Impact of Oral and Gut Microbiota Dysbiosis in Patients with Multiple Myeloma and Hematological Malignancies: A Narrative Review

Abstract

The interplay between the oral and gut microbiota and systemic health has garnered significant attention in recent years, particularly concerning hematological malignancies. Multiple myeloma and other hematological cancers are characterized by immune dysfunction, creating a bidirectional relationship with microbial communities. Dysbiosis, defined as an imbalance in microbial composition, may influence disease progression, treatment response, and overall prognosis. This narrative review is based on a non-systematic search of PubMed and Scopus (2010–2024) using terms related to oral microbiota, gut microbiota, dysbiosis, hematological malignancies, multiple myeloma, immune modulation, and treatment-related complications. Studies were selected for relevance to pathogenesis, immune regulation, clinical implications, and therapeutic interactions. As this is a narrative review, no quantitative synthesis or formal grading of evidence strength was performed; findings are therefore interpreted qualitatively based on the available literature. The role of microbial-derived metabolites, their effects on immune modulation, and their potential as biomarkers for disease and treatment outcomes have been explored. Specific attention is given to the implications of dysbiosis in chemotherapy-induced complications, such as mucositis and infections, and emerging therapeutic strategies, including probiotics, prebiotics, and fecal microbiota transplantation. Additionally, the influence of anticancer therapies on microbial ecosystems has been highlighted and the bidirectional impact of host–microbe interactions in shaping disease trajectory has been discussed. Understanding these complex interactions could lead to novel diagnostic and therapeutic approaches, ultimately improving patient outcomes. This review aims to provide clinicians and researchers with a comprehensive overview of current knowledge and future perspectives on the role of oral and gut microbiota in the context of hematological malignancies.

1. Introduction

Hematologic malignancies are a heterogeneous group of cancers that originate in the blood, bone marrow, and lymphatic system, including multiple myeloma, leukaemia, and lymphoma [1]. These conditions are characterized by the uncontrolled proliferation of hematopoietic cells, resulting in severe systemic implications. Alterations in the bone marrow microenvironment, immune dysregulation, and associated comorbidities contribute to the complexity of the clinical picture and variability of therapeutic responses [2]. The altered immune landscape can compromise the body’s defense mechanisms, making patients more susceptible to infections, inflammation, and secondary complications. In addition, treatments such as chemotherapy and stem cell transplantation further disrupt immune homeostasis, compounding these challenges [3]. Additionally, emerging evidence suggests that factors such as genetic predisposition, environmental influences, and lifestyle choices may also play significant roles in the pathogenesis of these malignancies [4].

The human microbiota, particularly those residing in the oral cavity and gut, is increasingly recognized as contributing to the maintenance of systemic health. These microbial communities participate in essential functions, such as nutrient metabolism, immune system modulation, and the maintenance of mucosal barriers [5]. The gut microbiota is the largest in the human body, containing more than 10 trillion microbes. These microbial ecosystems, composed of bacteria, archaea, viruses, fungi, and protozoa, influence innate and adaptive immunity, modulate metabolism, and protect against pathogen invasion [6]. The oral microbiota is the second largest after the intestinal microbiota, colonizing teeth, prosthetic surfaces, and mucosa, and forming adherent communities such as dental plaque [7]. Saliva also contains many oral bacteria. The composition of the oral microbiota includes over 700 bacterial species, as well as fungi, viruses, and protozoa [7]. Notably, the dynamic interplay between these microbiota can have profound implications for systemic health, as disturbances in one may influence the other, thereby affecting disease progression and overall immune responses [8].

The oral and intestinal microbiota should not be considered independent ecosystems. Oral bacteria are continuously swallowed with saliva and may reach the gastrointestinal tract, while inflammation, diet, and treatment-related mucosal injury can reshape both communities [5]. This oral–gut crosstalk involves barrier integrity, microbial metabolites, and mucosal immune signaling. In dysbiosis, barrier disruption may favor microbial translocation and systemic inflammation, potentially affecting immune competence and hematopoiesis [9]. Thus, assessing both niches may inform disease course and therapy-related complications.

New evidence highlights that microbiota not only reflect systemic health but also actively contribute to disease processes [10]. In fact, alterations in the composition and functionality of the microbiota, defined as dysbiosis, have been associated with various systemic diseases, including chronic inflammatory diseases, metabolic diseases, cardiovascular diseases, neurodegenerative diseases, autoimmune diseases and cancer [5]. In hematological malignancies, the most clinically relevant pathways link gut dysbiosis to systemic immune modulation, mucosal barrier integrity, and bone marrow–immune homeostasis [11]. Additionally, the role of the gut microbiota in hematopoiesis and immune cell differentiation is becoming an area of increasing interest, as specific microbial metabolites, such as short-chain fatty acids and secondary bile acids, have been implicated in modulating immune responses and influencing hematological malignancy progression [12].

In hematological malignancies, bidirectional interactions between the host immune system and microbial ecosystems are particularly critical, influencing disease progression and treatment outcomes [9]. It was seen that gut microbiota composition influences the efficacy and toxicity of chemotherapy, immunotherapy, and hematopoietic stem cell transplantation [13]. For example, beneficial commensal bacteria may enhance immune checkpoint inhibitor responses, while pathogenic bacteria could contribute to adverse treatment-related complications, such as graft-versus-host disease (GVHD) and mucositis [14]. Moreover, emerging research is exploring how modulation of microbiota, through dietary interventions, prebiotics, probiotics, and fecal microbiota transplantation, could optimize therapeutic strategies and improve patient outcomes [15].

This topic is particularly relevant in hematologic malignancies—and in multiple myeloma in particular—where immune dysfunction, prolonged treatment exposure, and frequent use of antibiotics and supportive therapies may amplify microbiota perturbations over time [4]. Moreover, mucosal complications and barrier disruption can increase vulnerability to infections and inflammatory sequelae, potentially impacting both quality of life and treatment continuity. Despite growing interest, the evidence remains fragmented, with gut-focused studies often outnumbering investigations on the oral niche and on the integrated oral–gut axis [8]. A clearer synthesis is needed to delineate consistent dysbiotic patterns, plausible mechanisms, and clinically meaningful microbial markers that could inform risk stratification or future interventional strategies [12].

