Open Access

Benefits of using probiotics as adjuvants in anticancer therapy (Review)

  • Authors:
    • Silvia Vivarelli
    • Luca Falzone
    • Maria Sofia Basile
    • Daria Nicolosi
    • Carlo Genovese
    • Massimo Libra
    • Mario Salmeri
  • View Affiliations

  • Published online on: June 3, 2019     https://doi.org/10.3892/wasj.2019.13
  • Pages: 125-135
  • Copyright: © Vivarelli et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Cancer is the second leading cause of mortality worldwide and the constant search for novel therapeutics aims to increase the overall survival of the affected population. The human microbiota evolves with the host throughout the course of its entire life, as a direct consequence of individual diet and lifestyle habits. The gut microbiota tremendously affects human homeostasis and it has been widely observed that maintaining a healthy gut may prevent diseases, as well as ameliorate pathological conditions. According to the World Health Organization, probiotics may confer a health benefit on the host when administered in adequate amounts. Anticancer therapy often causes severe side‑effects, including gastrointestinal toxicity. Several clinical trials have highlighted the efficacy of administering probiotics to cancer patients receiving anticancer care, with proven efficacy in reducing gut‑related and life‑threatening side‑effects. To corroborate the clinical results, recent translational studies have indicated that the specific administration of selected bacterial gut species are capable of improving the immune check‑point immunotherapy clinical outcome. Lactobacillus rhamnosus GG (LGG), a model probiotic widely studied in oncology, has been proven to be beneficial when administered during anticancer therapy. In this review, we report the up‑to‑date clinical advancements obtained following the administration of probiotics during anticancer therapy, with particular focus on the promising probiotic strain LGG.

1. Introduction

Every exposed human body surface, including the skin, genitourinary, gastrointestinal and respiratory tracts, are heavily colonized by as many as 10-100 trillion microorganisms, including bacteria, fungi, archaea and viruses (1). In the recent years, commensal microorganisms have been identified as key determinants of a host's homeostasis and health (2). In particular, among the human symbiotic microbial populations, the gut microbiota is the most extensively populated, hosting up to 70% of the microbes inhabiting the whole body (3). Gut microbiota is the name given to the heterogeneous population of commensal microorganisms, inhabiting the gastrointestinal tract, mostly the large intestine. This population constitutes an agent to which we are constantly exposed, at high doses, throughout an entire lifespan (4). The human gut is populated by 1,000 different bacterial species, prevalently belonging to the phyla of Firmicutes and Bacteroidetes (5).

The intestine is the interface between the gut commensal microbiota and the human body (6). On the one hand, the gastrointestinal enteroendocrine cells secrete over 30 different peptide hormones involved in key functions, including gastrointestinal motility, food digestion and neuromodulation (7). It has been demonstrated that gut-secreted hormones are able to modify the gut microbiome composition, as during the response to stress (8-10). On the other hand, the gut microbial population produces or transforms active molecules, which may be sensed by the gastrointestinal cells of the host (8). The derived functional effects range from the modulation of the host's metabolism to the maintenance of gut barrier integrity, xenobiotics metabolism, protection against gastrointestinal pathogens and modulation of the host's immune system (11-14). Notably, certain commensal bacteria produce essential micronutrients, including vitamin K and vitamin B. Additionally, a number of gut commensals can transform amino acids into signaling molecules, as for example glutamate into gamma-amino butyric acid (GABA) or histidine to histamine. Finally, several Bacteroidetes are able to catabolize phenolic compounds, as well as secondary bile acids, moreover to synthetize the anti-diabetics linoleic acid (15). Another class of hormone-like metabolites produced by the human gut commensals is represented by the short chain fatty acids (SCFAs), derived from the bacterial fermentation of dietary fibers (16). The SCFAs, once synthetized in the intestine, are transported to the liver where they are utilized as a key source of energy. Additionally, SCFAs play a role in controlling glucose and the lipid metabolism by affecting the gut epithelial hormone peptide secretion (17).

Given the reported functional crosstalk between the gastrointestinal microbiota and its host, the preservation of the equilibrium in both composition and the relative abundance of the gut microbial population is fundamental for the correct fulfilment of pivotal host's metabolic, as well as immune functions (18-20). Any disequilibrium in this delicate balance may lead to a defective microbiota, a condition known as dysbiosis, mostly linked to several human pathologies, including cancer (21).

The gut microbiome is defined as the whole genome of the host's gut microbiota, and it encodes 100-fold more genes than the human genome (22). Over the past 10 years, classical fecal-derived microbe cultivation studies have been strongly integrated with metagenomics approaches, combining next-generation sequencing (NGS) with the computational analysis of the 16S rRNA amplicons. Progresses in metagenomics studies, together with many advancements in transcriptomics and metabolomics, have allowed the characterization of both a diversity and abundance of the gut microbiome, with the final goal of determining the impact of each individual gut-populating species on the health of the host (23,24). These novel approaches are depicting the deep impact of the microbiome diversity and composition on human health, as disclosed by the Human Microbiome Project and the large number of originating publications (25-28).

A healthy gut microbiome is defined by a functional core of metabolic and other molecular functions, which are not necessarily performed by the same bacterial species in each different individual (29). The term ‘probiotic’ means pro-life. Probiotics are currently defined by the Food and Agriculture Organization of the United Nations and by the World Health Organization (FAO/WHO) as ‘live microorganisms, which, when consumed in adequate amounts, confer a health effect on the host’ (30). They are highly present in fermented food and yoghurt. The vast majority of these probiotics are lactic-acid producing, non-pathogenic bacteria, such as Lactobacillus, Streptococcus, Bifidobacterium, Propionibacterium and Enterococcus or non-pathogenic yeasts including Saccharomyces boulardii (30). Probiotics are administered orally and arrive alive in the intestine (30). They are often administered in combination with specific prebiotics (undigestible food specifically metabolized by probiotics), to form synbiotic mixes (31). Health benefits derived from administering probiotics to healthy individuals include improved digestion, immune defense mechanisms and nutrient absorption. Importantly, probiotics have been proven to be able to revert intestinal dysbiosis, which may play a role in the development of several degenerative diseases, as well as chronic diseases, including cancer (32).

A growing amount of clinical studies are currently investigating the impact of probiotics on the treatment of intestinal toxicity during chemotherapy, immunotherapy and radiation, generating promising results. The present review aimed to summarize the up-to-date clinical observations concerning the role played by probiotics administered in association with anticancer therapy.

2. Gut microbiota and cancer

The gut microbiota can be considered a factor to which we are exposed throughout an entire lifespan, whereas intestinal dysbiosis has been found to be linked to the tumorigenesis of both local gastro-intestinal cancers and tumors localized in distant sites of the body (33). Both environmental exposure (e.g., to cancerogenic substances or UV radiation) and lifestyle habits significantly influence individual cancer risk (34-37). This risk is associated with the dose, duration and the combination of these exposures among each other, also depending on the individual genetic background (38-43). In fact, neoplasms bear an intrinsic complexity, as they are derived from the stochastic acquisition of driver mutations within genes involved in key processes (including DNA duplication, DNA repair and oxidative stress response). Thanks to the accumulation of mutations over time and space, cancerogenic cells adapt to the hosting organism, therefore transforming from a normal cell into a malignant one (44-47). Moreover, given the stochastic gathering of mutations, together with the intrinsic tumor cellular genomic instability, epigenetics (including altered DNA methylation, as well as miRNA imbalance), transcriptional and post-transcriptional intracellular changes, from one original cancer can lead to the development of a molecularly varied bulk tumor, made of multiple cancer cell clones, each one presenting a differential sensitivity to the anticancer therapies (48-60).

