Cancer and Society
Quackeries Probiotics and cancer: ready for meal time?
www.thelancet.com/oncology Vol 16 April 2015
bacteria to stay healthy. Two sides of the same sword, or different swords altogether? So-called good bacteria for human consumption is a multibillion pound industry and targets the basic human weakness of the need to rectify the falls of an indulgent lifestyle. But does the holy grail of popular scientific research—the cure for cancer—lie in the bacteria or do bacteria form the basis for creating the healthy society? This concept is no doubt a contradiction, but what do we know about these miniscule creatures and how they affect our wellbeing? In the human body, bacteria outnumber human cells by a factor of 10. Most microbes reside in the gut, resulting in a complex ecological environment, which can both prevent and cause disease, but for the most part they seem to be a positive force, or so we think and presume. As such, the gut microbiome complements and serves to fill several gaps in metabolic pathways or to assist with the immune system by resisting bad bacteria from dominating the flora, and thus, it should come as no surprise that diet, drugs, and the environment can cause imbalances here. Sitting at the crossroad of immunity, inflammation, and metabolism, the human microbiota occupies a strategic position in modulating environmental stressors that target our genome. It is therefore natural to conclude that these versatile, amorphous tribes of prokaryotic companions could in fact be qualitatively different in patients with cancer, having turned “bad” by promoting inflammation and potentially aiding cancer progression. A widening series of unresolved questions in tumour biology or oncogenesis seem to interpret the microbiome as a contributory factor. Age, for example, one of the strongest risk factors for epithelial cancers, is a key determinant
of the decreasing diversity in the human microbiome, leading to an unopposed proinflammatory status. Equally, environmental variations affecting the microbiome could underlie the dynamic changes in cancer incidence reported in migrating populations. Indeed, we are now placing substantial responsibility on the shoulders of our anucleated acquaintances, whose perturbation or dysbiosis seems to have become the unequivocal root of poor health in the 21st century. Whether dysbiosis though is an ineluctable fate or rather a new battlefield for the pharmaceutical industry to deploy probiotics becomes the million dollar question: far too important to be answered by marketing claims in non-scientific terms. Probiotics are cultures of living organisms that can be ingested and often include species with elegant names such as Lactobacillus spp and Bifidobacteria spp, which produce lactic acid—thought to be good for the immune system. They are frequently referred to as so-called good bacteria and are widely commercially available and seen as a safe option to maintain a healthy state. The evidence associated with the use of probiotics and the tangible benefits of their use has been the subject of much discussion with some recent evidence. In one study in which fermentable milk was fed to rats who were subsequently injected with breast cancer cells, there was a reduction in tumour growth as a result
See Online for appendix
Scimat/Science Photo Library
Anyone who has been in cancer research for long enough will remember the wave of optimism that came with the complete sequencing of the human genome, an achievement received by a fascinated scientific community as the ultimate proof that everything we had ever been interested in, including incidence and mortality from cancer amd toxicity and efficacy from treatment, was coded within endless, repetitive sequences of nucleotides—the letters that make up our genetic material or DNA. Influenced by a mesmerising deterministic spell, we were all led to believe that everything was prearranged. A microscopic script, strong as Archimedes’ lever, was rehearsed and played every day by billions of cells, orchestrated by 3 billion DNA letters, to ultimately influence our destiny as human beings. It was a matter of time before we came to terms with the futility of our attempts to set our destiny aside from a delicate and often troubled relationship with the environment surrounding us, where the microscopic world of bacteria plays a key but often neglected part. It took the audacity and foresight of a geneticist, the Nobel Prize winning Joshua Lederberg to organise and give that microscopic world of colourful spheres and rods an identity and a voice: the microbiome. This was of course the dirty side of so-called omics we would have never expected to be dealing with, in a society that is now flooded by advertisements showing us how to eradicate bacteria and germs. In our ‘‘Dettol’’ clean crazy society that has survived the lethal burden of bacterial infection, the plague of many chronic diseases including cancer is expanding fast. As a further and perhaps more profitable paradox, the dogma of complete bacterial eradication is nowadays paralleled by the urgency to fill our guts with billions of good
371