Based on the above-mentioned evidence, this narrative review analyzes the interaction between oral and gut microbiota and hematological malignancies, with a focus on multiple myeloma. The role of microbial dysbiosis in immune regulation, disease progression, and treatment response is explored, also highlighting the potential of microbial metabolites as biomarkers. Furthermore, these microbial-derived molecules can modulate host immune responses and influence disease progression. Chemotherapy-induced complications and emerging therapeutic strategies, such as probiotics and fecal microbiota transplantation, are also evaluated.

2. Materials and Methods

From May to July 2025, an open literature search without time restrictions was performed in major electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar. This narrative review was developed by selecting articles according to the following inclusion criteria: (1) articles written in English; (2) studies addressing the interaction between oral and/or gut microbiota (including dysbiosis and microbial metabolites) and hematological malignancies, with particular attention to multiple myeloma; (3) study designs including in vivo and in vitro studies, prospective and retrospective studies, cross-sectional studies, narrative reviews, systematic reviews, and meta-analyses. Articles were excluded if they were (1) not available in English; (2) not relevant to oral/gut microbiota in hematological malignancies; or (3) opinion papers, editorials, or conference abstracts without full text. This was a narrative and non-systematic review; therefore, the included studies do not represent an exhaustive or comprehensive sample of all available literature. No systematic screening, risk-of-bias assessment, or quantitative synthesis was performed. As a result, the selection of evidence may be subject to selection bias, and the findings should be interpreted accordingly.

3. The Oral and Gut Microbiota: An Overview

3.1. Composition and Functions of Oral and Gut Microbiota

The human body is colonized by trillions of symbiotic microorganisms, and environmental differences across body sites shape distinct microbial ecosystems. Among these, the gastrointestinal tract and the oral cavity harbour highly diverse microbial communities [16]. The human gut microbiota consists of bacteria, archaea, eukaryotes, viruses, and parasites [17]. The intestinal environment primarily supports the growth of bacteria from seven dominant phyla: Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria, Proteobacteria, Verrucomicrobia, and Cyanobacteria, with Firmicutes and Bacteroidetes making up over 90% of the total population [18]. The gastrointestinal (GI) tract is divided into the stomach, small intestine (SI), and large intestine (LI), each characterized by distinct microbial compositions due to specific physical and chemical barriers: for example the stomach, once thought to be sterile, the stomach hosts acid-resistant bacteria like Streptococcus and Lactobacillus, as well as Helicobacter pylori, which originates from the oral cavity [19]. SI is divided into the duodenum, jejunum, and ileum and is crucial for digestion and absorption. The duodenum has low bacterial density, while the jejunum supports a higher load, primarily of Lactobacilli and Streptococci. The ileum hosts anaerobic and Gram-negative bacteria [20]. Moreover, the large intestine (LI) is essential for water absorption and fermentation, with a dense microbiota dominated by Firmicutes and Bacteroidetes. The Firmicutes/Bacteroidetes ratio is a health marker, and key genera include Bacteroides, Bifidobacterium, and Clostridium, with some pathogens present in low abundance [21].

The gut microbiota exerts its function in four different domains of the human body: metabolic, structural protective, and neurological [18]. The metabolic function of the gut microbiota is essential for nutrient metabolism. It aids in the digestion of carbohydrates, proteins, and fats, thereby facilitating efficient absorption of nutrients [22]. By fermenting indigestible dietary fibres, the microbiota produces short-chain fatty acids (SCFAs), such as butyrate, which serves as an important energy source for intestinal cells. These metabolites also influence glucose and lipid metabolism, contributing to the regulation of body weight and insulin sensitivity [23]. The structural function of the gut microbiota is vital for maintaining the integrity and functionality of the intestinal mucosa [21]. The microbiota produces molecules that promote the synthesis of the extracellular matrix and strengthen cell junctions, enhancing the barrier properties of the intestinal lining [24]. This barrier prevents the passage of pathogens and toxins into the bloodstream, maintaining the balance of the intestinal ecosystem and preventing inflammatory diseases. The protective function of the gut microbiota plays a key role in host defence against external pathogens. Beneficial bacteria compete with pathogens for resources and adhesion sites on the intestinal mucosa, thereby reducing the risk of infections [25]. Furthermore, the microbiota stimulates the host’s immune response by activating immune cells and inducing the production of anti-inflammatory molecules [24]. A healthy composition of the microbiota is therefore essential for preventing infectious and inflammatory diseases [12]. Lastly, the neurological function of the gut microbiota is increasingly recognized in the communication between the gut and the brain, known as the gut–brain axis [11]. The microbiota produces neurotransmitters and signalling molecules that influence mood and behaviour [26].

The oral cavity is the second-largest microbial ecosystem after the gut, hosting more than 770 bacterial species. The heterogeneity of oral surfaces, including teeth, mucosa, palate, and tongue, promotes the growth of a wide range of microorganisms, including bacteria, fungi, and viruses [27]. Bacteria, the main components of the oral microbiome, form specific communities depending on their colonization site and primarily belong to the phyla Firmicutes, Fusobacteria, Proteobacteria, and Actinobacteria, sometimes affected by chemical oral formulations or delivery agents as chlorhexidine [28]. The structural and nutritional differences within the oral cavity contribute to creating a unique microbial ecosystem essential for human health.

The commensal oral microbiota plays a crucial role in maintaining oral health, primarily by preventing the colonization of pathogens. Certain bacteria, such as Streptococcus sanguinis and Actinomyces naeslundii, hinder Porphyromonas gingivalis from adhering to oral surfaces, while species like Lactococcus lactis produce nisin, a bacteriocin with potential antitumor effects [29]. Additionally, the oral microbiota contributes to nitrate metabolism, promoting nitric oxide production, which exerts beneficial effects on cardiovascular health [30]. Finally, some commensal bacteria participate in helping buffer oral acidity, maintaining pH homeostasis and reducing the risk of dental caries [31].

The oral cavity and the intestinal tract are key components of the digestive system, each hosting a distinct yet interconnected microbiota. Interactions between the oral and gut microbiota occur through multiple pathways, including enteric, hematogenous, and immune routes, all of which play a crucial role in modulating the oral–gut microbiota axis [32] (Figure 1).