Anticancer therapies are designed with the final goal of being effective in the eradication of the targeted malignancy. As almost every available treatment is toxic towards normal cells, their use may be coupled with toxic side-effects, some of which can compromise the overall survival of the patients (61). Importantly, the intra-tumoral variety is tightly linked to the development of the resistance to therapy, considered the first cause of failure of the available treatments, as well as subsequent tumor relapses (62). To fight the resistance, integrated therapies and personalized approaches, based on the specific genetic features of the malignancy, are in constant development (62).

The host's immune system plays a fundamental role in fighting and eliminating tumor cells (63-65). On their side, malignant cells, thanks to their genetic instability, constantly develop novel strategies with which to escape from immunosurveillance (63,66). Targeted immunotherapy represents a novel anticancer approach, able to boost the host anti-tumor immune response, and, at the same time, help to ‘hit’ cancer resistance and recurrence mechanisms (67,68).

Taken together, radiotherapy, chemotherapy and immunotherapy, given their general toxicity, can compromise the gut microbiome of patients. At the same time, modulating the gut microbiome composition may deeply influence the outcome of patients to therapies (69). It is therefore of utmost importance to develop novel strategies with which to manipulate the gut microbiome, with the main goal of improving the therapeutic outcome of patients, without any associated risk (70,71).

3. Gut microbiota and anticancer therapy

A dysbiotic gut microbiota deeply influences both cancer pathogenesis and its therapeutic outcome, with the latter tightly connected with the ability of the gut microbiota to metabolize antitumoral compounds, as well as to modulate a host's immune response and inflammation pathways (72). The combination of these two effects explains the strong involvement of the patients' microbiome composition in affecting their final outcome to treatments (73).

As regards the effects of the gut microbiome on the host's immune system, the past year witnessed the publication of marking breakthrough, strongly coupling the patients' microbiome composition with the efficacy of immune checkpoint inhibitors-based immunotherapy (74-76). Immune checkpoint inhibition consists of the administration of therapeutic agents able to block the immune-inhibitory pathway, thus modulating T cell activation against tumor target cells [i.e., monoclonal antibodies blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1) or programmed death-ligand 1 (PD-L1) targets] (77,78).

In particular, Routy et al (74) observed that patients with melanoma treated with antibiotics along with the anti-PD1/anti-PD-L1 immunotherapy had a lower survival rate. Following the metagenomic fecal analysis, anti-PD1 responders were found enriched in two phyla (Akkermansia and Alistipes). Performing Fecal Microbiota Transplantation (FMT) from patients to germ-free mice, the authors found that Akkermansia muciniphila increased intra-tumoral cytotoxic T cell infiltrates, thus ameliorating the PD-1 blockade response in mice (74). Similarly, Gopalakrishnan et al (75) carried out the metagenomic analysis on stool samples from patients with melanoma, finding that the anti-PD1 responders' microbiome differed in composition compared with that of non-responders. In fact, there was an increase in the abundance of Clostridiales, Ruminococcaceae and Faecalibacteriae. Functional studies performed with FMT in germ-free mice have further demonstrated how the treatment of mice with the identified bacteria, along with the anti-PD1 therapy, significantly reduced the growth of melanoma (75). Likewise, Matson et al (76), accomplishing the metagenomic analysis of fecal samples from patients with melanoma treated with immune checkpoint inhibitors, found that responders had a different microbiome profile compared to not responders. They identified and functionally proved in vivo the role played by Bifidobacterium longum, Enterococcus faecium and Collinsella aerofaciens in ameliorating anti-PD-L1 efficacy (76).

Taken together, these results provide strong evidence of the pivotal role of selected gut resident strains in modulating the effects of both immunotherapy response and toxicity. Nevertheless, several obstacles still interfere with the robust translation of the described bench results to the bedside. In fact, the gastrointestinal microbiome of each single patient can be either detrimental or beneficial to tumor progression and therapy, depending on the prevailing inhabiting species. Moreover, the fact that often, cancer patients undergoing therapy are immunocompromised, has to be taken into careful consideration, as this delicate condition could lead to the development of defeating infections, due to the proliferation of opportunistic bacterial species. Consequently, it is necessary to carefully analyze both the risks and benefits of probiotics treatments coupled with anticancer therapy, with the final goal of pursuing only beneficial effects, without any safety issues.

4. Probiotics as adjuvants of anticancer therapy

Tremendous progress has been made over the past century to improve anti-cancer therapies, significantly reducing detrimental side-effects, with the final goal of improving the compliance of patients (79). Manipulating the intestinal microbiome through the oral delivery of probiotics is used to improve the safety, as well as to reduce the drastic gastrointestinal side-effects, which are often associated with anticancer treatments, mainly diarrhea and mucositis. In fact, probiotics have the great advantage of being inexpensive and are broadly regarded as safe (80,81). Generally, the use of probiotics in clinical practice has demonstrated that probiotics have a broad spectrum of benefits, including the amelioration of antibiotic- and Clostridium difficile-associated diarrhea, as well as respiratory tract infections (82). Repopulating the gut microbiota cancer of patients through the administration of probiotics, re-establishes both the abundance and the functionality of the commensal gut bacteria, which has been possibly depleted after the therapies (83). The main issues of administering probiotics to immunocompromised cancer patients are both the risk of opportunistic infections, as well as the potential transfer of antibiotics resistance (84,85). In spite of this, the administration of probiotics in multiple trials has shown the readjustment of a healthy intestinal microbiota composition, the amelioration of diarrhea and other types of therapy-associated damage to the gastrointestinal system, including mucositis (80). Moreover, probiotics containing the Lactobacillus species have been suggested as food supplements for the prevention of diarrhea and for the relief of mucositis in patients receiving chemotherapy and/or radiation therapy for a pelvic malignancy (86,87).

Fig. 1 summarizes both the benefits and the risks potentially associated with the administration of probiotics as adjuvants during anticancer therapy, highlighting how probiotics may modulate the delicate gut equilibrium, from a dysbiotic towards a healthy and functioning microbiota.

