AKKERMANSIA

Akkermansia muciniphila is a common member of the human gut microorganisms, accounting for 3% to 5% of the microbial community. In lung cancer immunotherapy, response rates are doubled in patients with this higher natural level. But unnaturally elevated levels caused by a rebound effect of antibiotics reduced treatment effects dramatically. Reasons why remain unclear, pre-clinical studies have shown negative inflammatory effects with over abundance of akkermanisa. So caution is needed after any antibiotic therapy.

Studies in melanoma response rates shows the complexity of connecting individuals microbiome to bacteria strains. Whilst a natural level of the most commonly seen bacteria including akkermanisa in high responders seems to be consistantly beneficial, when and what to supplement is not clear. In melanoma at least 6 other bacteria were linked with high responders. Others are seen in liver, gastric and kidney cancer responders, also known to be heavily influenced by microbiota during immunotherapy. In metastatic kidney cancers, the response to tyrosine kinase inhibitor therapy has also been linked presences of akkermansia levels, and other strains of gut bacteria rarely available in supplements. They need to be encouraged with diet including artichoke, garlic, onions and more. Oat glucans are also very effective promoters of beneficial gut bacteria. Research at least in melanoma has shown that dietary fiber intake decrease relative progression rates beyond use of supplements (see References).

Combined studies in prostate cancer patient and animal models associate improved androgen therapy outcomes to the presence of akkermansia at moderate levels (highlight 4).  Similarly, investigations into why colorectal cancer is increasing in younger age groups under 50 vs average onset >60 showed akkermansia presence increased overall survival in this group whilst the effect was not seen in the older patients. Akkermansia has evidence of beneficial metabolism of essential amino acid tryptophan. Dysregulation of tryptophan is often seen in progression.

Start investing in a healthy gut microbiota as soon as possible, use commercial supplements to help where needed to ensure diversity. Try to avoid antibiotics if they are used, seek advice on how to safely rebuild the microbiome.

TYPICAL ABSORPTION LEVELS

High

EXAMPLES OF IMPROVED OUTCOMES

YES
ANALYSIS

PRE-DIAGNOSIS OR PREVENTION

PENDING

Highlighted Studies

Unexpectedly, the relative abundance of A. muciniphila was found to be more influential on [lung cancer] survival than its mere presence or absence when stratifying clinical outcomes. Affected individuals benefit from a “normal” abundance of A. muciniphila (below 4.8%), exhibiting the longest median OS (27.2 months), while those with high levels (above 4.8%) had the shortest survival (7.8 months) compared to individuals who lacked A. muciniphila (15.5 months). From immunomodulatory perspe...

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A. muciniphila and Dorea formicigenerans were two species with high overall prevalence (65.8% and 85.9%, respectively) associated with ORR and PFS12 [immunotherapy for melanoma]..This panel contains taxa generally associated with healthy host conditions, including species with probiotic potential (Bifidobacterium pseudocatenulatum, Lactobacillus ruminis and Turicibacter sanguinis), as well as species involved in butyrate production (Roseburia spp., Eubacterium hallii and Butyric...

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In [kidney cancer] patients with clinical benefit (vs. no clinical benefit), Barnesiella intestinihominis and Akkermansia muciniphila were significantly more abundant …. This is the first prospective randomized study demonstrating modulation of the gut microbiome with a probiotic in mRCC [metastatic clear cell kidney cancer]. Probiotic supplementation successfully increased the Bifidobacterium spp. levels. Analysis of longitudinal stool specimens identified an association between B. int...

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We found that the increased AKK abundance and serum inosine level were associated with the more sensitive response to ADT [androgen therapy in prostate cancer] in PCa. AKK secreted inosine to alleviate intestinal barrier damage and reduce serum LPS level, thereby inhibiting castration resistance through the LPS/NF-κB/AR axis. Furthermore, we established a predictive model for CRPC combining AKK and clinical indicators. In summary, this study revealed the pathological mechanism and provided p...