3.2. Interactions Between Microbiota and Host Immune System

The microbiota plays a crucial role in shaping the host’s immune system. It contributes to the development of lymphoid structures, the homeostasis and maturation of immune cells, epithelial barrier function, T-cell differentiation, the activation of immune cascades, the production of antimicrobial peptides, influencing inflammation and susceptibility to autoimmune diseases [24].

Moreover, the microbiota influences the host’s biosynthesis of vitamins, hormones, and neurotransmitters, as well as the production of bacterial byproducts such as SCFAs. On the other hand, its composition is influenced by factors such as the host environment, diet, and antibiotic use. Microbial dysbiosis has been associated with various diseases, including gastrointestinal, neurological, metabolic, cardiovascular, and oncological disorders [25,33].

4. Dysbiosis and Haematological Malignancies

4.1. Definition and Characterization of Dysbiosis

Dysbiosis refers to an imbalance in the composition of the microbiota, which includes alterations in the diversity, relative abundance, and functional activity of the microorganisms that colonize the human body [34]. The gut microbiota, composed of trillions of bacteria, viruses, fungi, and other microorganisms, plays a fundamental role in immune modulation, digestion, and maintenance of metabolic homeostasis [35]. Under dysbiosis conditions, the increase in pathogenic species, the reduction in beneficial bacteria, and alterations in the production of microbial metabolites can contribute to chronic inflammatory processes and immune dysfunction, with implications for numerous diseases, including hematological malignancies [36,37].

Dysbiosis can therefore be triggered by three main causes:

• Loss of beneficial microbiota: a reduction in essential commensal bacteria such as Lactobacillus and Bifidobacterium.
• Overgrowth of pathogenic microbes: an increase in opportunistic bacteria such as Clostridium difficile or Escherichia coli, that disrupts microbial balance.
• Loss of microbial diversity: a decrease in the variety of microbial species, often linked to reduced resilience of the intestinal ecosystem [38].

To diagnose dysbiosis, advanced microbial DNA sequencing techniques, such as 16S rRNA gene sequencing, are used to characterize the composition of the microbiota. In addition, metabolomic analysis can provide insights into alterations in metabolites derived from microbial activity, offering a functional perspective on intestinal imbalances [39].

4.2. Evidence Linking Dysbiosis with Multiple Myeloma and Other Hematological Malignancies

Dysbiosis has been increasingly investigated in hematological malignancies, with studies reporting associations with clinical features and outcomes [9]. Multiple myeloma (MM) is a haematological malignancy characterised by the uncontrolled proliferation of plasma cells in the bone marrow. This leads to the overproduction of abnormal antibodies, immune dysfunction, and complications such as bone lesions, anemia, and renal impairment [40]. In MM, an increase in pro-inflammatory bacteria and a reduction in beneficial species have been observed, which could contribute to the activation of inflammatory and immunosuppressive pathways [41]. For example, one study showed that patients with MM had a higher prevalence of Prevotella and a reduction in Faecalibacterium prausnitzii, a bacterium known for its anti-inflammatory properties [42].

In addition to MM, other haematological malignancies, such as acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), are also associated with intestinal dysbiosis [43]. AML is a malignancy affecting myeloid precursor cells, resulting in the accumulation of abnormal white blood cells that interfere with normal hematopoiesis and increase susceptibility to infections and bleeding disorders [44]. ALL is a rapidly progressing cancer characterized by the excessive proliferation of immature lymphoid cells (lymphoblasts) in the bone marrow, leading to impaired blood cell production and immune system dysfunction [45]. In patients with ALL, a reduced microbial diversity has been found, accompanied by an increase in opportunistic bacteria such as Enterococcus and Streptococcus [43]. Studies in animal models have shown that dysbiosis can increase the growth of leukemic cells by controlling immune responses and creating a microenvironment favorable to tumor proliferation (Figure 2) [46].

4.3. Influence of Immune Dysfunction on Microbial Balance

Haematological malignancies are characterized by immune dysfunction that affects microbiota homeostasis [47]. In MM, disease-related immunodeficiency is characterized by an alteration of regulatory T cells and dendritic cells, which contribute to microbial instability [48]. Furthermore, hypogammaglobulinemia in MM patients impairs the body’s ability to control bacterial infections, facilitating the growth of opportunistic microbes [4] (Figure 3).

Moreover, immune dysfunction is relevant in patients undergoing intensive care [50]. Hematopoietic stem cell transplantation causes severe alterations of the microbiota, with a loss of microbial diversity that is associated with higher rates of mortality and infectious complications [51]. The profound dysbiosis observed in transplant recipients is characterized by a predominance of potentially pathogenic bacteria, such as Enterococcus and Enterobacteriaceae, while beneficial commensals, including Bifidobacterium and Faecalibacterium, are significantly depleted [52]. This imbalance compromises intestinal barrier integrity, promoting bacterial translocation and systemic inflammation, which in turn exacerbates the risk of sepsis, GVHD, and poor overall survival [53].

Recent studies suggest that maintaining a diverse and balanced microbiota can improve clinical outcomes in patients undergoing chemotherapy or stem cell transplantation. Targeted interventions, such as probiotics (live beneficial bacteria) and prebiotics (compounds that promote the growth of good bacteria), help restore microbial balance and support gut health [54]. Another key factor in this process is the role of microbial metabolite small molecules produced by gut bacteria that influence immune function. One important group of these metabolites is SCFAs, which are produced when beneficial bacteria ferment dietary fibers [55]. SCFAs help regulate the immune system by reducing inflammation and maintaining the integrity of the gut barrier. However, dysbiosis leads to diminished SCFAs production, promoting chronic inflammation, weakening the body’s defences and potentially creating an environment that promotes tumour progression [22].