Following this perspective, a growing number of clinical studies are currently ongoing, with the common intent of investigating the therapeutic potential of gut microbiota manipulation in cancer patients through the oral administration of probiotics as food supplements, along with their anticancer treatment. The results from the published clinical trials are encouraging. In 2010, a double-blind clinical trial, performed on cancer patients undergoing colorectal resection, demonstrated the positive effects of probiotic administration on the gut microbiota composition, as well as on the regulation of intestinal immune functions (88). In particular, Lactobacillus johnsonii, administered to patients, was able to adhere to the colonic mucosa, thereby reducing the concentration of gut pathogens and modulating the local immunity (88). In 2014, a double-blind controlled trial demonstrated the beneficial role of the probiotics Lactobacillus acidophilus and Bifidobacterium longum in reducing radiation-induced diarrhea, when administered to cancer patients receiving pelvic radiation therapy (89). Moreover, in 2015, a clinical trial evaluated the safety and efficacy of a probiotic formula consisting of 10 bacterial strains (including Lactobacilli and Bifidobacteria), orally administered along with irinotecan-based chemotherapy, to patients with colorectal cancer (CRC). The authors successfully found an effective reduction of diarrhea and gastrointestinal dysfunctions in patients receiving the probiotics (90). In 2016, another double-blind, randomized trial demonstrated that patients subjected to CRC resection exhibited a decreased risk of developing post-operatory irritable bowel syndrome (IBS), when co-treated with a synbiotic mix of prebiotics and probiotics (91). Also in 2016, another randomized trial performed in patients with colon-resected CRC came to the conclusion that Saccaromices bulardii effectively downregulated pro-inflammatory cytokines (92). In 2017, a randomized clinical trial demonstrated how the perioperative administration of a synbiotic mixture of probiotics and prebiotics significantly reduced post-operative infection rates in patients affected by CRC (93).

In addition to the described published findings, a number of clinical trials are currently ongoing to evaluate the safety and the efficacy of using probiotics with anticancer therapy. In fact, regardless the observed beneficial effects, it is of fundamental importance to truly establish the safety of administering probiotics to patients with severe cancer conditions in a larger cohort of cases. The complete list of the currently registered clinical studies (clinicaltrials.gov) untangling the effects of administering probiotics to cancer patients during their therapy, is reported in Table I.

Table I

Clinical studies registered at clinicaltrials.gov involving the use of probiotics in combination with anticancer therapy.

Table I

Clinical studies registered at clinicaltrials.gov involving the use of probiotics in combination with anticancer therapy.

Study IDTitle of the studyConditionsInterventionsStatusRef.
NCT00936572Probiotics In Colorectal Cancer PatientsCRCProbiotics (B. longum, L. johnsonii)C(88)
NCT01839721Impact of Probiotics BIFILACT® on Diarrhea in Cancer Patients Treated With Pelvic RadiationCANBIFILACT (L. acidophilus, B. longum)C(89)
NCT01410955Prevention of Irinotecan Induced Diarrhea by ProbioticsCRCColon Dophilus (Lactobacillus spp, Bifidobacterium spp)C(90)
NCT01479907Synbiotics and Gastrointestinal Function Related Quality of Life After Colectomy for CancerCRCSynbiotic Forte (Lactobacillus spp and prebiotics)C(91)
NCT01609660Impact of Probiotics on the Intestinal MicrobiotaCRCS. boulardiiC(92)
NCT01468779Effect of Probiotics in Patients Undergoing Surgery for Periampullary NeoplasmsPCProbiotic formulaC(93)
NCT03420443Action of Synbiotics on Irradiated GI Mucosa in CRC Treatment (FIPIREX)CRCSynbioticsC 
NCT01723592Orally Administered Probiotics to Improve the Quality of the Vaginal Flora of Women With Breast Cancer and ChemotherapyBCProbiotics (Lactobacillus spp)C 
NCT02771470Intestinal Microflora in Lung Cancer After ChemotherapyLCC. butyricumC 
NCT01895530Impact of Probiotics in Modulation of Intestinal MicrobiotaCRCS. boulardiiC 
NCT02021253Influence of Probiotics Administration Before Liver Resection in Liver DiseaseHCLactibiane (B. lactis, L. acidophilus, L. plantarum, L. salivarius)C 
NCT03531606The Effects of Mechnikov Probiotics on Symptom and Surgical OutcomeCRCProbioticsC 
NCT03782428An Evaluation of Probiotic in the Clinical Course of Patients With Colorectal CancerCRCHEXBIO (L. acidophilus, L. lactis, L. casei, B. longum, B. bifidum, B. infantis)C 
NCT03358511Engineering Gut Microbiome to Target Breast CancerBCPrimal Defense Ultra (Lactobacillus spp, Bifidobacterium spp)O 
NCT03785938Mucositis and Infection Reduction With Liquid Probiotics in Children With Cancer (MaCROS)PEDCSymprove (L. rhamnosus, E. faecium, L. acidophilus, L. plantarum)O 
NCT02944617Probiotic Yogurt Supplement in Reducing Diarrhea in Patients With Metastatic Kidney Cancer Being Treated With Vascular Endothelial Growth Factor-Tyrosine Kinase InhibitorRCCYogurtO 
NCT03704727The Effects of Probiotics on Intestinal Permeability in Gastrointestinal Cancer Patients in ChemotherapyGICVSL3 (Lactobacillus spp, Bifidobacterium spp)O 
NCT03742596The Effect of Probiotics Supplementation on the Side Effects of Radiation Therapy Among Colorectal Cancer PatientsCRCProbiotic Formula (Lactobacillus spp, Bifidobacterium spp)O 
NCT03177681The Effect of Yogurt in Cancer Patient With Moderate Gastrointestinal SymptomsCANYogurtO 
NCT02351089Probiotics in Radiation-treated Gynecologic Cancer (ProRad)GYCProbioticsO 
NCT03705442Probiotics as Adjuvant Therapy in the Treatment of Metastatic Colorectal Cancer (Probat-tmcc-17)CRCOmni-Biotic 10 (Lactobacillus spp, Bifidobacterium spp)O 
NCT03552458Effects of Probiotics in Preventing Oral MucositisHANL. ReuteriO 
NCT03518268Vivomixx for Prevention of Bone Loss in Women With Breast Cancer Treated With an Aromatase InhibitorBCVivomixx (Lactobacillus spp, Bifidobacterium spp)O 
NCT03574051Microbiota Associated With Iodine-131 Therapy and HypothyroidismTCProbiotics (B. infantis, L. acidophilus, E. faecalis)O 
NCT03642548Probiotics Combined With Chemotherapy for Patients With Advanced NSCLCNSCLCBifico (B. Coagulans)O 
NCT02751736The Effect Of Probiotics On Bowel Function Restoration After Ileostomy Closure In Patients With Rectal CancerCRCL. plantarumO 
NCT01790035Probiotic LGG for Prevention of Side Effects in Patients Undergoing Chemoradiation for Gastrointestinal CancerGICL. rhamnosus GGO(101)
NCT00197873Lactobacillus rhamnosus in Prevention of Chemotherapy-related DiarrhoeaCRCL. rhamnosus GGO 
NCT02544685Prevention of Febrile Neutropenia by Synbiotics in Pediatric Cancer PatientsCANProbio-Fix Inum and corn starch (L. rhamnosus GG, B. animalis)O 
NCT02819960Prevention of Irinotecan Induced Diarrhea by ProbioticsCANProbio-Fix Inum (L. rhamnosus GG, B. animalis)O 

[i] CRC, colorectal cancer; CAN, cancer; PC, periampullary carcinoma; BC, breast cancer; LC, lung cancer; HC, hepatocellular carcinoma; PEDC, pediatric cancer; RCC, renal cell cancer; GIC, gastrointestinal cancer; GYC, gynecological cancer; HAN, head-and-neck cancer; TC, thyroid cancer; NSCLC, non-small cell lung cancer; LGG, Lactobacillus rhamnosus GG; C, closed study; O, ongoing study.

