Cancer cells are comfy havens for bacteria. That conclusion arises from a rigorous study of over 1,000 tumor samples of different human cancers.
The study, headed by researchers at the Weizmann Institute of Science, found bacteria living inside the cells of all the cancer types – from brain to bone to breast cancer – and even identified unique populations of bacteria residing in each type of cancer.
The research suggests that understanding the relationship between a cancer cell and its “mini-microbiome” may help predict the potential effectiveness of certain treatments, or may point to ways of manipulating those bacteria to enhance the actions of anticancer treatments in the future. The findings of this study were published in Science.
Several years ago, Dr. Ravid Straussman of the Institute’s Molecular Cell Biology Department had discovered bacteria lurking within human pancreatic tumor cells; these bacteria were shown to protect cancer cells from chemotherapy drugs by “digesting” and inactivating these drugs.
When other studies also found bacteria in tumor cells, Straussman and his team wondered whether such hosting might be the rule, rather than the exception. To find out, Drs. Deborah Nejman and Ilana Livyatan in Straussman’s group and Dr. Garold Fuks of the Physics of Complex Systems Department worked together with a team of oncologists and researchers around the world.
The work was also led by Dr. Noam Shental of the Mathematics and Computer Science Department of the Open University of Israel.
Ultimately, the team would produce a detailed study describing, in high resolution, the bacteria living in these cancers – brain, bone, breast, lung, ovary, pancreas, colorectal and melanoma.
They discovered that every single cancer type, from brain to bone, harbored bacteria, and that different cancer types harbor different bacteria species. It was the breast cancers, however, that had the highest number and diversity of bacteria.
The team demonstrated that many more bacteria can be found in breast tumors compared to the normal breast tissue surrounding these tumors, and that some bacteria were preferentially found in the tumor tissue rather than in the normal tissue surrounding it.
To arrive at these results, the team had to overcome several challenges. For one, the mass of bacteria in a tumor sample is relatively small, and the researchers had to find ways to focus on these tiny cells-within-cells.
They also had to eliminate any possible outside contamination. To this end, they used hundreds of negative controls and created a series of computational filters to remove the traces of any bacteria that could have come from outside the tumor samples.
The team was able to grow bacteria directly from human breast tumors, and their results proved that the bacteria found in these tumors are alive. Electron microscopy visualization of these bacteria demonstrated that they prefer to nestle up in a specific location inside the cancer cells – close to the cell nucleus.
Different cells for different bacteria
The team also reported that bacteria can be found not only in cancer cells, but also in immune cells that reside inside tumors.
“Some of these bacteria could be enhancing the anticancer immune response, while others could be suppressing it – a finding that may be especially relevant to understanding the effectiveness of certain immunotherapies,” says Straussman.
Indeed, when the team compared the bacteria from groups of melanoma samples, they found that different bacteria were enriched in those melanoma tumors that responded to immunotherapy as compared to those that had a poor response.
Straussman thinks that the study can also begin to explain why some bacteria like cancer cells and why each cancer has its own typical microbiome: The differences apparently come down to the choice of amenities offered in each kind of tumor-cell environment.
That is, the bacteria may live off certain metabolites that are overproduced by or stored within the specific tumor types. For example, when the team compared the bacteria found in lung tumors from smokers with those from patients who had never smoked, they found variances.
These differences stood out more clearly when the researchers compared the genes of these two groups of bacteria: Those from the smokers’ lung cancer cells had many more genes for metabolizing nicotine, toluene, phenol and other chemicals that are found in cigarette smoke.
In addition to showing that some of the most common cancers shelter unique populations of bacteria within their cells, the researchers believe that the methods they have developed to identify signature microbiomes with each cancer type can now be used to answer some crucial questions about the roles these bacteria play: Are the bacteria freeloaders on the cancer cell’s surplus metabolites, or do they provide a service to the cell?
At what stage do they take up residence?
How do they promote or hinder the cancer’s growth? What are the effects that they have on response to a wide variety of anticancer treatments?
“Tumors are complex ecosystems that are known to contain, in addition to cancer cells, immune cells, stromal cells, blood vessels, nerves, and many more components, all part of what we refer to as the tumor microenvironment.