4.4. Role of Antibiotics in the Onset of Dysbiosis

In patients with hematological malignancies, the frequent use of broad-spectrum antibiotics, often required to prevent or treat infections during neutropenia, represents a major factor contributing to dysbiosis [56]. Antibiotics profoundly alter the microbial ecosystem by depleting beneficial commensal species, reducing overall microbial diversity, and favoring the expansion of opportunistic and multidrug-resistant pathogens [57]. These perturbations can persist over time, impair immune reconstitution, and compromise the metabolic and protective functions of the microbiota, thereby exacerbating systemic inflammation and infection risk [58]. In addition, antibiotic-induced dysbiosis may negatively influence treatment outcomes by promoting drug resistance and reducing chemotherapy efficacy, underscoring the importance of antibiotic stewardship and microbiota-preserving strategies in this vulnerable population [59].

5. Microbial-Derived Metabolites and Immune Modulation

5.1. Key Microbial Metabolites and Their Roles in Health and Disease

The gut and oral microbiota produce a vast array of metabolites that influence host physiology, immune responses, and disease progression [60,61]. Among the most studied microbial-derived metabolites are SCFAs, tryptophan metabolites (TRP), polyamines and secondary bile acids.

SCFAs, such as butyrate, propionate, and acetate, are fermentation byproducts of dietary fibre by commensal bacteria [23]. These metabolites play a crucial role in maintaining gut barrier integrity, regulating inflammatory responses, and modulating immune cell function. The oral cavity, as the second most abundant source of these metabolites, highlights its contribution to carbohydrate fermentation [62]. Butyrate, for example, is known to promote regulatory T cell (Treg) differentiation and suppress pro-inflammatory cytokine production, thereby contributing to immune homeostasis [61].

TRP is a rare and essential amino acid obtained exclusively through the diet. In addition to its role in protein synthesis, TRP is metabolized through two main pathways: the kynurenine (KYN) pathway and the serotonin (5-HT) pathway. These processes lead to the production of physiologically active metabolites, including kynurenic acid (KYNA) and NAD+, or 5-HT and melatonin [63]. Dysregulation of tryptophan metabolism has been implicated in immune suppression and cancer progression [26].

Polyamines, such as spermidine and putrescine, regulate cell proliferation, apoptosis, and immune cell differentiation. While essential for normal cellular function, aberrant polyamine metabolism has been linked to tumorigenesis and immune evasion in haematological malignancies [64].

Secondary bile acids, produced by gut bacteria through primary bile acid metabolism, impact immune function by modulating nuclear receptor pathways such as the foresaid X receptor (FXR) and the G-protein-coupled bile acid receptor (TGR5). These pathways influence inflammation, metabolism, and cellular differentiation, potentially affecting cancer progression [65].

5.2. Impact on Immune Regulation in Hematological Malignancies

Haematological malignancies, including multiple myeloma, leukaemia’s, and lymphomas, are characterized by profound immune dysregulation. Microbial-derived metabolites play a dual role, either promoting immune surveillance against malignant cells or contributing to immune evasion and tumour progression [66].

SCFAs have been shown to enhance anti-tumour immunity by promoting the differentiation and function of dendritic cells and cytotoxic T cells. Conversely, alterations in SCFA production due to dysbiosis may lead to chronic inflammation and immune suppression, fostering a tumour-permissive environment [67].

TRP catabolism through the KYN pathway was reported to play immunosuppressive actions across many types of cancer [68]. KYN acts as an oncometabolite by activating the aryl hydrocarbon receptor (AhR), which regulates pro-growth genes. Furthermore, KYN inhibits T cell activity, allowing tumour cells to evade immune surveillance. Therefore, targeting the Kyn pathway has emerged as a therapeutic strategy to counteract tumour growth and immune resistance [69].

Polyamine metabolism is frequently altered in tumours, leading to increased levels of these molecules in the tumour microenvironment. High polyamine concentrations can promote immunosuppression by modulating T cell activation, enhancing regulatory T cell function, and impairing cytotoxic immune responses. Additionally, polyamines interact with the gut microbiota and host metabolism, influencing the tumour microenvironment and modulating systemic immune responses [70].

Secondary bile acids can modulate the tumour microenvironment by influencing immune cell function. They interact with receptors such as FXR and TGR5, regulating T cell activity and inflammatory responses. By acting on both innate and adaptive immunity, these molecules can contribute to immunosuppression within the tumour microenvironment, potentially promoting tumour progression [71].

5.3. Potential of Microbial-Derived Metabolites and Biomarkers for Disease Progression and Treatment Outcomes

Microbial-derived metabolites are emerging as promising biomarkers in haematological malignancies, since their concentrations and activity often mirror immune status and disease progression. SCFAs, for example, can either sustain immune regulation or favour tumour escape: butyrate has been shown to suppress ICAM-1 expression on carcinoma cells, impairing leukocyte recruitment, and to reactivate oncogenic viruses such as Kaposi’s sarcoma-associated herpesvirus through epigenetic modulation [60]. Furthermore, SCFAs may impair anti-tumour immune responses by attracting myeloid-derived suppressor cells (MDSCs), expanding this immunosuppressive population of cells within the tumour microenvironment [72].

Particularly relevant is the tryptophan metabolic pathway. The catabolite KYN is frequently elevated in the plasma of patients with advanced-stage cancers, and a high KYN/TRP ratio has been associated with poor prognosis, especially in patients treated with PD-1 inhibitors for solid tumours such as melanoma, lung, and renal cell carcinoma [73]. These observations highlight that TRP metabolites and their ligands not only profoundly modulate immune responses but may also serve as predictive markers of immunotherapy response, as well as potential therapeutic targets in immune-related cancers [26].

Polyamines also represent key modulators and potential biomarkers. They regulate antitumor immune responses and may contribute to the development of “cold” tumours that are less responsive to immune checkpoint blockade. Their levels and activity within the tumour microenvironment are influenced by microbiota composition, dietary polyamine availability, and tissue responses, collectively modulating immunosuppression and tumour progression [70].

Finally, secondary bile acids, produced by gut bacteria from primary bile acids, modulate immune cell function. Their concentrations correlate with T cell regulation, inflammation, and cellular differentiation, highlighting their relevance as biomarkers for disease progression and therapeutic response [65].

6. Chemotherapy-Induced Complications and Dysbiosis

6.1. Role of Microbiota in Chemotherapy-Related Mucositis and Infections

Chemotherapy is often associated with significant side effects, including oral and intestinal mucositis and systemic infections [74]. These events are linked to microbiota dysfunction, highlighting its crucial role in modulating the host response to anticancer treatments (Figure 4) [75].

