Probiotics Reduce Chemotherapy-induced Diarrhoea – Clinical Trial

by NCN Health And Science Team Posted on November 25th, 2018

Houston, Texas, USA :  A high concentration of multi-strain probiotic helps to reduce mild to moderate episodes of chemotherapy-induced diarrhoea (CID) in cancer patients, according to results of a phase II/III study in India.

Presenting the final results of the study at ESMO 2018 Congress lead investigator, Atul Sharma, Professor of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India, remarked: “This is probably the first large, randomised, placebo-controlled study to look at the role of multi-strain, high dose probiotic in chemotherapy-induced diarrhoea,”.

“Though it did not meet its primary endpoint in reducing incidence of grade 3 and 4 diarrhoea [statistical significance was not met], it helped to reduce the incidence of all grades of diarrhoea. The probiotic also helped in reducing levels of inflammatory markers, the significance of which needs to be ascertained,” he added.

The incidence of grade 3 diarrhoea episodes was 8.0 percent for patients on probiotics, and 4.1 percent for those on placebo (p=0.088); and for grade 4 episodes the respective incidences were 2.0 percent and 0 percent (p=0.050). For all grades of diarrhoea, there were 199 and 220 episodes in probiotic and placebo groups respectively (p=0.019). Analysis of serum vascular endothelial growth factor (VEGF), clusterin, and faecal calprotectin showed levels were reduced in patients taking the multi-strain probiotic.

Chemotherapy changes the consistency of the gut microflora and as such it can lead to some serious side-effects. Sharma explained that, “chemotherapy-induced diarrhoea is an under-reported, unpleasant, and sometimes a serious side-effect of chemotherapy. It may be associated with weight-loss, malnutrition, fatigue and malaise, electrolyte imbalance and inability to deliver full dose of chemotherapy on time. It may also cause loss of body fluid resulting into acute renal injury and rarely death.”

To determine whether it improved the balance of intestinal flora and as such reduce these side effects, the study investigated the efficacy of a high potency multi-strain probiotic on patients experiencing CID while receiving fluropyrimidines and/or irinotecan-based cancer therapy.

The multi-strain probiotic consisted of 900 billion colony forming units (CFU) sachet of four strains of lactobacillus, three strains of bifidobacteria and one strain of streptococcus thermophiles. Patients were randomised to receive either one sachet of probiotic twice daily (n=145) or one sachet of placebo twice daily (n=146), started 14 days prior to chemotherapy, and continued for two weeks following chemotherapy cycle three. The vast majority of patients were men, approximately 80 percent; and aged approximately 46 years. There were no increased incidence of infections.

Adding comment on the study for ESMO was Prof. Michal Mego, Head of 2nd Department of Oncology, Comenius University, National Cancer Institute, Bratislava, Slovak Republic, said: “These data suggest that probiotics have potential to be a simple and novel approach in the reduction of chemotherapy-induced diarrhoea, however confirmatory studies are awaited. As probiotics are living microorganisms there is potential risk of iatrogenic infection in immuno-compromised cancer patients, therefore safety data and adverse events associated with probiotic administration could influence their future role in prevention of chemotherapy induced diarrhoea.”

Reflecting on the accumulation of evidence for the effect of the gut microbiome on cancer therapy, Prof. John B.A.G. Haanen, CSO Immunotherapy, Netherlands Cancer Institute, Amsterdam and Professor of Translational Immunotherapy of Cancer, Leiden University Medical Center, Leiden, The Netherlands, said: “Due to the effect of the gut microbiome on response and toxicity in cancer patients treated with immune checkpoint inhibitors and the recently initiated trials with faecal transplantation to improve outcome of checkpoint inhibitors, this study is of interest.”

“Currently unknown is whether probiotics used in this RCT positively or negatively influence the immune system, and with more patients being treated with immunotherapy, before embarking on large-scale usage of probiotics to reduce chemotherapy-induced diarrhoea, their effect on the immune system should be investigated,” he remarked.