Cancer and Society
of increasing the number of immune cells that cause cancer cell death. Not all studies, however, have shown such effects and studies in man showing a reduction in cancer are inconclusive. One large epidemiological study examined the incidence of cancer in rural parts of China compared with in metropolitan areas and showed that areas that have a high consumption of non-pasteurised dairy products with diverse bacterial content have lower incidences of colorectal cancers, leading to the logical assumption that probiotic supplementation to a a processed diet, such as that in developed countries, might reduce cancer incidence or alter its progression. However, populations living in developed countries are not born with Chinese genes and thus translating one geography to another could be futile. On top of this, underpowered studies, inconsistencies in primary outcome measures, and the presence of a various of probiotic preparations almost impossible to standardise for the purpose of clinical research, make the evaluation of probiotics in disease prevention and treatment a truly difficult task. Although little evidence supports the regular use of probiotics for cancer prevention, oncologists could have gladly identified a few billion microscopic friends to help manage anticancer treatment toxicities. Mechanistic evidence shows that administration of attenuated bacteria could result in faster bone marrow recovery in white cell or immune deprived (leukopenic) animals, suggesting a potential role
for probiotics as a measure to prevent anticancer treatment-related infections. Clinical evidence is insufficient and deciphering a true immune modulating effect promoted by probiotics is scientifically challenging. There is, however, good evidence to support the use of probiotics to prevent infections from a dysbiotic gut bacterium such as Clostridium difficile, a common cause of infectious diarrhoea in patients with cancer, and potentially beneficial effects could stem from the management of chemotherapy induced diarrhoea. Following the encouraging results of animal models of radiation-induced enteritis, results of several studies in patients receiving radiotherapy have given a mixed message in terms of efficacy, with a recent meta-analysis failing to show significant improvement in gastrointestinal toxicity. Substantial heterogeneity within individual studies and different use of bacterial strains are potential sources of bias, but a common theme from all these studies is the safety of use of probiotics—which seems very high. This in itself is an important observation and allows the use of these preparations in what can be sometimes desperate situations for patients. In one study, use of probiotics in a 12-week period reduced the incidence of post-operative bowel-related symptoms and improved quality of life in patients who had surgery for colorectal cancer compared with those given placebo. Once again lactic-acid producing strains in large concentrations were used, and
usually at higher doses than currently commercially available as over-thecounter preparations. The prokaryotic or bacterial cell biology might not have the intriguing sophistication of a proliferating cancer cell, but there is a diffused and intriguing suspicion that despite negative data from clinical trials and numerous hidden influences and confounders, the role of interventions to modulate the human microbiota might prove more relevant and beneficial than we currently appreciate in affecting cancer-related outcomes. Much work still remains to be done. Do we work together on one bacteria, one capsule, for one disease, or take faeces from one person to another and transplant them, a strategy that has proved so successful for C difficile infections. However, in a climate of generalised scientific uncertainty, the European Food Safety Authority has rejected claims of health benefits associated with probiotics for fear that manufacturers might circumvent stringent regulations associated with drug delivery and market these products to vulnerable individuals. Thus, while a yoghurt a day might not keep the disease at bay, bacteria may play a greater part in our wellbeing than we given them credit for. Perhaps the clean-conscious society we have become might need to rethink its strategy.
Janindra Warusavitarne, *Justin Stebbing Imperial College, London, UK [email protected]
Documentary NED (No Evidence of Disease) NED is several films at once, which are sometimes at cross purposes to each other. At its core, the film is an attempt to bring attention to the problems of gynaecological cancers, an understudied and dangerous 372
form of cancer without a diagnostic method for early detection. Because of this, many such cancers often go undetected until they have become quite advanced—every hour, ten women are diagnosed with cancers
of this type. One point that the film makes over and over is that women need to be aware of the symptoms, be conscious of them, and raise any concerns with your doctor. A 16-min presentation of signs and symptoms, www.thelancet.com/oncology Vol 16 April 2015
Quackeries Probiotics and cancer: ready for meal time?