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TABLE OF REFERENCES

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https://pmc.ncbi.nlm.nih.gov/articles/PMC9330544/4We performed shotgun metagenomics-based microbiome profiling using two different pipelines in 338 NSCLC patients. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICIFurthermore, within the Akk+ group, we found significant differences in the overall microbial composition between patients with OS ≥ 12 versus OS < 12 months, but this difference was not observed in Akk− patients (Figure 2A, p=0.009 versus p=0.07). LEfSe analysis within the Akk+ group exhibiting OS ≥ 12 months versus those with OS < 12 months unveiled increased relative abundance of Lachnospiraceae family members (Dorea formicigenerans, D. longicatena, Eubacterium rectale, E. hallii, R. intestinalis, Coprococcus comes) in patients with OS ≥ 12. Conversely, species belonging to the Gammaproteobacteria (E. coli), Clostridia class (R. lactatiformans) or Bacilli class (such as Lactobacillus gasseri, L. paragasseri, L. oris, L. vaginalis, Streptococcus parasanguinis) and Veillonella parvula were dominant in patients with OS < 12Screenshot from 2024-12-02 15-27-49
https://www.cell.com/cell-reports-medicine/pdf/S2666-3791(22)00167-7.pdf3.5Unexpectedly, the relative abundance of A. muciniphila was found to be more influential on [lung cancer] survival than its mere presence or absence when stratifying clinical outcomes. Affected individuals benefit from a “normal” abundance of A. muciniphila (below 4.8%), exhibiting the longest median OS (27.2 months), while those with high levels (above 4.8%) had the shortest survival (7.8 months) compared to individuals who lacked A. muciniphila (15.5 months). From immunomodulatory perspective, affected individuals colonized with A. muciniphila had stronger CD4+ T helper cells activation, increased exhaustion markers and IFN-related genes’ response in tumor biopsies, all associated with ICI responses. Microbiome profiling revealed that the A. muciniphila-positive group is associated with increased gut microbial diversity and enriched with Eubacterium hallii, B. adolescentis, and C. innocuum, and combination with this collateral composition improves prediction of ICIs responseA crucial point to take away from this study is that antibiotics significantly decreased the OS in NSCLC, independently from A. muciniphila status, which limits their potential utility to fine-tune A. muciniphila levels. The impact of gut microbiota shifted by antibiotics exposure should be further explored, and the dominant subtypes of antibiotics that dramatically eliminate A. muciniphila and its co-colonization should be studied in the context of ICI. 3 In conclusion, individual baseline gut microbiota profiling may represent prom- ising biomarkers to predict ICIs re- sponses as well as immune-related adverse effects
https://www.nature.com/articles/s41591-022-01695-53.5A. muciniphila and Dorea formicigenerans were two species with high overall prevalence (65.8% and 85.9%, respectively) associated with ORR and PFS12 [immunotherapy for melanoma]..This panel contains taxa generally associated with healthy host conditions, including species with probiotic potential (Bifidobacterium pseudocatenulatum, Lactobacillus ruminis and Turicibacter sanguinis), as well as species involved in butyrate production (Roseburia spp., Eubacterium hallii and Butyricimonas synergistica). A. muciniphila also belonged to this group, with significant association supporting previous findings on its role in immunotherapyThe gut microbiome has an important role to play in ICI response7,8, as we also confirmed here, but this role appears likely to be more complex than previously reported in initial studies, extending beyond differential microbial abundances and encompassing complex interactions of the gut microbiome with clinical predictors and biological factors that may be specific to geographies in patients who benefit from treatment with ICIs. The gut microbiome is unique in each individual, even when considering identical twins, and a large fraction of this uniqueness is encoded at the level of single strains
https://onlinelibrary.wiley.com/doi/10.1002/cam4.35693.5In [renal cell carcinoma] patients with clinical benefit (vs. no clinical benefit), Barnesiella intestinihominis and Akkermansia muciniphila were significantly more abundant (p = 7.4 × 10−6 and p = 5.6 × 10−3, respectively). This is the first prospective randomized study demonstrating modulation of the gut microbiome with a probiotic in mRCC. Probiotic supplementation successfully increased the Bifidobacterium spp. levels. Analysis of longitudinal stool specimens identified an association between B. intestinihominis, A. muciniphila, and clinical benefit with therapy.Our randomized, prospective study demonstrated that dietary interventions result in modulation of gut microbiome in patients with metastatic renal cell carcinoma receiving VEGF-TKI therapy. In addition, this study is the first to suggest that components of the stool microbiome, A. muciniphila and B. intestinihominis, may predict clinical benefit in patients with mRCC receiving VEGF-TKI therapy, distinct from previously reported predictors of checkpoint inhibitor response. We also demonstrate proof of principle, with the active ingredient of our probiotic supplement detectable specifically in patients randomized to receive it