5. LGG, a model probiotic for use as an anticancer adjuvant

The probiotic archetype Lactobacillus rhamnosus GG (LGG) represents one of the first studied bacteria in oncology (94). LGG is a gut-resident bacterium which has the ability to restore gut microbial balance, thanks to its anti-inflammatory properties (95-99). The benefits of administering LGG to cancer patients is supported by multiple in vitro, in vivo and clinical studies, as recently reviewed by our group (100). Moreover, 70 trials are currently registered at clinicaltial.gov, aiming to specifically determine the effects associated with the administration of LGG in several different conditions (Table II).

Table II

Clinical trials registered at clinicaltrials.gov assessing the benefits of administering LGG in association with a large number of different conditions.

Table II

Clinical trials registered at clinicaltrials.gov assessing the benefits of administering LGG in association with a large number of different conditions.

NCT No.StatusConditions
NCT01922895ActiveAcute Alcoholic Hepatitis
NCT03080818ActiveAging
NCT03449537ActiveAllergy Milk
NCT03256708Active Antibiotic-Associated Diarrhea
NCT03449459ActiveChronic Obstructive Pulmonary Disease
NCT03587545ActiveChronic Rhinosinusitis
NCT03647995ActiveDiarrhea, Clostridium difficile
NCT02544685ActiveFebrile Neutropenia
NCT01790035ActiveGastrointestinal Neoplasms
NCT02640625ActiveHuman Immunodeficiency Virus
NCT02748317ActiveLower Urinary Tract Symptoms
NCT02748356ActiveLower Urinary Tract Symptoms
NCT03383874ActiveMania, Neurotic
NCT03215784ActiveObesity, Pregnancy, Inflammation
NCT03277820ActiveOtitis Media
NCT03196453ActiveOverweight, Nutrition Disorder
NCT02462590ActivePneumonia, Infections, Diarrhea
NCT01454661ActivePremature Infant
NCT00490425CompletedAllergic Asthma
NCT01901380CompletedAllergy, Functional Gastrointestinal Disorders
NCT00748748Completed Antibiotic-Associated Diarrhea
NCT02711800CompletedAnxiety, Abdominal Pain
NCT00159523CompletedAsthma, Atopic Dermatitis
NCT01148667CompletedAtopic Dermatitis
NCT00325273CompletedAtopic Dermatitis, Allergic Rhinitis, Asthma
NCT00224432CompletedAtopic Dermatitis, Atopic Eczema
NCT03078179CompletedCaries, Dental
NCT01279265CompletedColic, Inflammation
NCT02466035CompletedCow’s Milk Allergy
NCT02779881CompletedCow’s Milk Allergy
NCT01956916CompletedCystic Fibrosis
NCT01961661CompletedCystic Fibrosis
NCT00318695CompletedEczema, Asthma, Allergic Rhinitis
NCT02642289CompletedFibromyalgia
NCT01773967Completed Gastroenteritis
NCT02144701CompletedGraft Versus Host Disease
NCT00620412CompletedHealthy
NCT00934453CompletedHealthy
NCT03168503CompletedHealthy
NCT01274598CompletedHealthy, Elderly
NCT01368029CompletedHealthy, Elderly
NCT01545349CompletedHealthy, Influenza
NCT03427515CompletedHealthy, Stress-related Problem, Anxiety
NCT01969331CompletedHelicobacter pylori Infection
NCT03307772CompletedHerpes Labialis
NCT03310294CompletedHerpes Labialis
NCT01439841CompletedHIV-1 Infection
NCT01616693CompletedImmunity to Oral Vaccines
NCT02046512CompletedInfection
NCT01551186CompletedInfectious Disease of Digestive Tract
NCT01130792CompletedInfectious Gastroenteritis
NCT No.StatusConditions
NCT02230345CompletedInflammation, Dyslipidemia
NCT01720329CompletedInfluenza
NCT03100266CompletedLow Back Pain
NCT01164124CompletedLow Birth Weight
NCT02288572CompletedMetabolic Syndrome X
NCT01670916CompletedNecrotizing Enterocolitis
NCT01868737CompletedNecrotizing Enterocolitis
NCT02807246CompletedNeonatal Hyperbilirubinemia
NCT02558192CompletedNosocomial Infection
NCT01870544CompletedObesity
NCT02444182CompletedPeriodontal Health, Dental Plaque Accumulation
NCT00282113CompletedPremature Infants
NCT02180581CompletedRespiratory Infections, Gastrointestinal Infections
NCT01229917CompletedRespiratory Tract Infections
NCT02110732CompletedUpper Respiratory Infection, Acute Otitis Media
NCT01782755CompletedVentilator Associated Pneumonia
NCT00445120CompletedVernal Keratoconjunctivitis

In line with these studies, a number of ongoing clinical trials are currently testing both the effectiveness and the safety of administering LGG to cancer patients subjected to anticancer therapy (NCT01790035, NCT00197873, NCT02544685, NCT02819960; Table I). Very recently, pre-results in support of the ongoing clinical trial NCT01790035 have been published. These results clearly show the mechanisms through which LGG is able to selectively protect colon normal cells during radiotherapy protocols, both in vitro and in vivo. LGG functions as a ‘time-release capsule’, able to deliver radioprotective lipoteichoic acid (LTA) within the intestinal crypts, thereby selectively protecting from the radiation-induced cell death the normal cells, but not the tumor cells (101). Notably, the group demonstrated that LGG-derived LTA activates peri-cryptal macrophages, in turn protecting the epithelial stem cells from radiation-induced apoptosis (101).

In addition to the cited clinical trials, two clinical trials designed by our group are currently opening and are about to be registered at clinicaltrials.gov. The two studies, entitled respectively: ‘Maintenance of normal gastrointestinal function with dietary supplement containing Lactobacillus rhamnosus GG in cancer patients treated with cytotoxic chemotherapy and/or targeted therapy’ and ‘Maintenance of normal gastrointestinal function with dietary supplement containing Lactobacillus rhamnosus GG in patients treated with abdominal or pelvic radiotherapy’, will assess the efficacy of LGG daily oral administration in the maintenance of normal gastrointestinal functions within cancer patients, treated either with chemotherapy and/or targeted therapy or abdominal/pelvic radiotherapy.

Once concluded, the currently ongoing clinical studies, will shed light into the efficacy and safety of the use of the promising probiotic, LGG, as an adjuvant in oncology. The studies will assess whether LGG is truly able to protect cancer patients from the detrimental gastrointestinal side-effects usually associated with anticancer therapy.

6. Conclusions

The human gut microbiota composition consists of a delicate balance, constantly modulated by several processes affecting the host during the entire lifespan (including aging, diet and lifetime exposure to heterogeneous environmental factors). A healthy microbiota is able to perform core symbiotic functions within his host, in a well-integrated host-microbiota relationship.

Cancer is a condition which tremendously affects the gut microbiota-host equilibrium, both during oncogenesis, as well as concurrently with anticancer therapy. This unbalanced equilibrium is often followed by the dysbiosis of the gut microbiota. Consequently, current research is constantly aiming at identifying methods with which to safely modulate a dysbiotic microbiota, helping to heal detrimental conditions, such as the gastrointestinal side-effects of chemotherapy, radiation therapy and immunotherapy (including mucositis, diarrhea and opportunistic infections).

