Akkermansia muciniphila: a potential booster to improve the effectiveness of cancer immunotherapy

Abstract

Cancer immunotherapy has emerged as a groundbreaking method of treating malignancies. However, cancer immunotherapy can only benefit a small percentage of patients, and the numerous side effects that might develop during treatment reduce its effectiveness or even put patients' lives in jeopardy. Surprisingly, the gut microbiome Akkermansia muciniphila (A. muciniphila) can significantly inhibit carcinogenesis and improve anti-tumor effects, thus increasing the effectiveness of cancer immunotherapy and decreasing the likelihood of side effects. In this review, we focus on the effects of A. muciniphila on the human immune system and the positive impacts of A. muciniphila on cancer immunotherapy, which can build on strengths and improve weaknesses of cancer immunotherapy. The potential clinical applications of A. muciniphila on cancer immunotherapy are also proposed, which have great prospects for anti-tumor therapy.

Introduction

In 2020, there were approximately 19.3 million new cancer cases and nearly 10 million cancer deaths globally, and in 2023, it is anticipated that there will be 1,958,310 new cancer cases and 609,820 cancer deaths in the United States (Siegel et al. 2023; Sung et al. 2021). Therefore, to decrease the cancer fatality rates and new cancer cases, it is imperative to implement efficient cancer control methods. The human immune system monitors and eliminates cancer cells through a series of progressive and iterative events, which is known as the cancer-immunity cycle (Chen and Mellman 2013). The seven phases of the cancer-immunity cycle are as follows: tumor antigens release, tumor antigens presentation, initiation and activation of effector T cells, activated effector T cells migrating into tumor tissues, T cells infiltrating into tumor tissues, T cells specifically recognizing and binding to tumor cells, and tumor cells clearance; additional tumor-associated antigens release when cancer cells are dead, thus broadening and deepening the subsequent responses of the cycle, and at the same time, the cycle is also characterized by inhibitory factors that result in immune regulatory feedback mechanisms, which can halt the development or restrict the immunity to prevent an excessive autoimmune inflammation (Chen and Mellman 2013). Tumor cells escape when they become resistant to anti-tumor immune response (Kennedy and Salama 2020). The mechanism by which tumor cells evolve this escape may be based on changes or lack of tumor antigens, manipulation of cytokine expression, upregulation of immune checkpoint proteins, and so on (Kennedy and Salama 2020). Cancer immunotherapy was developed on the basis of the mechanisms of tumor cells escape, and with the continuous development of medical technology, immunotherapy is considered as one of the most cutting-edge technologies in the field of clinical oncology today, showing its unlimited potential for oncotherapy.

The goal of cancer immunotherapy is to initiate or restart a self-sustaining cancer-immune cycle which can be expanded and spread to overcome the pathways leading to escape while avoiding the emergence of an uncontrolled autoimmune inflammatory responses (Chen and Mellman 2013; Kennedy and Salama 2020). An early method of cancer immunotherapy was targeting cytokines to affect immune cell function. For instance, interleukin 2 (IL-2) was the first cytokine to be successfully utilized to treat cancer, and high-dose IL-2 has been used to treat melanoma and renal cell carcinoma (RCC), with results showing that 7% patients with metastatic melanoma achieved complete regression and 10% patients had partial regression, as well as 7% patients with metastatic RCC experienced complete regression and 13% patients had partial regression (Choudhry et al. 2018; Krieg et al. 2010; Rosenberg et al. 1994). Subsequently, scientists have investigated therapeutic approaches to manipulate different stages of the immune system, proposing genetic engineering antibodies, immune checkpoint inhibitors (ICIs), adoptive cell therapy (ACT), cancer vaccines, and so on (Baxevanis et al. 2009; Szeto and Finley 2019). However, there are obvious limitations of cancer immunotherapy in clinical applications due to the occurrence of immune-related adverse events (irAEs), drug resistance and other unique toxicity profiles, resulting in poor therapeutic effects of many solid tumors (Kennedy and Salama 2020; Szeto and Finley 2019).

To break the dilemma of the clinical application of cancer immunotherapy, scientists dedicated to the research on the gut microbiome with the help of single-cell sequencing technologies, and have discovered that the diversity of the gut microbiome is closely related to the onset and progression of cancer (Derakhshani et al. 2021; Vernocchi et al. 2020). As a result, it is now critical to find efficient methods for improving cancer immunotherapy and increasing tumor clearance rate. Among the many beneficial microbes in the gut, Akkermansia muciniphila (A. muciniphila) has attracted a lot of attention from scientists, and it is becoming more and more clear that A. muciniphila affects the immune system, host metabolism, and the effectiveness of ICIs (Ansaldo et al. 2019; Greer et al. 2016; Routy et al. 2018b). A. muciniphila performs immune function by both directly contributing to the host’s immune response and simultaneously preserving the integrity of the intestinal barrier (Ansaldo et al. 2019; Zhu et al. 2020). This article reviews the advantages and disadvantages of cancer immunotherapy, the role of A. muciniphila on the immune system and the complementary role and application prospects of A. muciniphila in cancer immunotherapy. It is anticipated that A. muciniphila will contribute to the development of a new paradigm for anti-tumor immunotherapy.

Amazing therapeutic potential and limitations of cancer immunotherapy

Advantages and development prospects of cancer immunotherapy in clinical applications