www.thelancet.com/oncology Vol 16 April 2015
bacteria to stay healthy. Two sides of the same sword, or different swords altogether? So-called good bacteria for human consumption is a multibillion pound industry and targets the basic human weakness of the need to rectify the falls of an indulgent lifestyle. But does the holy grail of popular scientific research—the cure for cancer—lie in the bacteria or do bacteria form the basis for creating the healthy society? This concept is no doubt a contradiction, but what do we know about these miniscule creatures and how they affect our wellbeing? In the human body, bacteria outnumber human cells by a factor of 10. Most microbes reside in the gut, resulting in a complex ecological environment, which can both prevent and cause disease, but for the most part they seem to be a positive force, or so we think and presume. As such, the gut microbiome complements and serves to fill several gaps in metabolic pathways or to assist with the immune system by resisting bad bacteria from dominating the flora, and thus, it should come as no surprise that diet, drugs, and the environment can cause imbalances here. Sitting at the crossroad of immunity, inflammation, and metabolism, the human microbiota occupies a strategic position in modulating environmental stressors that target our genome. It is therefore natural to conclude that these versatile, amorphous tribes of prokaryotic companions could in fact be qualitatively different in patients with cancer, having turned “bad” by promoting inflammation and potentially aiding cancer progression. A widening series of unresolved questions in tumour biology or oncogenesis seem to interpret the microbiome as a contributory factor. Age, for example, one of the strongest risk factors for epithelial cancers, is a key determinant
of the decreasing diversity in the human microbiome, leading to an unopposed proinflammatory status. Equally, environmental variations affecting the microbiome could underlie the dynamic changes in cancer incidence reported in migrating populations. Indeed, we are now placing substantial responsibility on the shoulders of our anucleated acquaintances, whose perturbation or dysbiosis seems to have become the unequivocal root of poor health in the 21st century. Whether dysbiosis though is an ineluctable fate or rather a new battlefield for the pharmaceutical industry to deploy probiotics becomes the million dollar question: far too important to be answered by marketing claims in non-scientific terms. Probiotics are cultures of living organisms that can be ingested and often include species with elegant names such as Lactobacillus spp and Bifidobacteria spp, which produce lactic acid—thought to be good for the immune system. They are frequently referred to as so-called good bacteria and are widely commercially available and seen as a safe option to maintain a healthy state. The evidence associated with the use of probiotics and the tangible benefits of their use has been the subject of much discussion with some recent evidence. In one study in which fermentable milk was fed to rats who were subsequently injected with breast cancer cells, there was a reduction in tumour growth as a result
See Online for appendix
Scimat/Science Photo Library
Anyone who has been in cancer research for long enough will remember the wave of optimism that came with the complete sequencing of the human genome, an achievement received by a fascinated scientific community as the ultimate proof that everything we had ever been interested in, including incidence and mortality from cancer amd toxicity and efficacy from treatment, was coded within endless, repetitive sequences of nucleotides—the letters that make up our genetic material or DNA. Influenced by a mesmerising deterministic spell, we were all led to believe that everything was prearranged. A microscopic script, strong as Archimedes’ lever, was rehearsed and played every day by billions of cells, orchestrated by 3 billion DNA letters, to ultimately influence our destiny as human beings. It was a matter of time before we came to terms with the futility of our attempts to set our destiny aside from a delicate and often troubled relationship with the environment surrounding us, where the microscopic world of bacteria plays a key but often neglected part. It took the audacity and foresight of a geneticist, the Nobel Prize winning Joshua Lederberg to organise and give that microscopic world of colourful spheres and rods an identity and a voice: the microbiome. This was of course the dirty side of so-called omics we would have never expected to be dealing with, in a society that is now flooded by advertisements showing us how to eradicate bacteria and germs. In our ‘‘Dettol’’ clean crazy society that has survived the lethal burden of bacterial infection, the plague of many chronic diseases including cancer is expanding fast. As a further and perhaps more profitable paradox, the dogma of complete bacterial eradication is nowadays paralleled by the urgency to fill our guts with billions of good
371
Cancer and Society