The administration of probiotics during anticancer therapy is yielding promising clinical results, as it improves gut dysbiosis in cancer patients. Moreover, probiotics have been found capable of significantly ameliorating patients' compliance to treatments, as well as their overall quality of life. Among the characterized probiotics, recent studies have suggested that LGG, administered in vivo, is able to modulate the immune system, reducing the detrimental toxic intestinal effects following pelvic radiotherapy. This result is particularly promising and paves the way towards the auspicious ongoing trials on cancer patients undergoing anticancer treatments.

Despite the already published clinical results reporting the beneficial role of probiotics in alleviating the harmful side-effects of anticancer therapies, care needs to be pursued, as patients are often immunocompromised; therefore, it is important to evaluate the health risks possibly linked to the administration of probiotics to sensitive individuals. In the future, the design of novel experimental trials may undertake a personalized approach, considering the specific clinical and pathological background of each single patient to be enrolled, in order to gain only the positive outcomes of probiotics administration, possibly without any harmful side-effect.

Acknowledgements

The authors would like to thank the Italian League Against Cancer (LILT) for its support.

Funding

No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

SV and ML were involved in the conceptualization and design of this review article. LF, MSB and CG were involved in searching the literature for paragraphs 2 and 5. DN and MS were involved in searching the relevant literature and databases for paragraphs 3 and 4. SV and ML were involved in the preparation of the original draft and in the preparation of the figure and tables. SV, LF, MSB, DN, CG, ML and MS reviewed and edited the article. All authors have read and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

ML is the PI of a research grant founded by Dicofarm Spa to his University Department. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential competing interest.

References

1 

Ursell LK, Metcalf JL, Parfrey LW and Knight R: Defining the human microbiome. Nutr Rev. 70 (Suppl 1):S38–S44. 2012.PubMed/NCBI View Article : Google Scholar

2 

Zhang YJ, Li S, Gan RY, Zhou T, Xu DP and Li HB: Impacts of gut bacteria on human health and diseases. Int J Mol Sci. 16:7493–7519. 2015.PubMed/NCBI View Article : Google Scholar

3 

Feng Q, Chen WD and Wang YD: Gut Microbiota: An Integral Moderator in Health and Disease. Front Microbiol. 9(151)2018.PubMed/NCBI View Article : Google Scholar

4 

Lynch SV and Pedersen O: The Human Intestinal Microbiome in Health and Disease. N Engl J Med. 375:2369–2379. 2016.PubMed/NCBI View Article : Google Scholar

5 

Greenhalgh K, Meyer KM, Aagaard KM and Wilmes P: The human gut microbiome in health: Establishment and resilience of microbiota over a lifetime. Environ Microbiol. 18:2103–2116. 2016.PubMed/NCBI View Article : Google Scholar

6 

Neuman H, Debelius JW, Knight R and Koren O: Microbial endocrinology: The interplay between the microbiota and the endocrine system. FEMS Microbiol Rev. 39:509–521. 2015.PubMed/NCBI View Article : Google Scholar

7 

Ceranowicz P, Warzecha Z and Dembinski A: Peptidyl hormones of endocrine cells origin in the gut--their discovery and physiological relevance. J Physiol Pharmacol. 66:11–27. 2015.PubMed/NCBI

8 

Sandrini S, Aldriwesh M, Alruways M and Freestone P: Microbial endocrinology: Host-bacteria communication within the gut microbiome. J Endocrinol. 225:R21–R34. 2015.PubMed/NCBI View Article : Google Scholar

9 

Ravussin Y, Koren O, Spor A, LeDuc C, Gutman R, Stombaugh J, Knight R, Ley RE and Leibel RL: Responses of gut microbiota to diet composition and weight loss in lean and obese mice. Obesity (Silver Spring). 20:738–747. 2012.PubMed/NCBI View Article : Google Scholar

10 

Queipo-Ortuño MI, Seoane LM, Murri M, Pardo M, Gomez-Zumaquero JM, Cardona F, Casanueva F and Tinahones FJ: Gut microbiota composition in male rat models under different nutritional status and physical activity and its association with serum leptin and ghrelin levels. PLoS One. 8(e65465)2013.PubMed/NCBI View Article : Google Scholar

11 

Gensollen T, Iyer SS, Kasper DL and Blumberg RS: How colonization by microbiota in early life shapes the immune system. Science. 352:539–544. 2016.PubMed/NCBI View Article : Google Scholar

12 

Schmidt TSB, Raes J and Bork P: The Human Gut Microbiome: From Association to Modulation. Cell. 172:1198–1215. 2018.PubMed/NCBI View Article : Google Scholar

13 

Bultman SJ: Emerging roles of the microbiome in cancer. Carcinogenesis. 35:249–255. 2014.PubMed/NCBI View Article : Google Scholar

14 

Cani PD: Human gut microbiome: Hopes, threats and promises. Gut. 67:1716–1725. 2018.PubMed/NCBI View Article : Google Scholar

15 

Mohajeri MH, Brummer RJM, Rastall RA, Weersma RK, Harmsen HJM, Faas M and Eggersdorfer M: The role of the microbiome for human health: From basic science to clinical applications. Eur J Nutr. 57 (Suppl 1):1–14. 2018.PubMed/NCBI View Article : Google Scholar

16 

Fukui H, Xu X and Miwa H: Role of Gut Microbiota-Gut Hormone Axis in the Pathophysiology of Functional Gastrointestinal Disorders. J Neurogastroenterol Motil. 24:367–386. 2018.PubMed/NCBI View Article : Google Scholar

17 

Clarke G, Stilling RM, Kennedy PJ, Stanton C, Cryan JF and Dinan TG: Minireview: Gut microbiota: the neglected endocrine organ. Mol Endocrinol. 28:1221–1238. 2014.PubMed/NCBI View Article : Google Scholar

18 

Vaishnava S, Behrendt CL, Ismail AS, Eckmann L and Hooper LV: Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci USA. 105:20858–20863. 2008.PubMed/NCBI View Article : Google Scholar

19 

Belkaid Y and Naik S: Compartmentalized and systemic control of tissue immunity by commensals. Nat Immunol. 14:646–653. 2013.PubMed/NCBI View Article : Google Scholar

20 

Magnúsdóttir S, Ravcheev D, de Crécy-Lagard V and Thiele I: Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Front Genet. 6(148)2015.PubMed/NCBI View Article : Google Scholar

21 

Carding S, Verbeke K, Vipond DT, Corfe BM and Owen LJ: Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis. 26(26191)2015.PubMed/NCBI View Article : Google Scholar

22 

Grice EA and Segre JA: The human microbiome: Our second genome. Annu Rev Genomics Hum Genet. 13:151–170. 2012.PubMed/NCBI View Article : Google Scholar

23 

Geva-Zatorsky N, Sefik E, Kua L, Pasman L, Tan TG Ortiz-Lopez A, Yanortsang TB, Yang L, Jupp R, Mathis D, et al: Mining the Human Gut Microbiota for Immunomodulatory Organisms. Cell. 168:928–943.e11. 2017.PubMed/NCBI View Article : Google Scholar

24 

Haber AL, Biton M, Rogel N, Herbst RH, Shekhar K, Smillie C, Burgin G, Delorey TM, Howitt MR, Katz Y, et al: A single-cell survey of the small intestinal epithelium. Nature. 551:333–339. 2017.PubMed/NCBI View Article : Google Scholar