6.2. Chemotherapy-Induced Mucositis

Mucositis, characterized by inflammation and ulceration of the oral and gastrointestinal mucosa, is a very common complication in patients undergoing chemotherapy [14]. This phenomenon is due to the interaction between the epithelial damage caused by cytotoxic drugs and the alteration of the intestinal and oral microbiota [76,77]. Under physiological conditions, the microbiota provides a protective barrier, competing with pathogens for resources and space. However, chemotherapy causes a decrease in microbial diversity, favoring the proliferation of opportunistic bacteria such as Clostridium difficile, Escherichia coli and Klebsiella pneumoniae [14]. These microorganisms release toxins that further compromise the integrity of the mucosal barrier, amplifying the inflammatory damage. A study conducted by van Vliet et al. (2017) suggests that patients with mucositis have a reduced presence of beneficial bacteria such as Lactobacillus and Bifidobacterium, suggesting that maintaining microbial diversity could mitigate the severity of mucosal lesions [78]. The use of probiotics and prebiotics has been explored as a preventive strategy, with promising results in reducing the incidence and duration of mucositis [15,79].

6.3. Systemic Infections

Chemotherapy-induced dysbiosis contributes to a significant increase in the risk of systemic infections [80]. Bacterial translocation is a process in which microorganisms, or their products pass from the damaged mucosa into the bloodstream, causing bacteremia and sepsis [81]. This phenomenon is observed in immunocompromised patients, such as those undergoing intensive chemotherapy regimens [74]. Reduced microbial diversity is associated with an increased frequency of infections by antibiotic-resistant pathogens, including Enterococcus faecium and Pseudomonas aeruginosa [82]. A study by Taur et al. [83] suggests that the loss of SCFA-producing bacteria is associated with a decrease in intestinal barrier function and an increase in susceptibility to infections [84]. Targeted interventions, such as fecal microbiota transplantation (FMT), have been proposed to restore healthy microbiota and reduce the risk of systemic infections [85].

FMT is a therapeutic procedure in which healthy intestinal microbiota from a donor is transferred to a patient with intestinal dysbiosis, an imbalance in the microbial flora [86]. This intervention is particularly indicated for the treatment of recurrent Clostridioides difficile infections (CDI), an intestinal infection that is often resistant to antibiotics and associated with high morbidity and mortality [87]. FMT works by restoring the diversity and functionality of the intestinal flora. The transferred healthy microbiota promotes bacterial competition and the production of beneficial metabolites that inhibit the proliferation of opportunistic pathogens [86]. FMT can be administered through different routes, depending on the clinical indication and patient preference. Oral capsules containing freeze-dried fecal material represent a non-invasive option, while the enteral route via nasogastric or nasoduodenal tube allows delivery to the upper gastrointestinal tract. More direct methods for targeting the colon include colonoscopy or retention enema, which ensure precise delivery of the microbiota to the affected site [88].

It was seen that FMT is highly effective in preventing recurrences of CDI, achieving cure rates exceeding 90% compared to approximately 30% with conventional antibiotic therapies. Moreover, FMT not only reduces the risk of recurrence but also leads to significant improvements in patients’ quality of life [89]. Beyond CDI, FMT is emerging as a promising therapeutic option for other conditions linked to gut dysbiosis. These include systemic infections, where restoration of microbial balance could decrease bacterial translocation and lower the risk of sepsis in immunocompromised patients; inflammatory bowel diseases (IBD), where FMT may modulate gut inflammation in disorders such as Crohn’s disease and ulcerative colitis; and even metabolic and neurological disorders, including metabolic syndrome, type 2 diabetes, and neurodegenerative diseases such as Parkinson’s and Alzheimer’s [88].

6.4. Dysbiosis as a Consequence of Anticancer Therapies

Chemotherapy is one of the main causes of dysbiosis as it determines alterations in the composition and function of the microbiota. These changes can be transitory or permanent, depending on the type of treatment and the patient’s condition [90]. These effects may arise through multiple pathways. Chemotherapeutic agents can directly affect microbial communities—some drugs, such as 5-fluorouracil (5-FU), have reported antibacterial activity that may reduce commensal taxa [91]. In addition, chemotherapy can impair oral and intestinal epithelial barrier integrity, thereby facilitating microbial translocation and amplifying inflammatory responses [50]. Finally, treatment-related immunosuppression may weaken host control over opportunistic pathogens, further promoting dysbiotic shifts [92]. An example is the use of platinum-containing drugs, which results in a decrease in beneficial bacteria such as Bacteroides and Firmicutes, while increasing the proliferation of pro-inflammatory species [93].

Persistent dysbiosis after chemotherapy may have long-term implications on patient health, influencing the immune response and the risk of tumor recurrence [13]. For example, a chronic reduction in SCFA is associated with a low-grade inflammatory state that could favor disease progression [94]. It has been observed that microbiota do not always spontaneously recover after completion of chemotherapy, highlighting the importance of targeted interventions to support microbial recovery [13].

Several approaches have been proposed to prevent or treat chemotherapy-induced dysbiosis. One approach involves the use of probiotics and prebiotics, especially specific strains of Lactobacillus and Bifidobacterium, which have shown efficacy in improving microbial diversity and reducing inflammation [95]. Another promising, although still experimental, strategy is FMT. It is thought that FMT may help restore the microbial composition and potentially reduce infectious complications in patients undergoing chemotherapy [96]. In addition, personalized dietary interventions play a crucial role in maintaining intestinal balance. High-fiber diets, for example, support the production of short-chain fatty acids (SCFA), which contribute to intestinal homeostasis and overall gut health [97].

7. Emerging Microbiota-Targeted Therapeutic Strategies

7.1. Probiotics and Prebiotics: Current Evidence and Future Directions

Probiotics are live microorganisms that, when administered in adequate amounts, confer health benefits by modulating the gut microbiota and immune responses. Prebiotics, on the other hand, are non-digestible compounds that promote the growth of beneficial gut bacteria. The combined administration of probiotics and prebiotics, referred to as symbiotic, synergistically enhances these beneficial effects. Current evidence suggests that probiotics and prebiotics may support health in various pathological conditions, including inflammation, infections, and cancer therapies [98].