Citation: Abstract 1682O_PR ‘Final results of a phase II/III, randomized, double blind, placebo-controlled study to investigate the efficacy of a high potency multistrain probiotic, on chemotherapy induced diarrhea in cancer patients receiving Fluropyrimidines and/or Irinotecan based therapy’ will be presented by Dr Atul Sharma during Proffered paper Session on Sunday, 21 October 2018 14:45 to 16:15 (CEST) in Room 20 – Hall B3. Annals of Oncology, Volume 29 Supplement 8 October 2018

In a second study, probiotics increase bone volume in healthy mice

Probiotics Increase Bone Volume In Healthy Mice – Study

A widely-used probiotic stimulates bone formation in young female mice, according to a study published in the journal Immunity. In response to treatment with Lactobacillus rhamnosus GG (LGG), other intestinal microbes produced a metabolite called butyrate, which in turn activated bone-enhancing immune cells, including regulatory T cells.

“The significance of the study is that probiotics are, at least in mice, an effective means to increase bone density,” says senior study author Roberto Pacifici of Emory University. “Clinical trials are in progress to validate the efficacy of probiotics in humans.”

Fractures due to osteoporosis can have devastating consequences. For example, complications of hip fractures lead to mortality rates of 24%-30% during the first year following injury, and almost 50% rates of permanent disability. Unfortunately, most cases of osteoporosis remain untreated or ineffectively treated due to the cost and side effects of currently available drugs. There is an urgent need to identify and develop inexpensive, safe, and effective interventions for both the prevention and treatment of osteoporosis.

Small-scale studies in patients with osteoporosis have reported positive results from dietary supplementation with probiotics. In animals, probiotics can prevent disease-related bone loss, but their influence on the healthy skeleton remains less clear. “Because their mechanism of action in bone is unknown, they are regarded as some kind of alternative, esoteric, unproven treatment,” Pacifici says. “Our goal was to identify a biological mechanism of action of probiotics, a mechanism that makes sense to traditional scientists, hoping that this will make probiotics a mainstream treatment.”

In the new study, Pacifici and colleagues found that oral LGG supplementation for four weeks increased bone formation in female mice by stimulating the growth of butyrate-producing gut bacteria, including Clostridia. Notably, LGG supplementation did not increase bone mass in mice raised in a germ-free environment, suggesting that this probiotic indirectly exerts its effects through the metabolic activity of other microbes that normally inhabit the intestines.

Supplementation with either LGG or butyrate induced the expansion of regulatory T cells in the intestine and in bone marrow—the spongy tissue inside some bones. This caused T cells in the bone marrow to secrete a protein called Wnt10b, which is known to be critical for bone development. By contrast, treatments that inhibited the expansion of regulatory T cells prevented bone formation induced by LGG and butyrate.

“We were surprised by the potency of the gut microbiome in regulating bone and by the complexity of the mechanism of action of probiotics,” Pacifici says. “In general, there is a lot of interest in the concept that the gut bacteria regulate the function of distant organs. How this happens is largely unknown. We described a detailed mechanism by which changes in the composition of the gut microbiome induced by probiotics affect a distant system like the skeleton.”

Lactobacillus is the most common genus of bacteria with reported probiotic activities. According to the authors, the findings are likely to generalize beyond LGG to other bacteria that also produce lactic acid. But it remains to be determined whether other types of probiotics work in the same way.

“The controversies about probiotics are: Do they work for real, and which one is the best?” Pacifici says. “We show that they work for real in bone. Which one is the best remains unknown. However, the emerging concept is that the number of bacteria in a dose of probiotic may be as important or even more important than the type of probiotic used. It is possible that the response to probiotics might be influenced by mouse strain, gender, and age.”

Moving forward, the researchers will explore the role of the microbiota in bone diseases other than osteoporosis. They also plan to determine whether butyrate supplementation could prevent and treat osteoporosis, and whether probiotics could improve skeletal health in various disease states. In the future, the use of probiotics or butyrate to increase the number of regulatory T cells may find wider applications, such as in transplant medicine or as a treatment for inflammatory and autoimmune conditions.

“Our findings will need to be validated in human studies,” Pacific says. “If successful, this research could substantiate the use of butyrate or probiotics as a novel, safe, and inexpensive treatment for optimizing skeletal development in young people and to prevent osteoporosis in older people.”