of increasing the number of immune cells that cause cancer cell death. Not all studies, however, have shown such effects and studies in man showing a reduction in cancer are inconclusive. One large epidemiological study examined the incidence of cancer in rural parts of China compared with in metropolitan areas and showed that areas that have a high consumption of non-pasteurised dairy products with diverse bacterial content have lower incidences of colorectal cancers, leading to the logical assumption that probiotic supplementation to a a processed diet, such as that in developed countries, might reduce cancer incidence or alter its progression. However, populations living in developed countries are not born with Chinese genes and thus translating one geography to another could be futile. On top of this, underpowered studies, inconsistencies in primary outcome measures, and the presence of a various of probiotic preparations almost impossible to standardise for the purpose of clinical research, make the evaluation of probiotics in disease prevention and treatment a truly difficult task. Although little evidence supports the regular use of probiotics for cancer prevention, oncologists could have gladly identified a few billion microscopic friends to help manage anticancer treatment toxicities. Mechanistic evidence shows that administration of attenuated bacteria could result in faster bone marrow recovery in white cell or immune deprived (leukopenic) animals, suggesting a potential role
for probiotics as a measure to prevent anticancer treatment-related infections. Clinical evidence is insufficient and deciphering a true immune modulating effect promoted by probiotics is scientifically challenging. There is, however, good evidence to support the use of probiotics to prevent infections from a dysbiotic gut bacterium such as Clostridium difficile, a common cause of infectious diarrhoea in patients with cancer, and potentially beneficial effects could stem from the management of chemotherapy induced diarrhoea. Following the encouraging results of animal models of radiation-induced enteritis, results of several studies in patients receiving radiotherapy have given a mixed message in terms of efficacy, with a recent meta-analysis failing to show significant improvement in gastrointestinal toxicity. Substantial heterogeneity within individual studies and different use of bacterial strains are potential sources of bias, but a common theme from all these studies is the safety of use of probiotics—which seems very high. This in itself is an important observation and allows the use of these preparations in what can be sometimes desperate situations for patients. In one study, use of probiotics in a 12-week period reduced the incidence of post-operative bowel-related symptoms and improved quality of life in patients who had surgery for colorectal cancer compared with those given placebo. Once again lactic-acid producing strains in large concentrations were used, and
usually at higher doses than currently commercially available as over-thecounter preparations. The prokaryotic or bacterial cell biology might not have the intriguing sophistication of a proliferating cancer cell, but there is a diffused and intriguing suspicion that despite negative data from clinical trials and numerous hidden influences and confounders, the role of interventions to modulate the human microbiota might prove more relevant and beneficial than we currently appreciate in affecting cancer-related outcomes. Much work still remains to be done. Do we work together on one bacteria, one capsule, for one disease, or take faeces from one person to another and transplant them, a strategy that has proved so successful for C difficile infections. However, in a climate of generalised scientific uncertainty, the European Food Safety Authority has rejected claims of health benefits associated with probiotics for fear that manufacturers might circumvent stringent regulations associated with drug delivery and market these products to vulnerable individuals. Thus, while a yoghurt a day might not keep the disease at bay, bacteria may play a greater part in our wellbeing than we given them credit for. Perhaps the clean-conscious society we have become might need to rethink its strategy.
Janindra Warusavitarne, *Justin Stebbing Imperial College, London, UK [email protected]
Documentary NED (No Evidence of Disease) NED is several films at once, which are sometimes at cross purposes to each other. At its core, the film is an attempt to bring attention to the problems of gynaecological cancers, an understudied and dangerous 372
form of cancer without a diagnostic method for early detection. Because of this, many such cancers often go undetected until they have become quite advanced—every hour, ten women are diagnosed with cancers
of this type. One point that the film makes over and over is that women need to be aware of the symptoms, be conscious of them, and raise any concerns with your doctor. A 16-min presentation of signs and symptoms, www.thelancet.com/oncology Vol 16 April 2015