Probiotics are recognized for supporting health by enhancing the native gut microbiota, modulating host immune responses, lowering cholesterol, and performing various other beneficial functions. Additionally, their secreted metabolites (known as postbiotics) including bacteriocins, lactic acid, and hydrogen peroxide, play a crucial role as antimicrobial agents against a wide spectrum of pathogenic bacteria [99].

Prebiotics are generally food ingredients that not only support the growth of probiotic microorganisms in the human gut but also stimulate the immune system. Moreover, the consumption of fermented foods, which serve as a natural habitat for probiotic bacteria, plays a significant role in enhancing the management of various conditions, including intestinal disorders [100].

Overall, the scientific use of probiotics, postbiotics, prebiotics, paraprobiotics, and symbiotic represents a safe and promising strategy to prevent and manage microbial infections, particularly in the current and post-pandemic context. Therefore, continued research and updated knowledge in this field are essential to fully explore the potential applications of these interventions in both human and animal health [98].

7.2. Fecal Microbiota Transplantation: Potential and Limitations

FMT involves the transfer of faecal material from a healthy donor to a recipient in order to restore a balanced gut microbiota. Initially employed to treat recurrent Clostridioides difficile infections, FMT has shown promising results in the management of other gastrointestinal, metabolic, and immunopharmacological disorders [101,102].

FMT primarily works by restoring microbial diversity, modulating immune responses, improving intestinal barrier function, and promoting the production of beneficial metabolites, such as short-chain fatty acids. Recent studies indicate that FMT is safe and can alleviate immunotherapy-related side effects in cancer patients. For instance, radiotherapy often damages intestinal epithelial cells and negatively affects gut microbiota composition. Direct interaction of bacterial metabolites—including bile acids, vitamins, short-chain fatty acids, amino acids—with metabolite-sensitive receptors on intestinal immune cells triggers local immune responses and activates macrophages, dendritic cells, and T lymphocytes [103,104,105].

Despite its promising potential, FMT has limitations related to donor selection, safety, the risk of pathogen transmission, and variability in patient responses. Long-term effects are not yet fully understood, and regulatory and ethical considerations currently limit its widespread adoption. Overall, FMT represents a valuable therapeutic strategy, particularly in oncology and immune-mediated diseases, but further research is needed to standardize protocols and assess its long-term efficacy and safety [102].

7.3. Other Novel Microbiota-Targeted Interventions

Recent advances in microbiome research have led to the development of additional strategies aimed at modulating the gut and oral microbiota to improve health. In addition to probiotics, prebiotics, symbiotic, and faecal microbiota transplantation, these approaches include diet and paraprobiotics.

Diet has been shown to positively influence the immune system and the gut microbiota, and is therefore proposed not only as a potential tool in the clinical management of various pathological conditions, but also for the prevention and promotion of global health [106]. Dietary components can have a direct effect on the barrier added to gut microbiota populations and host metabolites, thus modulating the host’s immune system [107].

Paraprobiotics are microorganisms used in an inactivated form, unlike live probiotics. This characteristic makes them particularly suitable for immunocompromised patients, such as those undergoing chemotherapy, where live probiotics could pose risks [108]. Recent studies suggest that paraprobiotics may help manage chemotherapy-induced gastrointestinal toxicities, including mucositis and diarrhoea, without compromising patient safety [109]. Although further research is needed to confirm these findings, paraprobiotics represent a promising therapeutic alternative, especially in vulnerable clinical settings.

8. Bidirectional Interactions Between Host and Microbiota

The interaction between the microbiota and its host is a dynamic process that evolves over time in response to genetic, environmental and immune factors. The human microbiota is composed of a complex community of bacteria, fungi, viruses and archaea, which play a crucial role in regulating immune and metabolic homeostasis, significantly impacted by periodontitis and related long-term treatment [110]. Host genetics are a major determinant of the composition and function of human microbiota. Studies have shown that genetic variants associated with IBD influence microbial diversity and the hosts ability to respond to microbial signals [111]. For instance, variants in genes regulating autophagy and inflammation, such as NOD2, have been associated with changes in gut microbiota composition and increased susceptibility to inflammatory diseases [112]. The host immune system constantly interacts with microbiota, influencing its composition and function. Regulatory T cells, for example, modulate the immune response to microbial communities, preventing excessive inflammation [113]. In addition intestinal immunoglobulin A (IgA) acts selectively to maintain microbiota balance, inhibiting the overgrowth of pathogenic bacteria [12]. Dendritic cells and macrophages of the intestinal mucosa play a key role in recognizing microbes and regulating inflammation. This balance is essential to prevent the progression of chronic inflammatory diseases and to maintain intestinal homeostasis. Diet is one of the main environmental factors that influence human microbiota. A diet rich in fiber and prebiotics promotes the growth of beneficial bacteria, particularly SCFA producers, which play a key role in modulating inflammation and maintaining the intestinal barrier [114,115]. Prebiotics are non-digestible substances, mainly dietary fiber, that promote the growth and activity of beneficial bacteria in the gut. They are found naturally in foods such as onions, garlic, bananas, asparagus, and whole grains, or can be added to supplements and food products. Unlike probiotics, which are live bacteria, prebiotics act as “food” for the gut microbiota, contributing to digestive health and overall well-being [116]. A diet rich in saturated fats and simple sugars are associated with a reduction in microbial diversity and an increase in intestinal permeability, contributing to the development of metabolic and inflammatory diseases [117].

The microbiota not only contributes to homeostasis but also influences the progression of several diseases including hematological malignancies such as multiple myeloma [118,119]. Alterations in microbial composition and dysbiosis, can contribute to a chronic inflammatory response and create an immunosuppressive environment, thereby favoring tumor progression [120]. Multiple myeloma patients exhibit altered microbial composition, characterized by increased pro-inflammatory bacteria and a reduction in beneficial SCFA-producing bacteria [85]. This dysbiosis affects the function of immune cells, compromising the ability of the immune system to recognize and destroy tumor cells [121].