https://pmc.ncbi.nlm.nih.gov/articles/PMC6699990/3In this single-center study, we demonstrated that daily oral supplementation of 1010 bacteria either alive or pasteurized A.muciniphila for 3 months was safe and well tolerated. Compared to the Placebo, pasteurized A.muciniphila improved insulin sensitivity (+28.62±7.02%, P=0.002), reduced insulinemia (-34.08±7.12%, P=0.006) and plasma total cholesterol (-8.68±2.38%, P=0.02). Pasteurized A.muciniphila supplementation slightly decreased body weight (-2.27±0.92kg, P=0.091) as compared to the Placebo group, and fat mass (-1.37±0.82kg, P=0.092) and hip circumference (-2.63±1.14cm, P = 0.091) as compared to baseline. After 3 months of supplementation, A.muciniphila reduced the levels of relevant blood markers of liver dysfunction and inflammation while the overall gut microbiome structure was unaffected.After 3 months, the Placebo group exhibited a significant increase of fasting plasma insulin (P<0.05, T3 versus T0, Fig. 1a), contrary to participants receiving both forms of A.muciniphila in whom reduced plasma insulin levels (by about 30%) were observed as compared to the Placebo (Fig. 1a). This effect was significant between the Pasteurized A.muciniphila and the Placebo group (Fig. 1a). Fasting glycemia was not affected (Fig. 1b), however, the subjects were not highly hyperglycemic at baseline ...We also measured insulin sensitivity indexes and insulin resistance (HOMA method), and found that insulin sensitivity was significantly reduced at T3 in the Placebo group (Fig. 1c and d). Conversely, both forms of A.muciniphila improved this parameter... Pasteurized A.muciniphila markedly and significantly improved insulin sensitivity index by about 30%
https://www.mdpi.com/2076-2607/12/8/16533n summary, we found that the increased AKK abundance and serum inosine level were associated with the more sensitive response to ADT in PCa. AKK secreted inosine to alleviate intestinal barrier damage and reduce serum LPS level, thereby inhibiting castration resistance through the LPS/NF-κB/AR axis. Furthermore, we established a predictive model for CRPC combining AKK and clinical indicators. In summary, this study revealed the pathological mechanism and provided potential therapeutic targets and prognostic indicators for CRPC.This study indicated that some PCa patients and mice were more sensitive to ADT and entered CRPC later, which was related to the gut microbiota, especially the enrichment of Akkermansia muciniphila (AKK). Untargeted metabolomics analysis found that serum inosine level was upregulated in the treatment-sensitive group and significantly correlated with AKK. Furthermore, we revealed that intestinal permeability and serum lipopolysaccharide (LPS) levels increased in treatment-resistant mice. LPS stimulated the upregulation of p-NF-κB p65 and AR in tumors. Supplementing AKK metabolite inosine could alleviate intestinal barrier damage and reduce serum LPS level, ultimately inhibiting castration resistance via the LPS/NF-κB/AR axis.Screenshot from 2024-12-02 17-59-11
https://www.science.org/doi/10.1126/science.aan37063Differences in outcomes were noted across the groups , with significantly longer PFS observed in patients reporting sufficient dietary fiber intake and no probiotic use compared with all other groups (median PFS not reached versus 13 months). Similar positive associations were observed for ICB response in patients reporting sufficient dietary fiber intake and no probiotic use compared with all other groups (n = 123; 82 versus 59% responders; Table 1 and tables S11 and S12). Microbial alpha diversity and Ruminococcaceae family and Faecalibacterium genus abundances were also numerically higher in patients with sufficient dietary fiber intake and no probiotic use, although only 18% of patients met these criteriaWe assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti–programmed cell death 1 (anti–PD-1)–based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ–positive cytotoxic T cells in the tumor microenvironmentScreenshot from 2024-12-02 14-48-27
https://ascopubs.org/doi/full/10.1200/EDBK_1000412.5
https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00124-12.5Akkermansia muciniphila is another candidate probiotic that may boost immunotherapy efficacy in patients. In a retrospective analysis by Derosa et al., the result revealed a correlation between the presence of fecal A. muciniphila and improved ICI outcomes in patients with NSCLC.35 Subsequent investigation identified that supplementation of lyophilized encapsulated A. muciniphila (Akkp2611) can benefit patients who were exposed to antibiotics and lacked endogenous A. muciniphila.35 In general, further research is needed to confirm the observational findings and gain more understanding of the mechanistic functions of probiotics on the gut microbiome and immune system. Currently, there are multiple ongoing clinical trials investigating the manipulation of the gut microbiome in immunotherapy against various cancer types using different probiotic strains, including Bifidobacterium trifidum live powder BiFico, Probio-M9 (L. rhamnosus), and Bifidobacterium bifidumA high-fiber diet has been associated with positive effects in cancer patients receiving immunotherapy. This diet can promote the enrichment of beneficial commensal bacteria and improve antitumor immune response while reducing the risk of irAEs. In melanoma patients receiving combined neoadjuvant therapy and ICIs, a high-fiber diet was demonstrated to increase the abundance of Ruminococcaceae, leading to improved antitumor immune response and decreased risk of irAEs during immunotherapy.119,122 In another study by Spencer et al., increased dietary fiber intake was found to be significantly associated with improved PFS in patients receiving ICIs, especially for those who consumed sufficient dietary fiber and did not use probiotics.