Citation for second study: Immunity, Tyagi and Yu et al.: “The Microbial Metabolite Butyrate Stimulates Bone Formation via T Regulatory Cell-Mediated Regulation of WNT10B Expression” Cell. DOI: 10.1016/j.immuni.2018.10.013

A second study found that probiotics protect mice from estrogen deficiency-related bone loss

Probiotics protect mice from estrogen deficiency-related bone loss

After menopause, a decline in estrogen levels is linked to increases in inflammation that can cause osteoporosis. Intestinal bacteria have been shown to influence inflammation by modulating immune responses, and a new study suggests that differences in gut microbial populations may determine the extent of post-menopausal bone loss.

In this month’s issue of the JCI, a research team led by Roberto Pacifici at Emory University demonstrates a link between gut bacteria and the bone loss induced by estrogen deficiency. Mice lacking gut bacteria were protected against the estrogen deficiency-induced inflammation, gut permeability, and bone loss that occurred in mice with normal gut bacteria.

Further, treatment of normal mice with probiotics attenuated inflammation and bone loss induced by estrogen deficiency. Treatment with non-probiotic strains of bacteria did not prevent estrogen deficiency-induced bone loss.

These results indicate that gut bacteria drive responses to inflammation and point to therapeutic potential for probiotics in osteoporosis.

Citation for third study: Jameel Iqbal et al, From the gut to the strut: where inflammation reigns, bone abstains, Journal of Clinical Investigation. DOI: 10.1172/JCI87430

Should you take probiotics when you’re on antibiotics?

If you take antibiotics, there’s a good chance you’ll also get diarrhoea.

Antibiotics kill harmful bacteria that cause disease. But they also cause collateral damage to the microbiome, the complex community of bacteria that live in our gut. This results in a profound, though usually temporary, depletion of the beneficial bacteria.

One popular strategy to mitigate the disruption is to take a probiotic supplement containing live bacteria during, or following, a course of antibiotics.

The logic is simple: beneficial bacterial in the gut are damaged by antibiotics. So why not replace them with the “beneficial” bacterial strains in probiotics to assist gut bacteria returning to a “balanced” state?

But the answer is more complicated.

There is currently some evidence that taking probiotics can prevent antibiotic-associated diarrhoea. This effect is relatively small, with 13 people needing to take probiotics for one episode of diarrhoea to be averted.

But these studies have often neglected to evaluate potential harms of probiotic use and haven’t looked at their impact on the wider gut microbiome.

Pros and cons of probiotics

The assumption that there is little downside to taking probiotics was challenged in a recent Israeli study.

The participants were given antibiotics and split into two groups: the first group was given an 11-strain probiotic preparation for four weeks; the second was given a placebo, or dummy pill.

The researchers found the antibiotic damage to the gut bacteria of those in the first group allowed the probiotic strains to effectively colonise the gut. But this colonisation delayed the normal recovery of the microbiota, which remained perturbed for the entire six month study period.

In contrast, the microbiota of the second group returned to normal within three weeks of finishing antibiotics.

This research exposes a perhaps unexpected truth: we still don’t know what types of bacteria are truly beneficial or even what constitutes a healthy microbiome.

The answer is unlikely to be that individual bacterial strains are particularly helpful.

It’s more likely a diverse community of thousands of different types of microbes working together can provide health benefits. This microbial community is as individual as each one of us, meaning there is not just one configuration that will result in health or illness.

So, it’s unlikely that the addition of one or even 11 strains of bacteria in a probiotic could somehow balance this complex system.

A more effective (but less palatable) alternative?

The Israeli study also explored an alternative approach to microbiome restoration.

One group of participants had their own stool collected and frozen prior to antibiotic treatment. It was then re-instilled into their gut at the end of the antibiotic therapy.

This treatment, known as autologous faecal transplantation, was able to restore the microbiome to original levels after just eight days. The other group took 21 days to recover.

This approach has also been shown to effectively restore the gut microbiome following combined antibiotic and chemotherapy treatment. These patients are predictably at risk of serious complications, such as bloodstream infection, as a result of microbiome disruption.

Research currently underway will help us understand whether microbiome restoration with autologous faecal transplantation will translate into tangible benefits for these patients.

But such an approach would not be a realistic option for most people.

Feed the good bacteria

A more practical strategy to aid recovery is to provide the good bacteria in your gut with their preferred source of nutrition: fibre. Fibrous compounds pass undigested through the small intestine and into the colon, where they act as fuel for bacterial fermentation.

So if you’re taking antibiotics or have recently finished a course, make sure you eat plenty of vegetables, fruit and whole grains. Your gut bacteria will thank you for it.

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