25 

Nash AK, Auchtung TA, Wong MC, Smith DP, Gesell JR, Ross MC, Stewart CJ, Metcalf GA, Muzny DM, Gibbs RA, et al: The gut mycobiome of the Human Microbiome Project healthy cohort. Microbiome. 5(153)2017.PubMed/NCBI View Article : Google Scholar

26 

Lloyd-Price J, Mahurkar A, Rahnavard G, Crabtree J, Orvis J, Hall AB, Brady A, Creasy HH, McCracken C, Giglio MG, et al: Strains, functions and dynamics in the expanded Human Microbiome Project. Nature. 550:61–66. 2017.PubMed/NCBI View Article : Google Scholar

27 

Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, Costea PI, Godneva A, Kalka IN, Bar N, et al: Environment dominates over host genetics in shaping human gut microbiota. Nature. 555:210–215. 2018.PubMed/NCBI View Article : Google Scholar

28 

Korem T, Zeevi D, Suez J, Weinberger A, Avnit-Sagi T, Pompan-Lotan M, Matot E, Jona G, Harmelin A, Cohen N, et al: Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples. Science. 349:1101–1106. 2015.PubMed/NCBI View Article : Google Scholar

29 

Lloyd-Price J, Abu-Ali G and Huttenhower C: The healthy human microbiome. Genome Med. 8(51)2016.PubMed/NCBI View Article : Google Scholar

30 

Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L, Canani RB, Flint HJ, Salminen S, et al: Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 11:506–514. 2014.PubMed/NCBI View Article : Google Scholar

31 

Pandey KR, Naik SR and Vakil BV: Probiotics, prebiotics and synbiotics- a review. J Food Sci Technol. 52:7577–7587. 2015.PubMed/NCBI View Article : Google Scholar

32 

Tsai YL, Lin TL, Chang CJ, Wu TR, Lai WF, Lu CC and Lai HC: Probiotics, prebiotics and amelioration of diseases. J Biomed Sci. 26(3)2019.PubMed/NCBI View Article : Google Scholar

33 

Goodman B and Gardner H: The microbiome and cancer. J Pathol. 244:667–676. 2018.PubMed/NCBI View Article : Google Scholar

34 

Tomasetti C and Vogelstein B: Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science. 347:78–81. 2015.PubMed/NCBI View Article : Google Scholar

35 

Ashford NA, Bauman P, Brown HS, Clapp RW, Finkel AM, Gee D, Hattis DB, Martuzzi M, Sasco AJ and Sass JB: Cancer risk: Role of environment. Science. 347(727)2015.PubMed/NCBI View Article : Google Scholar

36 

Polo A, Crispo A, Cerino P, Falzone L, Candido S, Giudice A, De Petro G, Ciliberto G, Montella M, Budillon A, et al: Environment and bladder cancer: Molecular analysis by interaction networks. Oncotarget. 8:65240–65252. 2017.PubMed/NCBI View Article : Google Scholar

37 

Falzone L, Marconi A, Loreto C, Franco S, Spandidos DA and Libra M: Occupational exposure to carcinogens: Benzene, pesticides and fibers (Review). Mol Med Rep. 14:4467–4474. 2016.PubMed/NCBI View Article : Google Scholar

38 

Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B and Aggarwal BB: Cancer is a preventable disease that requires major lifestyle changes. Pharm Res. 25:2097–2116. 2008.PubMed/NCBI View Article : Google Scholar

39 

Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, Dicker DJ, Chimed-Orchir O, Dandona R, et al: Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 3:524–548. 2017.PubMed/NCBI View Article : Google Scholar

40 

Wang H, Naghavi M, Allen C, Barber RM, Bhutta ZA, Carter A, Casey DC, Charlson FJ, Chen AZ, Coates MM, et al: GBD 2015 Mortality and Causes of Death Collaborators: Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet. 388:1459–1544. 2016.PubMed/NCBI View Article : Google Scholar

41 

Rapisarda V, Salemi R, Marconi A, Loreto C, Graziano AC, Cardile V, Basile MS, Candido S, Falzone L, Spandidos DA, et al: Fluoro-edenite induces fibulin-3 overexpression in non-malignant human mesothelial cells. Oncol Lett. 12:3363–3367. 2016.PubMed/NCBI View Article : Google Scholar

42 

Rapisarda V, Ledda C, Matera S, Fago L, Arrabito G, Falzone L, Marconi A, Libra M and Loreto C: Absence of t(14;18) chromosome translocation in agricultural workers after short-term exposure to pesticides. Mol Med Rep. 15:3379–3382. 2017.PubMed/NCBI View Article : Google Scholar

43 

Fenga C, Gangemi S, Di Salvatore V, Falzone L and Libra M: Immunological effects of occupational exposure to lead (Review). Mol Med Rep. 15:3355–3360. 2017.PubMed/NCBI View Article : Google Scholar

44 

Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr and Kinzler KW: Cancer genome landscapes. Science. 339:1546–1558. 2013.PubMed/NCBI View Article : Google Scholar

45 

Guarneri C, Bevelacqua V, Polesel J, Falzone L, Cannavò PS, Spandidos DA, Malaponte G and Libra M: NF-κB inhibition is associated with OPN/MMP-9 downregulation in cutaneous melanoma. Oncol Rep. 37:737–746. 2017.PubMed/NCBI View Article : Google Scholar

46 

Salemi R, Falzone L, Madonna G, Polesel J, Cinà D, Mallardo D, Ascierto PA, Libra M and Candido S: MMP-9 as a Candidate Marker of Response to BRAF Inhibitors in Melanoma Patients With BRAFV600E Mutation Detected in Circulating-Free DNA. Front Pharmacol. 9(856)2018.PubMed/NCBI View Article : Google Scholar

47 

Leonardi GC, Falzone L, Salemi R, Zanghì A, Spandidos DA, Mccubrey JA, Candido S and Libra M: Cutaneous melanoma: From pathogenesis to therapy (Review). Int J Oncol. 52:1071–1080. 2018.PubMed/NCBI View Article : Google Scholar

48 

Bhang HE, Ruddy DA, Krishnamurthy Radhakrishna V, Caushi JX, Zhao R, Hims MM, Singh AP, Kao I, Rakiec D, Shaw P, et al: Studying clonal dynamics in response to cancer therapy using high-complexity barcoding. Nat Med. 21:440–448. 2015.PubMed/NCBI View Article : Google Scholar

49 

Kloor M and von Knebel Doeberitz M: The Immune Biology of Microsatellite-Unstable Cancer. Trends Cancer. 2:121–133. 2016.PubMed/NCBI View Article : Google Scholar

50 

Carter SL, Eklund AC, Kohane IS, Harris LN and Szallasi Z: A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet. 38:1043–1048. 2006.PubMed/NCBI View Article : Google Scholar

51 

Dagogo-Jack I and Shaw AT: Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol. 15:81–94. 2018.PubMed/NCBI View Article : Google Scholar

52 

Falzone L, Romano GL, Salemi R, Bucolo C, Tomasello B, Lupo G, Anfuso CD, Spandidos DA, Libra M and Candido S: Prognostic significance of deregulated microRNAs in uveal melanomas. Mol Med Rep. 19:2599–2610. 2019.PubMed/NCBI View Article : Google Scholar