Cancer immunotherapy is often used as an adjuvant therapy in combination with conventional therapies such as surgery and radiotherapy to remove residual tumor cells, improving the effectiveness of comprehensive oncotherapy and helping prevent tumor recurrence and metastasis. Among them, ICIs have had positive clinical outcomes, and their breakthroughs in the field of oncotherapy are increasingly reported, which is regarded as a milestone in cancer immunotherapy. One of the main factors in the induction of immune tolerance in tumorigenesis is the presence of immune checkpoint molecules, a class of immunosuppressive molecules that control the intensity and breadth of the immune response to prevent the damage and destruction of normal tissues (Zhang et al. 2021). ICIs, including anti-programmed death receptor 1/programmed death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), have the ability to reactivate T cells that have lost their effectiveness before to exert indirect but effective anti-tumor immune effects (Bagchi et al. 2021). Currently, the clinical applications of ICIs are mainly focused on anti-CTLA-4 antibodies (ipilimumab, tremelimumab), anti-PD-1 antibodies (pembrolizumab, nivolumab, cemiplimab) and anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab), and some ICIs have been approved by the US Food and Drug Administration (FDA) for first- and/or second-line treatment of different types of advanced unresectable malignant tumors such as melanoma, RCC, lung cancer, urothelial carcinoma (UC), and so on (Bagchi et al. 2021; Kennedy and Salama 2020). Although ICIs have shown amazing therapeutic potential in the management of human solid malignancies clinically, some patients still struggle to benefit from a single course of treatment. Clinical researchers are focusing on combination immunotherapy to improve the anti-tumor effects of immunotherapy (Kaur et al. 2021). According to the findings of a 4-year follow-up analysis, the combination of nivolumab and ipilimumab produced superior treatment outcomes in patients with advanced melanoma than ipilimumab alone (Hodi et al. 2018). The likelihood of untoward effects was not decreased by combination immunotherapy, though (Pires da Silva et al. 2021). It is critical to be cautious about the incidence of adverse reactions, and the foundation of combination immunotherapy is the establishment of safe and efficient combination treatment.

Additionally, results from multiple clinical trials support the use of ICIs in conjunction with chemotherapy for the treatment of a variety of malignancies. In a randomised, placebo-controlled, double-blind, phase 3 trial, researchers found that the addition of pembrolizumab to standard chemotherapy was effective in treating metastatic triple-negative breast cancer (TNBC) in first-line treatment, significantly improving patients’ progression-free survival (Cortes et al. 2020). Another phase 3 trial (CheckMate 649) demonstrated that compared with chemotherapy alone, the overall survival (OS) and progression-free-survival (PFS) of patients with advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma was considerably increased when nivolumab was combined with chemotherapy (Janjigian et al. 2021). Besides, ICIs combined with targeted therapy is now also the current research hotspot for the treatment of tumors: the two main alternatives for the treatment of gastric cancer are anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibodies and vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors in combination with ICIs (Li et al. 2021). Thus, ICIs have widened the path for the original oncotherapy system. The ICIs that are currently widely used in clinical trials are listed in Table 1. What’s more, a study found that A. muciniphila was able to improve the efficacy of PD-1 therapy, which highlights the significance of A. muciniphila in immunotherapy (Routy et al. 2018b). The emphasis on A. muciniphila’s adjuvant function in ICIs will make it easier to create more effective immunotherapeutic strategies for the clinical oncotherapy. Taken together, it is worthwhile for researchers to further investigate how to select an appropriate combination treatment strategy based on the patient's specific pathology, to develop individualized treatment protocols and to improve the efficacy of the treatment.

Table 1.

ICIs that are currently used in clinical trials

Cancer immunotherapy		Drugs or treatment	Cancer	Outcomes	References
ICIs	Anti-PD-1	Pembrolizumab	Advanced melanoma	Significantly longer recurrence-free survival (1-year rate of recurrence-free survival, 75.4% vs. 61.0%) without new toxic effects identified than placebo	Eggermont et al. (2018)
			RCC	A significant improvement in disease-free survival (disease-free survival at 24 months, 77.3% vs. 68.1%) after surgery versus placebo	Choueiri et al. (2021)
			NSCLC	Significantly longer PFS (median PFS, 10.3 months vs. 6.0 months) and OS (OS at 6 months, 80.2% vs. 72.4%), and with fewer adverse events (occurring in 73.4% vs. 90.0% of patients) than platinum-based chemotherapy	Reck et al. (2016)
		Nivolumab	Advanced oesophageal squamous cell carcinoma	A significant improvement in OS (median OS, 10.9 months vs. 8.4 months) and a favorable safety profile (adverse events occurring in 18% vs. 63% of patients) versus chemotherapy	Kato et al. (2019)
		Cemiplimab	Advanced NSCLC	Significantly improved PFS (median PFS, 8.2 months vs. 5.7 months) and OS (median OS, not reached vs. 14.2 months) versus chemotherapy	Sezer et al. (2021)
	Anti-PD-L1	Atezolizumab	Locally advanced or metastatic UC	Encouraging durable response rates (the objective and complete response rate at 17.2 months’ median follow-up, 23% and 9%) and survival (median PFS, 2.7 months; median OS 15.9 months)	Balar et al. (2017)
		Avelumab	Locally advanced or metastatic UC	Significantly longer OS (OS at 1 year, 71.3% vs. 58.4%) in the treatment of avelumab plus best supportive care than best supportive care alone	Powles et al. (2020)
		Durvalumab	Locally advanced or metastatic UC	Favorable clinical activity (median PFS and OS, 1.5 months and 18.2 months) and an encouraging and manageable tolerability (median duration of response, not reached)	Powles et al. (2017)
			NSCLC	Significantly longer PFS (median PFS, 16.8 months vs. 5.6 months) with durvalumab than with placebo	Antonia et al. (2017)
	Anti-CTLA-4	Ipilimumab	Metastatic melanoma	Significantly longer PFS (median PFS, 10.1 months vs. 6.4 months) than gp 100	Hodi et al. (2010)
		Tremelimumab	Malignant mesothelioma	Clinical and immunological activity (patients achieving disease control, 52%; four immune-related-partial responses recorded after a median follow-up of 21.3 months), and a good safety profile (no death recorded)	Calabro et al. (2015)
	Combination	Ipilimumab + nivolumab	Advanced melanoma	Significantly longer OS (OS at 5 years, 52% vs. 26%) without apparent loss of quality of life than ipilimumab	Larkin et al. (2019)
			MSI-H/dMMR mCRC	Robust and durable clinical benefit (median PFS and median OS, not reached)	Lenz et al. (2022)
			Advanced RCC	Significantly longer OS (OS at18 months, 75% vs. 60%) and higher objective response rate (42% vs. 27%) with nivolumab plus ipilimumab than with sunitinib	Motzer et al. (2018)
		Tremelimumab + durvalumab	HCC	Longer OS (median OS, 18.7 months vs. 15.1 months vs. 13.6 months) than tremelimumab or durvalumab alone	Kelley et al. (2021)
Combination of ICIs with other conventional therapies	ICIs + chemotherapy	Pembrolizumab + chemotherapy	Metastatic triple-negative breast cancer	A significant and clinically meaningful improvement in PFS (median PFS, 9.7 months vs. 5.6 months) with pembrolizumab-chemotherapy versus placebo-chemotherapy among patients with PD-L1 CPS ≥ 10	Cortes et al. (2020)
		Nivolumab + chemotherapy	Advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma	Significantly longer OS (median OS, 15.5 months vs. 9.6 months) and PFS (median PFS, 8.5 months vs. 4.3 months) versus chemotherapy alone among patients with PD-L1 CPS ≥ 5	Janjigian et al. (2021)
		Nivolumab + platinum-based chemotherapy	NSCLC	Significantly longer event-free survival (median event-free survival, 31.6 months vs. 20.8 months) and a higher percentage of patients with a pathological complete response (24.0% vs. 2.2%) than chemotherapy alone, without increasing the incidence of adverse events or impeding the feasibility of surgery	Forde et al. (2022)
		Durvalumab + platinum-etoposide	ES-SCLC	Significantly longer OS (OS at 18 months, 34% vs. 25%) than platinum-etoposide alone	Paz-Ares et al. (2019)
	ICIs + targeted therapy	Pembrolizumab + lenvatinib	Advanced gastric cancer	Promising anti-tumor activity (median follow-up, 12.6 months) with an acceptable safety profile in patients (no grade 4 treatment-related adverse events)	Kawazoe et al. (2020)
		Avelumab + axitinib	Advanced RCC	Significantly longer PFS (median PFS, 13.8 months vs. 8.4 months) with avelumab plus axitinib than with sunitinib alone	Motzer et al. (2019)
Combination of ICIs with other immuno-therapies	ICIs + cytokine therapy	Nivolumab + IL-15 superagonist (ALT-803)	Metastatic NSCLC	Promising clinical activity, and a good safety profile (no grade 4 or 5 adverse events)	Wrangle et al. (2018)
	ICIs + ACT	Pembrolizumab + CAR-T cell therapy	Malignant pleural disease	Encouraging clinical activity (median OS, 23.9 months; OS at 1 year, 83%) and safety (no dose-limiting toxicities; no grade 5 adverse events)	Adusumilli et al. (2021)
	ICIs + cancer vaccines	Ipilimumab + talimogene laherparepvec	Advanced and unresectable melanoma	Significantly greater anti-tumor activity (objective response rate, 39% vs. 18%) with talimogene laherparepvec plus ipilimumab than ipilimumab alone	Chesney et al. (2018)