In addition, metabolites produced by microbiota, such as butyrate and propionate, can modulate the function of immune cells, influencing the antitumor response [122]. The microbiota also plays a key role in the response to cancer therapies, to immune checkpoint inhibitors (ICIs) and chemotherapy treatments [120]. The composition of microbiota can influence the efficacy of ICIs by modulating T cell activation and the systemic inflammatory response [123]. In particular, Akkermansia muciniphila has been identified as one of the main taxa associated with an improved response to ICIs in patients with solid tumors, as demonstrated by Routy. [124]. The clinical benefit has been attributed to the ability of this bacterium to enhance dendritic cell function and promote effector T cell activity, favoring a more effective antitumor immune response [123]. Furthermore, microbiota can affect treatment toxicity. Some intestinal bacteria can metabolize chemotherapy drugs, reducing their efficacy or increasing side effects [90]. For example, some bacterial strains can convert cyclophosphamide into less active metabolites, compromising the efficacy of the therapy (Figure 5) [125].

9. Implication for Clinical Practice

9.1. Translation of Current Knowledge into Clinical Settings

Recent evidence suggests that the composition and diversity of the gut and oral microbiota have relevant clinical implications in patients with haematological malignancies. Reduced microbial diversity has been linked to increased mortality and infectious complications in hematopoietic stem cell transplantation (HSCT) recipients [42]. Similarly, specific microbial patterns, such as the predominance of Enterococcus or the depletion of beneficial SCFA-producing bacteria, have been correlated with worse outcomes [54].

These findings underline the potential role of microbiota profiling as a clinical biomarker for risk stratification in MM and other haematological cancers. In addition, the interaction between microbiota and treatment response is increasingly recognized: beneficial commensals have been shown to enhance the efficacy of immune checkpoint inhibitors, while dysbiosis may impair immunotherapy responses [123]. Therefore, integrating microbiota monitoring into the clinical setting may allow clinicians to identify patients at higher risk of treatment-related complications, tailor supportive care, and optimize therapeutic strategies.

9.2. Potential Diagnostic and Therapeutic Applications

Microbiota-derived metabolites represent promising diagnostic and prognostic biomarkers. For example, altered SCFA levels have been associated with disease progression and impaired immune regulation [67], while elevated kynurenine-to-tryptophan ratios have been linked to poor prognosis in cancer patients treated with immunotherapy [73]. Monitoring these metabolic pathways could therefore provide valuable insights into both disease activity and treatment response.

On the therapeutic side, different strategies aimed at modulating the microbiota are under investigation. The use of probiotics and prebiotics has shown encouraging results in reducing the incidence and severity of chemotherapy-induced mucositis and diarrhoea [15]. Symbiotic, by combining both, may further enhance these effects [98].

FMT, although primarily employed in recurrent Clostridioides difficile infection, has recently shown promising results in restoring microbial diversity and improving responsiveness to immunotherapy in cancer patients [101,102]. Although its application in haematological malignancies remains experimental, it represents a potential adjunctive therapeutic approach in the near future.

Furthermore, paraprobiotics (inactivated microbial preparations) have been proposed as a safe alternative for immunocompromised patients, reducing the risks associated with live microorganisms while maintaining beneficial immunomodulatory effects [108].

Finally, dietary interventions aimed at supporting SCFA production and microbial diversity, such as high-fibre diets, may represent a practical and non-invasive strategy to promote intestinal homeostasis and enhance treatment outcomes [97].

Microbiota-focused approaches show increasing potential in clinical practice. Although further randomized trials are needed to confirm their efficacy and safety in patients with multiple myeloma and other haematological malignancies, integrating microbiota profiling, metabolite monitoring, and targeted interventions could enable personalized care and optimized therapy.

10. Future Perspective

In recent years, interest in the role of the oral and intestinal microbiota in patients with MM and other hematological malignancies has grown significantly. This has led to an increase in studies in this area; however, many unknowns still prevent a comprehensive understanding of the influence of microbiota on pathogenesis, disease progression, and response to therapies [126].

One of the main obstacles is the strong methodological heterogeneity and technological limitations. Indeed, there are numerous variations in microbiome sequencing techniques, sampling protocols and bioinformatics approaches, which makes it difficult to compare results between different studies [127].The use of different sequencing platforms, such as next-generation sequencing (NGS) or shotgun metagenomics, can lead to discordant results, complicating the identification of reliable correlations between the microbiota and clinical outcomes [128]. To overcome this limitation, it would be essential to adopt standardized protocols and exploit shared databases, thus improving the reproducibility of studies [129].

Another aspect that is still unclear is the specific function of the different bacterial species present in the microbiota. Although many studies have now characterized the composition of the microbiome in cancer patients, the functional role of these microorganisms remains largely unknown [130]. The integration of advanced technologies, such as functional metagenomics and multi-omics approaches (metabolomics, proteomics and transcriptomics), could help to clarify the mechanisms through which the microbiota influences the immune response and disease progression [129].

A particularly interesting topic concerns the interaction between the microbiome and the immune system, especially in relation to immunotherapy. In patients with solid tumors, clinical and translational studies have reported associations between gut microbiota composition and response to immune checkpoint inhibitors, suggesting a potential modulatory role of the microbiome [12]. However, it remains unclear whether similar dynamics apply to hematological malignancies, and evidence in multiple myeloma is still limited. Studying the microbiota in patients undergoing stem cell transplantation or advanced therapies such as CAR-T could offer new perspectives, helping to identify possible predictive biomarkers of response to treatments [8].

Influence of the oral microbiota on the intestinal microbiota: the relationship between the oral and intestinal microbiota is little studied. Some studies suggest that bacterial translocation from the oral environment may contribute to gut dysbiosis in patients with hematological malignancies, but the mechanisms of this interaction remain unclear [131]. Longitudinal studies examining the microbiota from both environments could provide useful data to better understand this connection [132]. Effects of cancer treatments on microbiota: chemotherapy and radiotherapy can significantly alter the composition of microbiota, but the duration and consequences of these changes are not yet fully understood. Identifying strategies to decrease the adverse effects of therapy on the microbiome could improve patient management and reduce gastrointestinal and immune side effects [127]. To fill these gaps, a multidisciplinary approach integrating expertise from microbiology, oncology, immunology and bioinformatics is needed. Different strategies could help improve the quality and impact of future studies, allowing a deeper understanding of the role of microbiomes in hematological diseases [133].