2.5In our [liver cancer] case series, pretreatment abundance of Akkermansia and low fecal calprotectin concentration were associated with DC. This confirms the association of Akkermansia with a better response reported in patients with other solid tumors treated with ICIs, and is consistent with the anti‐inflammatory properties of Akkermansia.( 9 ) In agreement with these findings, patients who achieved DC had a lower fecal calprotectin concentration at baseline, which is indicative of a lower degree of intestinal inflammation. Persistent gut‐derived inflammation in patients with cirrhosis leads to exhaustion and paralysis of the immune system, and is an additional factor triggering tumor immune escape.Although the exact immunomodulatory effects of Akkermansia muciniphila are still unclear and probably correlated with its anti‐inflammatory action and protective role on the intestinal barrier, it has been shown that its supplementation can enhance the effects of ICIs therapy.( 12 ) This can be of paramount importance in some categories of patients, such as those with NAFLD; indeed, a recent study showed a suboptimal response to ICIs in patients with NAFLD‐related HCC,( 2 ) in whom a profound derangement of the gut microbiota was demonstrated.( 4 ) Therefore, we think that the role of Akkermansia administration as adjuvant therapy to enhance the response to ICIs in patients with HCC deserves further evaluation in future studies.
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(24)00015-X/fulltext2.5 Correlation analysis also revealed that the presence of Akkermansia in yoCRC [young onset colorectal cancer] was associated with longer overall survival (OS) . However, this association was not observed in aoCRC [average age of onset]. Similarly, an abundance of Fusobacterium was linked to a shorter OS in yoCRC (R2 = −0.23, p = 0.001), but not in aoCRC (R2 = 0.19, p = 0.259). On the other hand, no significant association was found between disease recurrence and specific bacteria in both the cohortsWe further demonstrated that the relative abundance of Akkermansia in yoCRC tumors correlated with a longer OS. We also found that early-stage (stages I–III) tumors in the younger patients were relatively enriched in Bacteroides as compared to stage IV primary tumors. These distinct behaviors of the Akkermansia and Bacteroides genera in yoCRC dysbiosis suggests important directions for future studies. The intestinal mucosal barrier plays a vital role in maintaining homeostasis by shielding the intestinal epithelium from gut microorganisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC8632301/2.5Common responses encompassed modulation of amino acid metabolism, characterized by reduced levels of arginine and alanine, alongside several intermediates of tyrosine, phenylalanine, tryptophan, and glutathione metabolism. The global increase in levels of acylcarnitines together with specific modulation of acetoacetate also suggested induction of ketogenesis through enhanced β-oxidation. Moreover, our data pinpointed some metabolites of interest considering their emergence as substantial compounds pertaining to health and diseases in the more recent literature.Briefly, our data raise the hypothesis that administration of A. muciniphila in prediabetic subjects with metabolic syndrome enhances hepatic fatty acids delivery and subsequent β-oxidation, but attenuates acetyl-CoA oxidation in the TCA cycle, leading preferentially to ketogenesis. Downstream metabolomic effects of A. muciniphila also lead to downregulation of the metabolism of several amino acids, whose implications in various metabolic disorders are convincingly demonstrated in the scientific literature. We notably identified a global downregulation of the tyrosine and phenylalanine metabolism as a potential mechanism contributing to the hepato-protective effects of A. muciniphila. Our analysis also revealed specific modulations of metabolites with emerging implications in health and diseases, including disorders for which A. muciniphila was shown to be negatively associated with
