plaque material composed of lipid or fibrous substances in the entire aorta and arterial roots. The main mechanism of atherosclerosis: ① With the improvement of people’s living standard, high-fat diet gradually becomes people’s daily diet pattern. Long-term consumption of high-energy diets can induce obesity and cause abnormalities in the body’s lipid metabolism. As a result, high levels of oxidized low-density lipoprotein cholesterol in the plasma are not transferred out of the plasma in time to be deposited in the inner wall of the arterial vessels and trigger inflammation, resulting in the gradual formation of atheromatous deposits in the lumen of the arteries. Over time, this deposit eventually becomes fibrotic, resulting in narrowing of the arterial lumen, causing a loss of wall elasticity and plaque rupture. The ruptured plaques circulate with the blood, easily blocking the blood vessels and causing thrombosis, eventually leading to the occurrence of adverse CVD, including myocardial infarction and angina pectoris, which is fatal for human health and life (116). Oral administration of A. muciniphila can reverse weight gain and abnormal lipid metabolism caused by a high-fat diet and reduce plasma cholesterol levels. In addition, A. muciniphila can enhance intestinal barrier function, which effectively inhibits LPS-induced inflammation and indirectly prevents CVD. ② Choline, phosphatidylcholine, and L-carnitine are abundant in red meat, shellfish, eggs, and fish. These three substances can be metabolized by intestinal microbiota to TMA, a CVD biomarker. TMO absorbed by the organism is further converted to TMAO by hepatic flavin monooxygenase 3 (FMO3) in the liver. Pasteurized A. muciniphila can counteract the increase in FMO3 levels induced by high-fat diet, suggesting the possibility of A. muciniphila intervention in TMAO production. Furthermore, supplementing obese mice with A. muciniphila could promote the excretion of TMA and TMAO through urine, thereby reducing their levels in plasma. In conclusion, A. muciniphila can effectively inhibit the occurrence of CVD through different pathways.

NAFLD is a pathological syndrome characterized by excessive deposition of lipids in liver cells caused by factors other than alcohol and clear liver damage factors (primarily drugs, viral infections, and autoimmunity) (117). It has a high prevalence and incidence in many countries and can be divided into three categories based on its pathological process: simple fatty liver, non-alcoholic steatohepatitis (NASH), and liver cirrhosis. Intestinal microbiota has gained considerable attention as a potential therapeutic target for NAFLD. Studies showed that abundance of A. muciniphila was significantly reduced in gut of NASH and NAFLD patients (118) ( Table 2 ). A study conducted on 46 NASH patients and 38 healthy controls also confirmed the above findings based on qPCR results of their stool samples (119). In addition, using saccharin/sucalose to induce the NAFLD mouse model resulted in a significant decrease in the abundance of A. muciniphila (120). However, while most studies suggest a negative relationship between the two, some findings contradict it. GV Moreira et al. induced a mouse model with NAFLD phenotype using a high-fat diet and observed an increase in the abundance of A. muciniphila in the intestinal tract of the model (4). The inconsistency of conclusions suggests the need for further exploration of the relationship between the two. The significant reduction in the abundance of A. muciniphila in NAFLD patients suggests its potential role in alleviating NAFLD. Yong Rao et al. used high cholesterol and high fat to induce mice and administered A. muciniphila at a dose of 1x10⁸ CFU/mL/day for 6 weeks. The results showed that it effectively reversed NAFLD in the liver, including hepatic steatosis, inflammation, and liver injury (121). At the same time, A. muciniphila supplementation can significantly reduce liver fat and the risk of NAFLD. Currently, no clinical data support this conclusion, and further verification is needed.

Abnormal accumulation of fat in liver cells is a prerequisite for the formation of NAFLD, which is caused by disorders of liver lipid metabolism. The homeostasis of hepatocyte lipid metabolism mainly depends on the dynamic balance of fatty acid uptake, fatty acid synthesis, and lipolysis processes. Glycerol and fatty acids are the raw materials required for synthesizing triglycerides. Glycerol is converted from dihydroxyacetone phosphate produced by glucose in the intestine. Fatty acids are primarily derived from three sources: ① Triglycerides in adipose tissue are decomposed into FFA, and some FFA participate in fat synthesis in the liver. The fat synthesized through this pathway accounts for 59% of the total fat in the liver. This process is primarily associated with regulating insulin signaling. Adipose tissue will abnormally decompose excess FFAs into the liver after insulin resistance, promoting NAFLD development. ② Glucose and fructose from carbohydrates in the food are digested and absorbed by the small intestine to form fatty acids through the adipogenesis pathway. The fatty acids are then transported to the liver for fat synthesis, which accounts for 26% of the total fat in the liver. ③ Excessive intake of saturated fatty acids in the diet will also affect the synthesis of liver fat, which accounts for 15% of the total fat in the liver. A. muciniphila can alleviate the abnormal decomposition of adipose tissue by reducing insulin resistance ( Table 2 ). Additionally, supplementing pasteurized A. muciniphila reduces carbohydrate absorption, thereby reducing the production of glucose and fructose and effectively inhibiting the production of FFAs. The formation of NAFLD is also related to the timely consumption of fatty acids or fats. Supplementation with A. muciniphila increased the levels of L-aspartate in the gut-liver axis. L-Aspartate stimulated lipid oxidation and released energy by activating the hepatic LKB1-AMPK axis, thereby reducing liver fat accumulation. In conclusion, A. muciniphila can reduce the accumulation of fatty acids or fat in the liver through a variety of mechanisms, thereby alleviating NAFLD.