Our studies, as well as studies by other labs, clearly demonstrate that bacteria are also an integral part of the tumor microenvironment. We hope that by finding out how exactly they fit into the general tumor ecology, we can figure out novel ways of treating cancer,” Straussman says.
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.
- 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).
- 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.
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.
- 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.
Clinical studies registered at clinicaltrials.gov involving the use of probiotics in combination with anticancer therapy.
|Study ID||Title of the study||Conditions||Interventions||Status||Ref.|
|NCT00936572||Probiotics In Colorectal Cancer Patients||CRC||Probiotics (B. longum, L. johnsonii)||C||(88)|
|NCT01839721||Impact of Probiotics BIFILACT® on Diarrhea in Cancer Patients Treated With Pelvic Radiation||CAN||BIFILACT (L. acidophilus, B. longum)||C||(89)|
|NCT01410955||Prevention of Irinotecan Induced Diarrhea by Probiotics||CRC||Colon Dophilus (Lactobacillus spp, Bifidobacterium spp)||C||(90)|
|NCT01479907||Synbiotics and Gastrointestinal Function Related Quality of Life After Colectomy for Cancer||CRC||Synbiotic Forte (Lactobacillus spp and prebiotics)||C||(91)|
|NCT01609660||Impact of Probiotics on the Intestinal Microbiota||CRC||S. boulardii||C||(92)|
|NCT01468779||Effect of Probiotics in Patients Undergoing Surgery for Periampullary Neoplasms||PC||Probiotic formula||C||(93)|
|NCT03420443||Action of Synbiotics on Irradiated GI Mucosa in CRC Treatment (FIPIREX)||CRC||Synbiotics||C|
|NCT01723592||Orally Administered Probiotics to Improve the Quality of the Vaginal Flora of Women With Breast Cancer and Chemotherapy||BC||Probiotics (Lactobacillus spp)||C|
|NCT02771470||Intestinal Microflora in Lung Cancer After Chemotherapy||LC||C. butyricum||C|
|NCT01895530||Impact of Probiotics in Modulation of Intestinal Microbiota||CRC||S. boulardii||C|
|NCT02021253||Influence of Probiotics Administration Before Liver Resection in Liver Disease||HC||Lactibiane (B. lactis, L. acidophilus, L. plantarum, L. salivarius)||C|
|NCT03531606||The Effects of Mechnikov Probiotics on Symptom and Surgical Outcome||CRC||Probiotics||C|
|NCT03782428||An Evaluation of Probiotic in the Clinical Course of Patients With Colorectal Cancer||CRC||HEXBIO (L. acidophilus, L. lactis, L. casei, B. longum, B. bifidum, B. infantis)||C|
|NCT03358511||Engineering Gut Microbiome to Target Breast Cancer||BC||Primal Defense Ultra (Lactobacillus spp, Bifidobacterium spp)||O|
|NCT03785938||Mucositis and Infection Reduction With Liquid Probiotics in Children With Cancer (MaCROS)||PEDC||Symprove (L. rhamnosus, E. faecium, L. acidophilus, L. plantarum)||O|
|NCT02944617||Probiotic Yogurt Supplement in Reducing Diarrhea in Patients With Metastatic Kidney Cancer Being Treated With Vascular Endothelial Growth Factor-Tyrosine Kinase Inhibitor||RCC||Yogurt||O|
|NCT03704727||The Effects of Probiotics on Intestinal Permeability in Gastrointestinal Cancer Patients in Chemotherapy||GIC||VSL3 (Lactobacillus spp, Bifidobacterium spp)||O|
|NCT03742596||The Effect of Probiotics Supplementation on the Side Effects of Radiation Therapy Among Colorectal Cancer Patients||CRC||Probiotic Formula (Lactobacillus spp, Bifidobacterium spp)||O|
|NCT03177681||The Effect of Yogurt in Cancer Patient With Moderate Gastrointestinal Symptoms||CAN||Yogurt||O|
|NCT02351089||Probiotics in Radiation-treated Gynecologic Cancer (ProRad)||GYC||Probiotics||O|