ICIs immune checkpoint inhibitors, PD-1 programmed death receptor 1, RCC renal cell carcinoma, NSCLC non-small-cell lung cancer, PFS progression-free-survival, OS overall survival, PD-L1 programmed death ligand 1, UC urothelial carcinoma, CTLA-4 cytotoxic T lymphocyte antigen 4, gp 100 glycoprotein 100, MSI-H microsatellite-instability-high, dMMR mismatch repair-deficient, mCRC metastatic colorectal cancer, HCC hepatocellular carcinoma, CPS combined positive score, ES-SCLC extensive-stage small-cell lung cancer, IL-15 interleukin 15, ACT adoptive cell therapy, CAR chimeric antigen receptor

Except for ICIs, the application of genetic engineering antibodies is one of the most impressive advances in tumor immunotherapy, such as trastuzumab for breast cancer treatment (Baxevanis et al. 2009). In addition, IL-2 and interferon-γ (IFN-γ) are further genetic engineering cytokines that have been approved by FDA for the treatment of cancer (Baxevanis et al. 2009). In ACT, immune effector cells that have been expanded and activated in vitro relayed back into the tumor-bearing host by to enable T cells to recognize and eradicate cancer cells (Wang and Cao 2020). For example, chimeric antigen receptor (CAR) T cells are endowed with the ability to recognize tumor-associated antigens for the treatment of hematologic malignancies and have been studied in a variety of solid tumor types (D'Aloia et al. 2018). Preventive and therapeutic vaccines are representative strategies in cancer immunotherapy. The former is vaccinated in healthy people to induce immune memory to prevent the development of specific cancer, while the latter is utilized in disease management by strengthening or reactivating the patient’s own immune system (Igarashi and Sasada 2020). For instance, sipuleucel-T, approved by the FDA, was used to treat castration-resistant prostate cancer, prolonging the OS of patients (Kantoff et al. 2010). These immunotherapies can also be used in conjunction with ICIs, which are listed in Table 1. Taken together, these cancer immunotherapies offer fresh perspectives on how to treat various types of tumors in the clinical practice and have achieved good results in clinical trials, which bring good news to cancer patients.