53 

Battaglia R, Palini S, Vento ME, La Ferlita A, Lo Faro MJ, Caroppo E, Borzì P, Falzone L, Barbagallo D, Ragusa M, et al: Identification of extracellular vesicles and characterization of miRNA expression profiles in human blastocoel fluid. Sci Rep. 9(84)2019.PubMed/NCBI View Article : Google Scholar

54 

Basile MS, Fagone P, Mangano K, Mammana S, Magro G, Salvatorelli L, Li Destri G, La Greca G, Nicoletti F, Puleo S and Pesce A: KCNMA1 Expression is Downregulated in Colorectal Cancer via Epigenetic Mechanisms. Cancers (Basel). 11pii. (E245)2019.PubMed/NCBI View Article : Google Scholar

55 

Falzone L, Scola L, Zanghì A, Biondi A, Di Cataldo A, Libra M and Candido S: Integrated analysis of colorectal cancer microRNA datasets: Identification of microRNAs associated with tumor development. Aging (Albany NY). 10:1000–1014. 2018.PubMed/NCBI View Article : Google Scholar

56 

McCubrey JA, Fitzgerald TL, Yang LV, Lertpiriyapong K, Steelman LS, Abrams SL, Montalto G, Cervello M, Neri LM, Cocco L, et al: Roles of GSK-3 and microRNAs on epithelial mesenchymal transition and cancer stem cells. Oncotarget. 8:14221–14250. 2017.PubMed/NCBI View Article : Google Scholar

57 

Falzone L, Candido S, Salemi R, Basile MS, Scalisi A, McCubrey JA, Torino F, Signorelli SS, Montella M and Libra M: Computational identification of microRNAs associated to both epithelial to mesenchymal transition and NGAL/MMP-9 pathways in bladder cancer. Oncotarget. 7:72758–72766. 2016.PubMed/NCBI View Article : Google Scholar

58 

Hafsi S, Candido S, Maestro R, Falzone L, Soua Z, Bonavida B, Spandidos DA and Libra M: Correlation between the overexpression of Yin Yang 1 and the expression levels of miRNAs in Burkitt's lymphoma: A computational study. Oncol Lett. 11:1021–1025. 2016.PubMed/NCBI View Article : Google Scholar

59 

Falzone L, Lupo G, Rosa GRM, Crimi S, Anfuso CD, Salemi R, Rapisarda E, Libra M and Candido S: Identification of Novel MicroRNAs and Their Diagnostic and Prognostic Significance in Oral Cancer. Cancers (Basel). 11pii. (E610)2019.PubMed/NCBI View Article : Google Scholar

60 

Falzone L, Salemi R, Travali S, Scalisi A, McCubrey JA, Candido S and Libra M: MMP-9 overexpression is associated with intragenic hypermethylation of MMP9 gene in melanoma. Aging (Albany NY). 8:933–944. 2016.PubMed/NCBI View Article : Google Scholar

61 

Dy GK and Adjei AA: Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin. 63:249–279. 2013.PubMed/NCBI View Article : Google Scholar

62 

McGranahan N and Swanton C: Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 27:15–26. 2015.PubMed/NCBI View Article : Google Scholar

63 

Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, Porta-Pardo E, Gao GF, Plaisier CL, Eddy JA, et al: Cancer Genome Atlas Research Network: The Immune Landscape of Cancer. Immunity. 48:812–830.e14. 2018.PubMed/NCBI View Article : Google Scholar

64 

Presti M, Mazzon E, Basile MS, Petralia MC, Bramanti A, Colletti G, Bramanti P, Nicoletti F and Fagone P: Overexpression of macrophage migration inhibitory factor and functionally-related genes, D-DT, CD74, CD44, CXCR2 and CXCR4, in glioblastoma. Oncol Lett. 16:2881–2886. 2018.PubMed/NCBI View Article : Google Scholar

65 

Mangano K, Mazzon E, Basile MS, Di Marco R, Bramanti P, Mammana S, Petralia MC, Fagone P and Nicoletti F: Pathogenic role for macrophage migration inhibitory factor in glioblastoma and its targeting with specific inhibitors as novel tailored therapeutic approach. Oncotarget. 9:17951–17970. 2018.PubMed/NCBI View Article : Google Scholar

66 

Basile MS, Mazzon E, Russo A, Mammana S, Longo A, Bonfiglio V, Fallico M, Caltabiano R, Fagone P, Nicoletti F, et al: Differential modulation and prognostic values of immune-escape genes in uveal melanoma. PLoS One. 14(e0210276)2019.PubMed/NCBI View Article : Google Scholar

67 

Emens LA, Ascierto PA, Darcy PK, Demaria S, Eggermont AMM, Redmond WL, Seliger B and Marincola FM: Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer. 81:116–129. 2017.PubMed/NCBI View Article : Google Scholar

68 

Toh HC: Cancer immunotherapy-the end of the beginning. Linchuang Zhongliuxue Zazhi. 7(12)2018.PubMed/NCBI View Article : Google Scholar

69 

Roy S and Trinchieri G: Microbiota: A key orchestrator of cancer therapy. Nat Rev Cancer. 17:271–285. 2017.PubMed/NCBI View Article : Google Scholar

70 

Nayak RR and Turnbaugh PJ: Mirror, mirror on the wall: Which microbiomes will help heal them all? BMC Med. 14(72)2016.PubMed/NCBI View Article : Google Scholar

71 

Fessler JL and Gajewski TF: The Microbiota: A New Variable Impacting Cancer Treatment Outcomes. Clin Cancer Res. 23:3229–3231. 2017.PubMed/NCBI View Article : Google Scholar

72 

Schwabe RF and Jobin C: The microbiome and cancer. Nat Rev Cancer. 13:800–812. 2013.PubMed/NCBI View Article : Google Scholar

73 

Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A and Wargo JA: The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy. Cancer Cell. 33:570–580. 2018.PubMed/NCBI View Article : Google Scholar

74 

Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al: Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 359:91–97. 2018.PubMed/NCBI View Article : Google Scholar

75 

Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al: Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 359:97–103. 2018.PubMed/NCBI View Article : Google Scholar

76 

Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ and Gajewski TF: The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 359:104–108. 2018.PubMed/NCBI View Article : Google Scholar

77 

Chen Q, Wang C, Chen G, Hu Q and Gu Z: Delivery Strategies for Immune Checkpoint Blockade. Adv Healthc Mater. 7(e1800424)2018.PubMed/NCBI View Article : Google Scholar

78 

Buchbinder EI and Desai A: CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol. 39:98–106. 2016.PubMed/NCBI View Article : Google Scholar

79 

Falzone L, Salomone S and Libra M: Evolution of Cancer Pharmacological Treatments at the Turn of the Third Millennium. Front Pharmacol. 9(1300)2018.PubMed/NCBI View Article : Google Scholar

80 

Mego M, Holec V, Drgona L, Hainova K, Ciernikova S and Zajac V: Probiotic bacteria in cancer patients undergoing chemotherapy and radiation therapy. Complement Ther Med. 21:712–723. 2013.PubMed/NCBI View Article : Google Scholar