A first fundamental step would be the development of large-scale longitudinal studies. Currently, most research is based on cross-sectional studies, which provide only a static snapshot of the composition of the microbiome. Longitudinal studies, on the other hand, would allow us to monitor the changes in the microbiota over time and evaluate how cancer treatments influence the microbial ecosystem in the long term. This type of analysis could offer crucial information on the evolution of the disease and the response to therapies [129].

Another key element is the standardization of analysis methodologies. The adoption of shared protocols for sampling and analyzing the microbiome would reduce variability between studies, making data more easily comparable. Furthermore, collaboration through international research consortia could facilitate access to large datasets, increasing the reliability of conclusions and allowing a more global vision of the relationship between the microbiome and hematological diseases [127].

The integration of multi-omics approaches represents a further step forward. Combining metagenomics, meta transcriptomics and metabolomics could provide a more complete view of the link between microbiome and hematological diseases. These technologies would allow, for example, to identify metabolites produced by the microbiome and to understand their impact on the pathophysiology of multiple myeloma, opening new perspectives in research [134].

Another crucial goal is the identification of microbial biomarkers useful for prognosis and personalized therapies. The discovery of microbial signatures associated with multiple myeloma progression or response to treatments could revolutionize the approach to personalized medicine. Predictive models based on the microbiome could help stratify patients based on the risk of complications or the likelihood of responding positively to specific therapies, thus improving the clinical management of the disease [8].

In parallel, exploring microbiome-based therapeutic interventions could open new treatment possibilities. Microbiome-targeted interventions, including fecal microbiota transplantation and selected pre-/probiotic or dietary approaches, are being explored to modulate dysbiosis in patients with hematological malignancies [135]. However, in the context of multiple myeloma, efficacy and safety are not yet established and require well-designed randomized clinical trials [132]. In addition, artificial intelligence (AI) and machine learning approaches are emerging as valuable tools for the evaluation of complex microbiota datasets in hematological malignancies. Preliminary studies suggest that AI-driven analyses may help identify microbial signatures associated with disease subtypes and clinical outcomes, although external validation and standardized datasets are needed before clinical implementation [136]. Specifically, Woerner et al. utilized random forest classifiers based on circulating bacterial content to distinguish between different myeloid malignancy subtypes (AML, MDS, MPN, MDS/MPN), achieving high classification accuracy. Integrating AI into microbiome research could therefore enhance biomarker discovery, improve prognostic stratification, and support personalized therapeutic strategies in this vulnerable patient population.

Finally, the analysis of the oral microbiota could represent a further diagnostic and therapeutic opportunity. Considering the role of the oral environment in systemic health, monitoring the oral microbiome could help to identify early alterations that predispose to intestinal dysbiosis and hematological complications [137]. Studies aimed at defining the oral microbiome profile in patients with multiple myeloma could lead to the identification of new biomarkers useful for early diagnosis and risk stratification [129].

11. Discussion

This narrative review summarises the current evidence on oral and gut microbiota alterations in haematological malignancies, with a specific focus on multiple myeloma (MM). Overall, the available data suggest that dysbiosis is frequently observed in these patients and may accompany different phases of the disease course and treatment exposure [41]. Associations have been reported between microbial imbalances and clinically relevant outcomes such as infections, mucositis, and treatment tolerance, indicating that microbiota could act as a potential modifier of risk rather than a mere epiphenomenon of disease. However, MM-specific findings are still relatively sparse and heterogeneous and should therefore be interpreted with caution [49].

From a biological standpoint, several mechanistic pathways have been proposed to explain how microbiota alterations might influence host immunity and clinical outcomes. These include disruption of mucosal barrier integrity with increased microbial translocation, changes in microbially derived metabolites that modulate immune signaling, and treatment-related immunosuppression that may favor expansion of opportunistic or pro-inflammatory taxa [23]. Such mechanisms are supported by preclinical models and by clinical observations in related hematologic settings, particularly in the context of intensive chemotherapy and hematopoietic stem cell transplantation. In MM, however, direct clinical demonstration of these pathways remains limited, and most mechanistic links should be regarded as hypothesis-generating rather than definitively established [49].

When the available studies are considered collectively, the strength of evidence appears uneven across topics. Associations between gut microbiota profiles and infectious or inflammatory complications are relatively more consistent, whereas data on the oral microbiome, on the oral–gut axis, and on microbiota-based interventions in MM are still preliminary and often based on small cohorts [8]. In addition, many studies are observational and not primarily designed to evaluate microbiota as a main endpoint, which increases the risk of residual confounding and makes it difficult to disentangle cause–effect relationships from correlations driven by disease status, treatment intensity, or comorbid conditions [36].

Taken together, these elements indicate that the microbiota represents a promising but as yet incompletely defined dimension of MM pathophysiology and patient management. At present, microbial signatures and mechanistic hypotheses should be viewed as useful tools to generate testable predictions and to refine research questions, rather than as ready-to-use biomarkers or therapeutic targets in routine clinical practice [49]. A more detailed discussion of methodological challenges and research priorities, as well as potential avenues for clinical translation, is provided in the “Future perspectives” section.

12. Conclusions

Currently available evidence indicates that alterations in the oral and intestinal microbiota are common in patients with multiple myeloma and other haematological malignancies, but its interpretation must remain cautious. The reported associations—regarding inflammation, immunomodulation, infectious complications, and treatment response—are derived primarily from observational studies, often heterogeneous in terms of clinical settings (transplant vs. non-transplant), type of hematologic disease, and microbiota characterization methodologies. The narrative nature of this review and the lack of standardized protocols controlled comparative analyses, and assessments of the certainty of the evidence do not allow for definitive conclusions or immediate clinical applications. The potential roles of microbial profiles or metabolites as biomarkers, as well as targeted interventions (dietary, probiotic, prebiotic, or FMT), must be considered preliminary research hypotheses. Longitudinal, integrated multi-omics studies, and controlled clinical trials are needed to clarify the biological and clinical relevance of these observations in different haematological settings. Only with more robust evidence will it be possible to evaluate whether and under what conditions the microbiota can contribute to prognostic stratification or the personalization of therapeutic interventions.