The dilemma of cancer immunotherapy in clinical applications

Although cancer immunotherapy has shown amazing therapeutic potential in cancer patients, there are still problems with its clinical application. First, one of the main problems facing ICIs is the limited therapeutic effect, resulting in the fact that the majority of people do not benefit from cancer immunotherapy (He et al. 2021). Take colorectal cancer (CRC) as an example, ICIs have a significant effect on the microsatellite-instability-high (MSI-H)/mismatch repair-deficient (dMMR) CRC, which is known as "hot" tumor because its tumor microenvironment (TME) contains a large number of infiltrating T cells and is easily recognized by immune cells to trigger immune responses, igniting the hope of life for patients with advanced CRC (Lenz et al. 2022; Wei et al. 2022). However, only a tiny percentage of cases of CRC are the MSI-H/dMMR subtype, while other subtypes of CRC, which account for most of the proportion, are immunosuppressive “cold” tumors that lack T cell infiltration in TME and are insensitive to immunotherapy (He et al. 2021; Wei et al. 2022). Therefore, how to promote the conversion of cold to hot tumors is the foundation of ICIs treatment, which has become a research hotspot to improve the effectiveness of immunotherapy. Previous studies have shown that the specific gut microbiome participated in the immune regulation of TME and affected the anti-tumor immune responses, which significantly improved the efficacy of ICIs therapy for “cold” tumors (Xu et al. 2020). The world’s first clinical trial on reversing the efficacy of PD-1 antibody by fecal microbiota transplantation (FMT) found that when patients with advanced cancer who did not respond to PD-1 treatment previously received FMT, and then received PD-1 treatment, there was a miraculous reversal: the tumor was completely remitted (Baruch et al. 2021). The use of extracted microbiota from the feces of cancer patients who responded well to PD-1 for FMT in cancer patients who did not respond to PD-1 surprisingly found that these patients achieved long-term survival after receiving PD-1 treatment (pembrolizumab) again (Davar et al. 2021). These studies suggest that the gut microbiome, immunity, and TME are closely related, so restoring the balance of the gut microbiome can have a synergistic effect with immunotherapy and produce a significant anti-tumor immune response. Second, the appearance of irAEs during the use of ICIs is also one of the biggest clinical concerns, which often has an impact on the decision about whether to continue treatment (Thompson 2018). The degree of toxicity caused by different monoclonal antibodies has certain differences: the main adverse events associated with treatment with pembrolizumab are arthralgia, pneumonitis and hepatic toxicities, while nivolumab causes mainly endocrine toxicity; those who receive atezolizumab have a higher risk of hypothyroidism, nausea, and vomiting; the main adverse events related to ipilimumab are skin, gastrointestinal and renal toxicities (Martins et al. 2019). As can be observed, the range of organs or systems that irAEs may affect is very broad. We show the organs or systems that irAEs may influence and toxicities that organs or systems may exhibit in Fig. 1. The mechanisms by which irAEs occur are still unclear, but scientists have led researchers to hypothesize that they may be associated with the over-activation of T lymphocytes, which would cause the body’s immune tolerance to be disrupted by a new, specific immune response (Johnson et al. 2016). To increase the number of patients benefiting from ICIs, it is necessary to propose effective measures to mitigate irAEs. The European Society for Medical Oncology (ESMO) Clinical Practice Guideline (CPG) provides specific guidance on the management of irAEs, including the general guidance for immunosuppression: diagnosis and grading of irAEs, ruling out differential diagnoses and pre-immunosuppression testing, selecting an appropriate immunosuppression strategy for grade ≥ 2 events, and active evaluation within 72 h to accommodate treatment (Haanen et al. 2022). Depending on the specific organ or system invaded and the degree of toxicity, symptomatic treatments such as corticosteroid therapy and steroid therapy should also be administered (Haanen et al. 2022). The creation of early-emerging biomarkers for the diagnosis and forecasting of irAEs is equally crucial. Due to the association between the gut microbiome and irAEs, the gut microbiome may potentially become a candidate biomarker (von Itzstein et al. 2020). This demonstrates another potential of the gut microbiome in immunotherapy. Third, the drug resistance is yet another intractable issue in the clinical application of ICIs, despite the existence of bispecific antibodies targeting transforming growth factor-β (TGF-β) and PD-L1 (termed YM101 and BiTP) that exhibit potent anti-tumor effect and may be able to overcome ICIs resistance in partial cancer patients (Yi et al. 2021, 2022). The studies on resistance mechanisms are numerous and complex, but one research found that tumor resistance to ICIs can be mainly attributed to the abnormality in the composition of the gut microbiome (Morad et al. 2021; Routy et al. 2018b). Taken together, we cannot discount the importance of the gut microbiome in the dilemma of clinical applications of ICIs.

Fig. 1.

Immune‐related adverse events of various organs or systems caused by immune checkpoint inhibitors. The immune adverse events mainly consisted of the skin, endocrine glands, liver, gastrointestinal tract, lungs, arthrosis, muscles, nerves, cardiovascular system, kidneys and eyes (Created with BioRender.com)

Scientists have also concentrated on the challenges faced in the therapeutic application of ACT in addition to the widespread concern about the limitations of ICIs in clinical. Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and cytopenias are the main challenges for patients receiving CAR-T immunotherapy (Schubert et al. 2021). Among them, CRS begins with a fever and can develop into a potentially fatal capillary leakage condition with hypoxia and hypotension (Frey and Porter 2019). CRS is the result of the activation of T cells following contact between CAR-T cells and their target cells, leading to a systemic inflammatory response, with IL-6 being a significant participant in CRS (Schubert et al. 2021). Since evidence-based guidelines for the management of CRS are not yet available, physicians should base their judgments on the unique clinical situations of each patient (Schubert et al. 2021). Clinical trials have shown that CRS is regulated by the gut microbiome and that the development of CRS is associated with alterations in the specific gut microbiome (Hu et al. 2022). This finding reveals the potential of the gut microbiome to become a novel biomarker for predicting treatment outcome and CRS severity, thus optimizing CRS management. In conclusion, cancer immunotherapy has unique limitations that should be addressed in clinical applications, and scientists should explore novel biomarkers to assist in clinical diagnosis and treatment based on the gut microbiome. While A. muciniphila, as an important component of the gut microbiome, has been shown to be related to the enhancement of the efficacy of PD-1, so whether it can play an active role in the clinical application of cancer immunotherapy and its specific mechanisms merits more attention.

Effects of A. muciniphila on the human immune system and different disorders

Immune function of A. muciniphila

In 2004, Derrien et al. identified a new mucin-degrading bacteria in the human intestine: A. muciniphila, which is an ellipsoidal Gram-negative bacterium that colonizes the intestine in early life (Derrien et al. 2004, 2008). A. muciniphila induces cytokine production and adaptive immune response, as well as improves intestinal and mucosal barrier function through toll-like receptor (TLR), which shows its immune function (Ansaldo et al. 2019; Ghotaslou et al. 2023).