https://pmc.ncbi.nlm.nih.gov/articles/PMC6699990/#abstract12 Compared to the Placebo, pasteurized A.muciniphila improved insulin sensitivity (+28.62), reduced insulinemia (-34.08) and plasma total cholesterol .. After 3 months of supplementation, A.muciniphila reduced the levels of relevant blood markers of liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study shows that the intervention was safe and well-tolerated and that the supplementation with A.muciniphila improves several metabolic paramaters.After 3 months, the Placebo group exhibited a significant increase of fasting plasma insulin (P<0.05, T3 versus T0, Fig. 1a), contrary to participants receiving both forms of A.muciniphila in whom reduced plasma insulin levels (by about 30%) were observed as compared to the Placebo (Fig. 1a). This effect was significant between the Pasteurized A.muciniphila and the Placebo group (Fig. 1a). Fasting glycemia was not affected (Fig. 1b), however, the subjects were not highly hyperglycemic at baseline ...We also measured insulin sensitivity indexes and insulin resistance (HOMA method), and found that insulin sensitivity was significantly reduced at T3 in the Placebo group.... Conversely, both forms of A.muciniphila improved this parameter. Indeed, Pasteurized A.muciniphila markedly and significantly improved insulin sensitivity index by about 30%... and Alive A.muciniphila significantly improved the insulin resistance score
https://www.sciencedirect.com/science/article/pii/S07533322240030072Overall, the role of A. muciniphila in CRC development or inhibition is still unclear and controversial. Various methods of bacterial supplementation, such as viability, bacterial number, and abundance, could all influence the colonization effect of A. muciniphila administration and CRC progression. Overall, A. mucinipila has been revealed to modulate the therapeutic potential of immune checkpoint inhibitors. Preliminary human data propose that oral consumption of A. muciniphila is safe, but its efficacy needs to be confirmed in more human clinical studies.A. muciniphila, as a potential probiotic that can efficiently utilize gastrointestinal mucin, plays an important role in CRC progression through host immune regulation. A. muciniphila may cause CAC by exacerbating inflammation in the early stages of CRC and increasing the proliferation of IECs. The role of A. muciniphila in CRC is controversial. Various methods of bacterial supplementation, such as viability, bacterial number, and abundance, could all influence the colonization effect of A. muciniphila administration and CRC progression. Viable bacteria could produce several virulence factors, possibly resulting in immune overactivation.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10731290/3Dysbiosis is a hallmark of inflammation and intestinal cancers. A. muciniphila is an important component of the normal microbiota, and changes in its abundance affect the course of the disease. A. muciniphila is capable of inducing both proinflammatory and anti-inflammatory mechanisms. Studies on the role of A. muciniphila in intestinal inflammation show its protective properties in barrier restoration and control of inflammation, while data obtained in colorectal cancer models remain contradictory. Some studies indicate a decrease in tumor burden, while others report an increase in tumor growth when the bacterium is introduced. We attempted to directly compare different experimental protocols using A. muciniphila in various models of intestinal cancer and concluded that the introduction of large amounts of A. muciniphila, especially after a course of antibiotics, provokes dysbiosis, disrupts the intestinal barrier functions (62), and aggravates the inflammation that provokes cancer (46). At the same time, lower doses of the bacterium or its derivatives without prior depletion of the microbiota have a positive effect on the course of the disease. This assumption is supported by the clinical study on the correlation between the presence of A. muciniphila and the effectiveness of checkpoint therapy. The results of this study demonstrated that moderate, but not high A. muciniphila load in the stool correlated with a good prognosis (21). Thus, delicate modulation of the microbiota by A. muciniphila may become a promising strategy for adjunctive therapy of inflammatory bowel diseases and colorectal cancer.
https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01789-23.5We find that the feces of patients with OC demonstrate different characteristics from benign controls. After fecal microbiota transplantation (FMT) from patients with OC into OC-bearing mice, the tumor development accelerates. Further, an Akkermansia supplementation with FMT significantly suppresses OC progression in mice. RNA sequencing of tumors shows that T cell activation pathways are upregulated after Akkermansia supplementation with FMT. Moreover, acetate accumulation accompanies Akkermansia abundance elevation, which is associated with enhanced interferon γ (IFNγ) secretion of CD8+ T cells and also its tumor-killing property. This work highlights the importance of protective gut microbiome in immune surveillance of OC, which connects accumulation of acetate and the cytotoxic function of CD8+ T cells by increasing IFNγ secretion.In the present study, we utilized fecal microbiota transplantation (FMT) to explore how the gut microbiota from patients with OC influences OC progression in vivo. We identified the critical role of the gut microbiota in regulating the immune microenvironment to suppress OC progression. Furthermore, the transcriptome and metabolome were evaluated to determine the potential immunological reaction by which the corrected gut microbiota, as well as the gut barrier, played on the immune surveillance of OC. Our study raised an integrated view of OC, gut microbiota, and immune environment to depict the host tumor-feature environment and shed a light on the design of future biotherapy of OC

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