|NCT03705442||Probiotics as Adjuvant Therapy in the Treatment of Metastatic Colorectal Cancer (Probat-tmcc-17)||CRC||Omni-Biotic 10 (Lactobacillus spp, Bifidobacterium spp)||O|
|NCT03552458||Effects of Probiotics in Preventing Oral Mucositis||HAN||L. Reuteri||O|
|NCT03518268||Vivomixx for Prevention of Bone Loss in Women With Breast Cancer Treated With an Aromatase Inhibitor||BC||Vivomixx (Lactobacillus spp, Bifidobacterium spp)||O|
|NCT03574051||Microbiota Associated With Iodine-131 Therapy and Hypothyroidism||TC||Probiotics (B. infantis, L. acidophilus, E. faecalis)||O|
|NCT03642548||Probiotics Combined With Chemotherapy for Patients With Advanced NSCLC||NSCLC||Bifico (B. Coagulans)||O|
|NCT02751736||The Effect Of Probiotics On Bowel Function Restoration After Ileostomy Closure In Patients With Rectal Cancer||CRC||L. plantarum||O|
|NCT01790035||Probiotic LGG for Prevention of Side Effects in Patients Undergoing Chemoradiation for Gastrointestinal Cancer||GIC||L. rhamnosus GG||O||(101)|
|NCT00197873||Lactobacillus rhamnosus in Prevention of Chemotherapy-related Diarrhoea||CRC||L. rhamnosus GG||O|
|NCT02544685||Prevention of Febrile Neutropenia by Synbiotics in Pediatric Cancer Patients||CAN||Probio-Fix Inum and corn starch (L. rhamnosus GG, B. animalis)||O|
|NCT02819960||Prevention of Irinotecan Induced Diarrhea by Probiotics||CAN||Probio-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.
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).
Clinical trials registered at clinicaltrials.gov assessing the benefits of administering LGG in association with a large number of different conditions.
|NCT01922895||Active||Acute Alcoholic Hepatitis|
|NCT03449459||Active||Chronic Obstructive Pulmonary Disease|
|NCT03647995||Active||Diarrhea, Clostridium difficile|
|NCT02640625||Active||Human Immunodeficiency Virus|
|NCT02748317||Active||Lower Urinary Tract Symptoms|
|NCT02748356||Active||Lower Urinary Tract Symptoms|
|NCT03215784||Active||Obesity, Pregnancy, Inflammation|
|NCT03196453||Active||Overweight, Nutrition Disorder|
|NCT02462590||Active||Pneumonia, Infections, Diarrhea|
|NCT01901380||Completed||Allergy, Functional Gastrointestinal Disorders|
|NCT02711800||Completed||Anxiety, Abdominal Pain|
|NCT00159523||Completed||Asthma, Atopic Dermatitis|
|NCT00325273||Completed||Atopic Dermatitis, Allergic Rhinitis, Asthma|
|NCT00224432||Completed||Atopic Dermatitis, Atopic Eczema|
|NCT02466035||Completed||Cow’s Milk Allergy|
|NCT02779881||Completed||Cow’s Milk Allergy|
|NCT00318695||Completed||Eczema, Asthma, Allergic Rhinitis|
|NCT02144701||Completed||Graft Versus Host Disease|
|NCT03427515||Completed||Healthy, Stress-related Problem, Anxiety|
|NCT01969331||Completed||Helicobacter pylori Infection|
|NCT01616693||Completed||Immunity to Oral Vaccines|
|NCT01551186||Completed||Infectious Disease of Digestive Tract|
|NCT03100266||Completed||Low Back Pain|
|NCT01164124||Completed||Low Birth Weight|
|NCT02288572||Completed||Metabolic Syndrome X|
|NCT02444182||Completed||Periodontal Health, Dental Plaque Accumulation|
|NCT02180581||Completed||Respiratory Infections, Gastrointestinal Infections|
|NCT01229917||Completed||Respiratory Tract Infections|
|NCT02110732||Completed||Upper Respiratory Infection, Acute Otitis Media|
|NCT01782755||Completed||Ventilator Associated Pneumonia|
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.
More information: Deborah Nejman et al. The human tumor microbiome is composed of tumor type–specific intracellular bacteria, Science (2020). DOI: 10.1126/science.aay9189
Chloe E. Atreya et al. Probing the tumor micro(b)environment, Science (2020). DOI: 10.1126/science.abc1464
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