A. muciniphila, as the "star intestinal bacterium" in recent years, has received a lot of attention from scientists for its mechanism of interaction with the host immune system, and after nearly a decade of research, the immunomodulatory mechanism of A. muciniphila has been gradually revealed. A. muciniphila can trigger intestinal adaptive immune responses by inducing immunoglobulin G1 (IgG1), immunoglobulin A (IgA), and antigen-specific T cell responses that is limited to T follicular helper (T_FH) cells during homeostasis (Ansaldo et al. 2019). Besides, the lipopolysaccharide (LPS) of A. muciniphila stimulated peripheral blood mononuclear cells (PBMCs) to produce IL-8, IL-6 and small amounts of IL-10 and tumor necrosis factor (TNF-α) via TLR4, while an outer membrane protein of A. muciniphila, Amuc_1100, is a strong TLR2 activator that induces IL-1β, IL-6, IL-8, IL-10, and TNF-α production in PBMCs (Ottman et al. 2017). Additionally, the active component of A. muciniphila, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), can promote the secretion of TNF-α and IL-6 via TLR2-TLR1 heterodimers (Bae et al. 2022). Due to the fact that these cytokines are involved in immune response, immunomodulation, and inflammatory response, playing an important role in maintaining a normal host immune system, A. muciniphila cannot be explicitly classified as anti- or pro-inflammatory but may instead have a more complex role in preserving the balance of the gut ecosystem (Ottman et al. 2017; Ozato et al. 2002). Thus, A. muciniphila has the ability to regulate the host immune response in the above-mentioned manner. What’s more, A. muciniphila can activate colonic RORγt regulatory T cell (Treg)-mediated immune responses via TLR4 in colitis (Liu et al. 2022). RORγt Treg cells stand for a stable regulatory T-cell effector lineage that have enhanced anti-inflammatory and immune-suppressive properties during colitis, thus mitigating colitis to maintain intestinal homeostasis (Liu et al. 2022). Moreover, A. muciniphila can induce the proliferation of intestinal stem cells, which have the ability to repair the damaged intestinal barrier, by activating the Wnt/β-catenin signaling pathway, thus maintaining the integrity of the intestinal mucosal tissue barrier (Ring et al. 2014; Zhu et al. 2020). The mucosal tissue barrier is a component of the mucosal immune system, and therefore this contributes to the immune role of the intestinal mucosal immune system (Ahluwalia et al. 2017). In summary, the immune function of A. muciniphila is mainly related to T/B cell-mediated adaptive immune response and mucosal immunity, but the specific mechanisms need to be further investigated. A. muciniphila can participate in immunomodulation by inducing the production of numerous cytokines and antibodies, but scientists have not revealed how it maintains a balance of pro- or anti-inflammatory factors, so it is not clear what role A. muciniphila can play in the case of intestinal homeostasis or invasion by different pathogenic factors. Figure 2 illustrates how A. muciniphila regulates the human immune system.

Fig. 2.

The mechanisms by which A. muciniphila regulates the human immune system. A. muciniphila can activate colonic RORγt Treg-mediated immune responses via TLR4, thus mitigating colitis to maintain intestinal homeostasis. The LPS of A. muciniphila stimulated PBMCs to produce IL-8, IL-6 and small amounts of IL-10 and TNF-α via TLR4. An outer membrane protein of A. muciniphila, Amuc_1100, induced IL-1β, IL-6, IL-8, IL-10, and TNF-α production in PBMCs via TLR2. A diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE) of A. muciniphila, can promote the secretion of TNF-α and IL-6 via TLR2-TLR1 heterodimers. A. muciniphila preserves the balance of the gut ecosystem by inducing these previously mentioned anti- or pro-inflammatory cytokines. A. muciniphila can trigger intestinal adaptive immune responses by inducing IgG1, IgA, and antigen-specific T cell responses that is limited to T_FH cells during homeostasis. A. muciniphila can induce the proliferation of intestinal stem cells, which have the ability to repair the damaged intestinal barrier, by activating the Wnt/β-catenin signaling pathway, thus maintaining the integrity of the intestinal mucosal tissue barrier. (Created with BioRender.com). A. muciniphila, Akkermansia muciniphila, Treg regulatory T cell, TLR toll-like receptor, LPS lipopolysaccharide, IL-8 interleukin 8, PBMCs peripheral blood mononu clear cells, TNF-α tumor necrosis factor, IgG1 immunoglobulin G1, Ig A immunoglobulin A, T_FH T follicular helper

The beneficial impacts of A. muciniphila in preventing the development of various diseases

A. muciniphila has a metabolic regulatory function except for its powerful immune function, which allows it to exert a protective effect against a wide range of diseases. Most of the studies related to A. muciniphila have focused on its ability to manage obesity induced by high-fat diet (HFD): three newly isolated strains of A. muciniphila from the human intestine (EB-AMDK 10, EB-AMDK 19 and EB-AMDK 27) inhibited weight gain, calorie intake, adiposity, lipogenesis, total serum cholesterol levels and inflammatory damage in HFD-induced obesity mice, suggesting that A. muciniphila is effective in preventing HFD-induced obesity and associated metabolic disorders (Yang et al. 2020). To date, the role of A. muciniphila in reducing obesity has been partially elucidated: the regulation of adipose tissue storage and metabolism as well as the maintenance of the integrity of the intestinal barrier to reduce inflammation (Everard et al. 2013; Lee et al. 2022; Lukovac et al. 2014; Reunanen et al. 2015). Table 2 provides detailed information on the processes through which A. muciniphila reduces obesity. Additionally, negative associations have been reported for A. muciniphila in diseases such as diabetes, fatty liver disease (FLD), and inflammatory bowel disease (IBD), and numerous studies have revealed the modulatory effects of A. muciniphila on these diseases (Ghotaslou et al. 2023). Table 2 summarizes some of the mechanisms that A. muciniphila modulates these diseases. However, further mechanisms by which A. muciniphila improves related diseases remain to be studied. Moreover, compared with animal experiments, A. muciniphila is still less studied in human, and its safety and efficacy need to be further clearly verified.

Table 2.