81 

Maria-Aggeliki KS, Nikolaos KL, Kyrias GM and Vassilis KE: The potential clinical impact of probiotic treatment for the prevention and/or anti-inflammatory therapeutic effect against radiation induced intestinal mucositis. A review. Recent Pat Inflamm Allergy Drug Discov. 3:195–200. 2009. View Article : Google Scholar

82 

Rondanelli M, Faliva MA, Perna S, Giacosa A, Peroni G and Castellazzi AM: Using probiotics in clinical practice: Where are we now? A review of existing meta-analyses. Gut Microbes. 8:521–543. 2017.PubMed/NCBI View Article : Google Scholar

83 

Zitvogel L, Ma Y, Raoult D, Kroemer G and Gajewski TF: The microbiome in cancer immunotherapy: Diagnostic tools and therapeutic strategies. Science. 359:1366–1370. 2018.PubMed/NCBI View Article : Google Scholar

84 

Vanderhoof JA and Young R: Probiotics in the United States. Clin Infect Dis. 46 (Suppl 2):S67–S72; discussion S144-S151. 2008.PubMed/NCBI View Article : Google Scholar

85 

Redman MG, Ward EJ and Phillips RS: The efficacy and safety of probiotics in people with cancer: A systematic review. Ann Oncol. 25:1919–1929. 2014.PubMed/NCBI View Article : Google Scholar

86 

Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J and Committee EG: ESMO Guidelines Committee Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 26 (Suppl 5):v139–v151. 2015. View Article : Google Scholar

87 

Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, McGuire DB, Migliorati C, Nicolatou-Galitis O, Peterson DE, et al: Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO): MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 120:1453–1461. 2014.PubMed/NCBI View Article : Google Scholar

88 

Gianotti L, Morelli L, Galbiati F, Rocchetti S, Coppola S, Beneduce A, Gilardini C, Zonenschain D, Nespoli A and Braga M: A randomized double-blind trial on perioperative administration of probiotics in colorectal cancer patients. World J Gastroenterol. 16:167–175. 2010.PubMed/NCBI View Article : Google Scholar

89 

Demers M, Dagnault A and Desjardins J: A randomized double-blind controlled trial: Impact of probiotics on diarrhea in patients treated with pelvic radiation. Clin Nutr. 33:761–767. 2014.PubMed/NCBI View Article : Google Scholar

90 

Mego M, Chovanec J, Vochyanova-Andrezalova I, Konkolovsky P, Mikulova M, Reckova M, Miskovska V, Bystricky B, Beniak J, Medvecova L, et al: Prevention of irinotecan induced diarrhea by probiotics: A randomized double blind, placebo controlled pilot study. Complement Ther Med. 23:356–362. 2015.PubMed/NCBI View Article : Google Scholar

91 

Theodoropoulos GE, Memos NA, Peitsidou K, Karantanos T, Spyropoulos BG and Zografos G: Synbiotics and gastrointestinal function-related quality of life after elective colorectal cancer resection. Ann Gastroenterol. 29:56–62. 2016.PubMed/NCBI

92 

Consoli ML, da Silva RS, Nicoli JR, Bruña-Romero O, da Silva RG, de Vasconcelos Generoso S and Correia MI: Randomized Clinical Trial: Impact of Oral Administration of Saccharomyces boulardii on Gene Expression of Intestinal Cytokines in Patients Undergoing Colon Resection. JPEN J Parenter Enteral Nutr. 40:1114–1121. 2016.PubMed/NCBI View Article : Google Scholar

93 

Flesch AT, Tonial ST, Contu PC and Damin DC: Perioperative synbiotics administration decreases postoperative infections in patients with colorectal cancer: A randomized, double-blind clinical trial. Rev Col Bras Cir. 44:567–573. 2017.PubMed/NCBI View Article : Google Scholar

94 

Goldin BR, Gualtieri LJ and Moore RP: The effect of Lactobacillus GG on the initiation and promotion of DMH-induced intestinal tumors in the rat. Nutr Cancer. 25:197–204. 1996.PubMed/NCBI View Article : Google Scholar

95 

Banna GL, Torino F, Marletta F, Santagati M, Salemi R, Cannarozzo E, Falzone L, Ferraù F and Libra M: Lactobacillus rhamnosus GG: An Overview to Explore the Rationale of Its Use in Cancer. Front Pharmacol. 8(603)2017.PubMed/NCBI View Article : Google Scholar

96 

Lee CS, Ryan EJ and Doherty GA: Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: The role of inflammation. World J Gastroenterol. 20:3751–3761. 2014.PubMed/NCBI View Article : Google Scholar

97 

Khailova L, Baird CH, Rush AA, Barnes C and Wischmeyer PE: Lactobacillus rhamnosus GG treatment improves intestinal permeability and modulates inflammatory response and homeostasis of spleen and colon in experimental model of Pseudomonas aeruginosa pneumonia. Clin Nutr. 36:1549–1557. 2017.PubMed/NCBI View Article : Google Scholar

98 

Wang Y, Liu L, Moore DJ, Shen X, Peek RM, Acra SA, Li H, Ren X, Polk DB and Yan F: An LGG-derived protein promotes IgA production through upregulation of APRIL expression in intestinal epithelial cells. Mucosal Immunol. 10:373–384. 2017.PubMed/NCBI View Article : Google Scholar

99 

Fong FLY, Kirjavainen PV and El-Nezami H: Immunomodulation of Lactobacillus rhamnosus GG (LGG)-derived soluble factors on antigen-presenting cells of healthy blood donors. Sci Rep. 6(22845)2016.PubMed/NCBI View Article : Google Scholar

100 

Vivarelli S, Salemi R, Candido S, Falzone L, Santagati M, Stefani S, Torino F, Banna GL, Tonini G and Libra M: Gut Microbiota and Cancer: From Pathogenesis to Therapy. Cancers (Basel). 11pii. (E38)2019.PubMed/NCBI View Article : Google Scholar

101 

Riehl TE, Alvarado D, Ee X, Zuckerman A, Foster L, Kapoor V, Thotala D, Ciorba MA and Stenson WF: GG protects the intestinal epithelium from radiation injury through release of lipoteichoic acid, macrophage activation and the migration of mesenchymal stem cells. Gut. 68:1003–1013. 2018.PubMed/NCBI View Article : Google Scholar

Related Articles

Journal Cover

May 2019
Volume 1 Issue 3

Print ISSN: 2632-2900
Online ISSN:2632-2919

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Vivarelli, S., Falzone, L., Basile, M.S., Nicolosi, D., Genovese, C., Libra, M., & Salmeri, M. (2019). Benefits of using probiotics as adjuvants in anticancer therapy (Review). World Academy of Sciences Journal, 1, 125-135. https://doi.org/10.3892/wasj.2019.13
MLA
Vivarelli, S., Falzone, L., Basile, M. S., Nicolosi, D., Genovese, C., Libra, M., Salmeri, M."Benefits of using probiotics as adjuvants in anticancer therapy (Review)". World Academy of Sciences Journal 1.3 (2019): 125-135.
Chicago
Vivarelli, S., Falzone, L., Basile, M. S., Nicolosi, D., Genovese, C., Libra, M., Salmeri, M."Benefits of using probiotics as adjuvants in anticancer therapy (Review)". World Academy of Sciences Journal 1, no. 3 (2019): 125-135. https://doi.org/10.3892/wasj.2019.13