Possible mechanisms of A. muciniphila in the amelioration of related diseases

Diseases	Possible mechanisms	Research methods	Significance	References
Obesity	(a) A. muciniphila has the ability to reduce the expression of proteins involved in adipocyte differentiation, fatty acid metabolism and energy metabolism in adipocytes (b) Treatment with A. muciniphila under HFD conditions increases the mRNA expression of markers of adipocyte differentiation and promoted lipid oxidation, without affecting lipogenesis markers, demonstrating that A. muciniphila affects adipose tissue metabolism (c) A. muciniphila and its metabolite propionate also involve in the expression of various transcription factors and genes that regulate cellular lipid metabolism, such as Fiaf, Gpr43, HDACs and PPARγ, all of which are essential for modulation of transcription factors, control of cell cycle, lipolysis and satiety (d) A. muciniphila can adhere to enterocytes and reduce the occurrence of endotoxemia in HFD-induced obese mice, suggesting that it helps maintain the integrity of the intestinal barrier in obese individuals thereby reducing the occurrence of obesity-related diseases (e) A. muciniphila administration increases the levels of endocannabinoids in the intestine, which could control inflammation, thus reversing metabolic endotoxemia in vivo	Cell experiments (a, d); animal experiments (b, c, e)	A. muciniphila may be effective biotherapeutics for reducing obesity	Everard et al. (2013); Lee et al. (2022); Lukovac et al. (2014); Reunanen et al. (2015)
Diabetes	(a) Pasteurized A. muciniphila increases insulin sensitivity and decreases total plasma cholesterol (b) The glucagon-like peptide-1-inducing protein secreted by A. muciniphila helps mice maintain better glucose homeostasis	Human experiments (a); animal experiments (b)	Supplementation with A. muciniphila is safe and well tolerated, improving several metabolic parameters	Depommier et al. (2019); Yoon et al. (2021)
FLD	A. muciniphila suppresses the expression of the SREBP gene, which is involved in the synthesis of triglycerides in vivo, and inhibits the release of IL-6, which is involved in liver inflammation, thereby preventing FLD	Animal experiments	The relationship between A. muciniphila administration and FLD provides possible therapeutic targets for clinical practice	(Kim et al. 2020)
IBD	(a) A. muciniphila improves colonic mucosal barrier damage (b) A. muciniphila induces modification of the gut microbiome (c) A. muciniphila modulates the inflammatory response such as inhibiting the expression of pro-inflammatory cytokines (TNF-α, IL-6, IFN-γ and IL-1α) and promoting the production of anti-inflammatory cytokine (IL-10)	Animal experiments	A. muciniphila may be a potential probiotic agent for ameliorating colitis	Bian et al. (2019)

A. muciniphila Akkermansia muciniphila, HFD high-fat diet, FLD fatty liver disease, IBD inflammatory bowel disease, Fiaf fasting-induced adipose factor, Gpr43 G protein-coupled receptor 43, HDACs histone deacetylases, PPARγ peroxisome proliferator-activated receptor gamma, SREBP sterol regulatory element binding protein, TNF-α tumor necrosis factor, IL-6 interleukin 6, IFN-γ interferon-γ

More notably, a growing number of studies in recent years have shown that A. muciniphila is closely associated with cancer and plays an important role in its development and treatment (Ghotaslou et al. 2023). Previous studies have revealed that reduced abundance of A. muciniphila is associated with the development of many malignancies and that A. muciniphila has a positive role in oncotherapy (Niederreiter et al. 2018). It has been shown that the recombinant protein Amuc_1434 (Amuc_1434*), derived from A. muciniphila, degraded the major component of the intestinal mucosal layer Mucin2 (Muc2), thus inhibiting the proliferation of CRC cells LS174T; Amuc_1434* also blocked the G0/G1 phase of the LS174T cell cycle and upregulated the expression of tumor protein 53 (p53), a cell cycle-related protein; Amuc_1434* promoted apoptosis in LS174T cells and increased reactive oxygen species (ROS) in mitochondria in LS174T cells; Amuc_1434* could also activate the death receptor pathway and the mitochondrial pathway of apoptosis by upregulating tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL), thereby inhibiting LS174T cell viability (Meng et al. 2020). Therefore, A. muciniphila prevents CRC development and progression through the aforementioned pathways. Another experiment revealed that A. muciniphila-derived extracellular vesicles (Akk-EVs) reduced the tumor load of prostate cancer (PCa) without causing significant toxicity in normal tissues, and the mechanism may be that Akk-EVs raised the proportion of granzyme B-positive (GZMB⁺) and interferon gamma-positive (IFN-γ⁺) lymphocytes in cluster of differentiation 8 (CD8)-positive T cells, induced macrophage recruitment, and increased the number of tumor-killing M1 macrophages while decreased the number of immunosuppressive M2 macrophages, thereby inhibiting the proliferation and invasion of PCa cells (Luo et al. 2021). In just a decade, A. muciniphila has rapidly attracted a lot of attention and research resources in the academic community due to its beneficial effects found in many diseases. Nevertheless, the mechanisms by which A. muciniphila regulates different diseases still need to be further investigated. A new therapeutic approach for the comprehensive clinical treatment of disorders associated with A. muciniphila imbalance, including cancer, will be viable if the precise mechanism and target of A. muciniphila in terms of disease development can be better clarified.

The auxo-action of A. muciniphila on the efficacy of cancer immunotherapy

The selection of appropriate biomarkers to regulate and optimize cancer immunotherapies in response to the limitation and adverse effects that occur in the clinical application of cancer immunotherapies is crucial, which can achieve precision medicine. The homeostasis of the gut microbiome is essential for maintaining the health of the host, and the disordered gut microbiome is involved in the development of cancer, so scientists optimize oncotherapy targeted for the gut microbiome (Gopalakrishnan et al. 2018). When contrasting the fecal microbiome of patients treated with anti-PD-1 antibodies or anti-PD-L1 antibodies for different types of malignancies, significantly higher levels of A. muciniphila in the feces of partial responders compared to non-responders was observed (Routy et al. 2018b). Further animal experiments demonstrated that A. muciniphila contributes to the therapeutic efficacy of PD-1 via FMT (Routy et al. 2018b). A few more studies have also shown that A. muciniphila is associated with PD-1/PD-L1, becoming a major contributor to the clinical application of PD-1/PD-L1 (Ansaldo et al. 2019; Derosa et al. 2022). Its positive effect in PD-1 therapeutic efficacy may depend on the T helper 1 (Th1) cell cytokine IL-12 secreted by dendritic cells (DCs), and is associated with a reduction of forkhead box protein P3 (Foxp3)-positive Tregs in tumor infiltrating CD4⁺ T cell populations as well as the formation of intratumoral granulomas (Routy et al. 2018a, b). Researchers colonized mice with feces from responders whose feces are rich in A. muciniphila and non-responders to PD-1 treatment separately and found differences in the immune TME between the two groups of mice: tumor resident cytotoxic CD8⁺ IFN-γ⁺ T cells were increased in responder-colonized mice compared to non-responder mice (Newsome et al. 2022). What’s more, responder tumors had significantly more CD4⁺ T cells expressing CXC-chemokine receptor 3 (CXCR3) and researchers also found that increased numbers of intra-tumor neutrophils as well as tumor-associated macrophages (TAMs) in the TME of responder-colonized tumors (Newsome et al. 2022). These findings suggest that, in contrast to the non-responder microbiome-colonized mice, the immune TME of responder microbiome-colonized mice exhibits an anti-tumor cellular phenotype after anti-PD-1 treatment (Newsome et al. 2022). Besides, A. muciniphila may maintain the normal efficacy of anti-PD-1 antibodies by influencing the metabolism of glycerophospholipid to stimulate the expression of IFN-γ and IL-2 in the TME, because promoting IFN-γ and IL-2 production may be associated with inhibiting PD-1/PD-L1 binding, which can greatly improve the killing effectiveness of effector-target cells (Xu et al. 2020). A. muciniphila can also produce stimulator of interferon genes (STING) agonist cyclic diadenylate AMP (cdAMP), which reshapes the innate immune tumor microenvironment and improves the anti-tumor response via the type I interferon (IFN-I)–natural killer (NK)–dendritic cell (DC) axis, thus promoting the efficacy of PD-1 (Lam et al. 2021). In summary, A. muciniphila has been shown to be a beneficial bacterium in PD-1/PD-L1 treatment, so it may be possible to deliver A. muciniphila to the intestine of patients via FMT to re-establish immune checkpoint blockade in non-responders. However, the use of A. muciniphila is limited since the safety of FMT has not yet been fully established, and there are still potential risks that could arise from the clinical application of FMT, including infections and brief side effects, such as constipation, diarrhea, bloating and even death (Fong et al. 2020). The potential mechanisms through which A. muciniphila improves the effects of PD-1 therapy is displayed in Fig. 3.

Fig. 3.

The possible mechanisms by which A. muciniphila enhances the efficacy of PD-1/PD-L1 treatment. In mice, oral gavage with A. muciniphila from patients who had a response (responders) to PD-1 increased IL-12 production by DCs, thereby passing CD4⁺ CCR9⁺ TCM cells from mLNs to TME via tumor dLNs. Moreover, Foxp3⁺ Tregs reduced in these mice. Tumor resident cytotoxic CD8⁺ IFN-γ⁺ T cells, CD4⁺ T cells expressing CXCR3, intra-tumor neutrophils and TAMs in the TME were increased in the mice colonized with feces from responders whose feces are rich in A. muciniphila, thus enhancing the efficacy of PD-1 therapy. Additionally, to regulate macrophage polarization and NK-DC crosstalk, A. muciniphila can produce STING agonist cdAMP, which stimulates intratumoral monocytes to release IFN-I. NK cells are the primary source of DC recruiting chemokines XCL1 and CCL5. In response to IFN-I, these DCs produce IL-15/IL-15R that support and activate NK cells, triggering a positive feedback loop to promote anti-tumor immunity. Besides, mice whose gastrointestinal tract is rich in A. muciniphila responded actively to PD-1 antibody immunotherapy for the reason that A. muciniphila may inhibiting PD-1/PD-L1 binding to maintain the normal efficacy of anti-PD-1 antibodies by influencing the metabolism of glycerophospholipid to stimulate the expression of IFN-γ and IL-2 in the TME (Created with BioRender.com). A. muciniphila, Akkermansia muciniphila, PD-1 programmed death receptor 1, IL-12 interleukin 12, DCs dendritic cells, CD4 cluster of differentiation 4, CCR9 CC-chemokine receptor 9, TCM central memory T, mLNs mesenteric lymph node, TME tumor microenvironment, dLNs draining lymph nodes, Foxp3 forkhead box protein P3, Tregs regulatory T cells, IFN-γ interferon-γ, CXCR3 CXC-chemokine receptor 3, TAMs tumor-associated macrophages, STING stimulator of interferon genes, cdAMP cyclic diadenylate AMP, IFN-I, type I interferon, NK natural killer, DC dendritic cell, XCL1 C-chemokine ligand 1, CCL5 CC-chemokine ligand 5, IL-15R interleukin 15 receptor, PD-L1 programmed death ligand 1

Furthermore, oral administration of A. muciniphila in mice with CRC significantly enhanced the therapeutic response of IL-2, and the combination treatment of IL-2 and A. muciniphila had a stronger anti-tumor effect on tumor cells derived from CRC patients (Shi et al. 2020). IL-2 is also a way of cancer immunotherapy, and it can be combined with ICIs to treat tumors, so the adjuvant effect of A. muciniphila on IL-2 has greatly expanded the clinical application of cancer immunotherapy. A. muciniphila has been demonstrated to be effective in lung cancer chemotherapy in addition to playing an adjuvant role in cancer immunotherapy (Chen et al. 2020). A. muciniphila combined with cisplatin (CDDP) can upregulate the levels of factor-associated suicide (Fas) proteins, INF-γ, IL-6, and TNF-α, while downregulating the levels of ki-67, p53, and Fas ligand proteins. They can also inhibit the expression of CD4⁺ CD25⁺ Foxp3⁺ Tregs in the peripheral blood and spleen of mice, thus enhancing immunomodulation and exerting anti-tumor effects in mice with lung cancer (Chen et al. 2020). Chemotherapy can be combined with ICIs, so this finding reveals that A. muciniphila may have a beneficial anti-tumor effect when ICIs and chemotherapy are used together. Taken together, A. muciniphila can directly enhance the anti-tumor effect of PD-1/PD-L1 or enhance the effect of other anti-tumor methods to indirectly enhance the anti-tumor effect of these means combined with PD-1/PD-L1. However, the current research on A. muciniphila to enhance the efficacy of cancer immunotherapy is basically limited to PD-1/PD-L1 in ICIs, so future studies should also focus on determining the impacts of A. muciniphila on other cancer immunotherapies and the mechanisms involved.

Potential clinical applications of A. muciniphila in oncotherapy: prevention and diagnosis

Given the positive role of A. muciniphila in cancer immunotherapy, A. muciniphila has great potential to be used against tumor in clinical, while A. muciniphila can also play an important role in the prevention and diagnosis of cancer. Studies have shown that feeding A. muciniphila suppresses colorectal tumorigenesis in mice, and the safety and tolerability of oral administration of A. muciniphila to obese patients have been demonstrated (Depommier et al. 2019; Fan et al. 2021). Therefore, perhaps A. muciniphila could be directly supplemented to patients as a novel oral probiotic to prevent tumorigenesis. However, its safe dosage in humans, suitable crowd, and comprehensive medication regimen need to be investigated.

A. muciniphila also predicted clinical response to PD-1 blockade in patients with advanced NSCLC (Derosa et al. 2022). Akk⁺ patients had longer survival than Akk⁻ patients, and researchers verified in mice that Akk⁻ feces conferred resistance to PD-1, but Akk^high (overabundance of Akk > 4.799) resulted in shorter survival compared with a normal Akk abundance (“normal” relative abundance of Akk < 4.799), which may reflect an underlying pathophysiological disturbance of the intestinal barrier in patients with advanced cancer (Derosa et al. 2022). This study reveals the potential of A. muciniphila in predicting the sensitivity of PD-1 treatment. Thus, A. muciniphila is anticipated to play a predictive role as an emerging biomarker in clinical diagnosis and prognosis. We expect more prospective studies in the future to reveal the role of A. muciniphila in cancer prevention and diagnosis, thus providing more ideas for clinical oncotherapy.

Conclusion

In the past few years, the gut microbiome and its association with cancer development and treatment have been intensively studied. Researchers have looked into how the immune metabolism of specific microbiome is regulated. Currently, there is a growing interest in A. muciniphila because of its positive effects on the human immune system and its ability to influence cancer development and treatment. A. muciniphila has been proven to improve the effectiveness of cancer immunotherapies, and may also serve as a biomarker to predict prognosis. However, there are many aspects of research on the relationship between A. muciniphila and cancer immunotherapy that merit investigation. First, research on how A. muciniphila can improve cancer immunotherapy has largely been focused on PD-1/PD-L1, but its impact and mechanism on other cancer immunotherapies have not been well understood. Second, the gut microbiome can help a number of cancer immunotherapy drawbacks, including irAEs and drug resistance, but it’s not clear if A. muciniphila alone can do so. Third, it's still not known how A. muciniphila should be supplemented by the human body in various situations, so more precise confirmation of its safety, tolerability and efficacy in clinical applications in cancer patients is needed. Overall, A. muciniphila has beneficial effects in the fight against cancer, opening up innovative and promising therapeutic options for cancer patients, but more research is still needed.

Abbreviations

A. muciniphila

Akkermansia muciniphila

IL-2

Interleukin 2

RCC

Renal cell carcinoma

ICIs

Immune checkpoint inhibitors

ACT

Adoptive cell therapy

irAEs

Immune-related adverse events

PD-1

Programmed death receptor 1

PD-L1

Programmed death ligand 1

CTLA-4

Cytotoxic T lymphocyte antigen 4

FDA

Food and Drug Administration

UC

Urothelial carcinoma

TNBC

Triple-negative breast cancer

OS

Overall survival

PFS

Progression-free survival

HER2

Human epidermal growth factor receptor-2

VEGF

Vascular endothelial growth factor

VEGFR

Vascular endothelial growth factor receptor

IFN-γ

Interferon-γ

CAR

Chimeric antigen receptor T

NSCLC

Non-small-cell lung cancer

gp 100

Glycoprotein 100

MSI-H

Microsatellite-instability-high

dMMR

Mismatch repair-deficient

mCRC

Metastatic colorectal cancer

HCC

Hepatocellular carcinoma

CPS

Combined positive score

ES-SCLC

Extensive-stage small-cell lung cancer

CRC

Colorectal cancer

TME

Tumor microenvironment

FMT

Fecal microbiota transplantation

ESMO

European Society for Medical Oncology

CPG

Clinical Practice Guideline

TGF-β

Transforming growth factor-β

CRS

Cytokine release syndrome

ICANS

Immune effector cell-associated neurotoxicity syndrome

CAR-T

Chimeric antigen receptor T-cell immunotherapy

Treg

Regulatory T cell

TLR

Toll-like receptor

LPS

Lipopolysaccharide

PBMCs

Peripheral blood mononuclear cells

TNF-α

Tumor necrosis factor

IgG1

Immunoglobulin G1

IgA

Immunoglobulin A (IgA)

T_FH

T follicular helper

HFD

High-fat diet

FLD

Fatty liver disease

IBD

Inflammatory bowel disease

Muc2

Mucin2

p53

Protein 53

ROS

Reactive oxygen species

TRAIL

Tumor-necrosis-factor-related apoptosis-inducing ligand

Akk-EVs

A. muciniphila-derived extracellular vesicles

PCa

Prostate cancer

GZMB

Granzyme B

CD8

Cluster of differentiation 8

Fiaf

Fasting-induced adipose factor

Gpr43

G protein-coupled receptor 43

HDACs

Histone deacetylases

PPARγ

Peroxisome proliferator-activated receptor gamma

SREBP

Sterol regulatory element binding protein

Th1

T helper 1

DCs

Dendritic cells

Foxp3

Forkhead box protein P3

TME

Tumor microenvironment

CXCR3

CXC-chemokine receptor 3

TAMs

Tumor-associated macrophages

STING

Stimulator of interferon genes

cdAMP

Cyclic diadenylate AMP

IFN-I

Type I interferon

NK

Natural killer

DC

Dendritic cell

XCL1

C-chemokine ligand 1

CCL5

CC-chemokine ligand 5

IL-15R

Interleukin 15 receptor

CDDP

Cisplatin

Fas

Factor-associated suicide

Author contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by grants from the Graduate Research- Innovation Project in Jiangsu province (SJCX22_1816), the Graduate Research and Practice Innovation Plan of Graduate Education Innovation Project in Jiangsu Province (No. SJCX211644), Social development project of key R & D plan of Jiangsu Provincial Department of science and technology (BE2022773), and Hospital level management project of Subei People's Hospital YYGL202228, the Social Development-Health Care Project of Yangzhou, Jiangsu Province (No. YZ2021075).

Availability of data and material

Not applicable.

Declarations

Conflict of interest

The authors declare that they have no competing interests.