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Probiotics are touted as good for the gut. They may be trouble for the immune system - CAMcheck

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Probiotics are touted as good for the gut. They may be trouble for the immune system

Posted 12 April 2019

By Meghana Keshavan

StatNews April 2, 2019

Probiotics are wildly popular. After all, the microbial cocktails are available over the counter and have been shown to be helpful in the treatment of gastrointestinal illnesses for some people.

But some scientists worry probiotics aren’t as innocuous as they seem – and might be affecting the way other medicines work in the body.

The latest cautionary note comes in the form of a preliminary study released Tuesday, in which researchers found that melanoma patients were 70 percent less likely to respond to cancer immunotherapy if they were also taking probiotic supplements. The study group was small – just 46 patients – but the findings support broader suggestions that probiotics might actually upset the balance of so-called “good” bacteria in the gut and interfere with the immune response.

The research was conducted by MD Anderson Cancer Center in Houston and the Parker Institute for Cancer Immunotherapy in San Francisco.

“We wanted to bring this to the forefront of people’s minds: That probiotics sold over the counter aren’t necessary,” said Dr. Jennifer Wargo, lead author of the study and an associate professor of surgical oncology at MD Anderson. “They may not help you, and might even harm you.”

The microbiome – or rather, the trillions of distinct bacteria that flourish in every single gut – is now believed to play a substantial role in regulating a person’s overall health. The demand for probiotic supplements is expanding rapidly, as consumers attempt to self-correct perceived imbalances in their guts; the global market, in 2013, was valued at $36 billion.

But because probiotics – like vitamins and other such supplements – are only loosely regulated by the Food and Drug Administration, consumers are free to sprinkle these prepackaged bacterial spores in with their standard therapeutic regimens. And that could have serious implications for their medical outcomes.

“I strongly, strongly question why the general public takes probiotics when medical evidence to this routine is not really available,” said Eran Elinav, an immunology researcher at the Weizmann Institute of Science in Israel.

Probiotic mixes vary dramatically from pill to pill. Companies aren’t even required to maintain the same combination of bacterial strains from one batch to the next, meaning what people put in their bodies could vary widely. Some of these strains may hinder the efficacy of one medicine, while others may enhance it.

There are too many unknowns to render any given probiotic totally safe, said Dr. Pieter Cohen, an associate professor of medicine at Harvard Medical School and an internist at Cambridge Health Alliance, who wrote about the issue last year in JAMA Internal Medicine.

Probiotics do work for some people, and some conditions: They’re helpful in treating irritable bowel syndrome, for instance, and other gastrointestinal illnesses, said Dr. Rishi Sharma, a gastroenterologist in Walnut Creek, Calif.

Cancer patients often take probiotics to help mitigate some of the side effects of treatment – particularly diarrhea that stems from chemotherapy. While oncologists tend to be loathe to suggest their patients take over-the-counter probiotics, many with cancer still do: The MD Anderson study found that 42 percent of the patients studied were also taking probiotic supplements.

“When you see a study like this, suggesting immunotherapy might not work that well – I’d just avoid taking the probiotic,” Sharma said. “Your whole goal is to treat the cancer. And when it comes to probiotics, there’s just a lot of really bad data out there.”

Immunotherapies generally work in about a quarter of patients with certain cancers, but it’s still unclear exactly why. The MD Anderson/Parker Institute study was designed to probe whether there was a correlation between diet, the gut microbiome, and patient response to immunotherapy.

Forty-six metastatic melanoma patients beginning treatment at MD Anderson were asked to take a survey on what they ate and drank, and what supplements they took. Before the start of the therapy, researchers also took fecal samples from each patient – profiling the bacterial makeup of their respective microbiomes. The study also found that higher fiber intake was correlated with more lush microbiomes – and stronger responses to immunotherapy.

The research was presented as an abstract at the American Association of Cancer Research meeting this week in Atlanta. It hasn’t yet been published in a peer-reviewed journal.

“This study shows you that a patient’s response to immunotherapy is highly modulated by the microbiome,” said Elinav.

Elinav said the findings “are in perfect agreement” with conclusions from his own research: He published a pair of studies in Cell in 2018, finding that probiotic supplements actually decreased the diversity of participants’ microbiomes after they’d taken a course of antibiotics. In fact, the guts of those who took probiotics took much longer than those who did not to fully recover.

The MD Anderson/Parker Institute findings are far from conclusive. Wargo said that she and her team have been expanding the patient cohort being studied; they are also working with Seres Therapeutics, a Cambridge, Mass.-based biotechnology company, on whether bespoke combinations of probiotics might actually improve immunotherapy responses. Still, not all researchers are convinced by the early conclusions.

The Parker Institute is now conducting such a trial in collaboration with MD Anderson and Seres Therapeutics. This randomized, placebo-controlled clinical study is evaluating whether a specially designed oral microbiome pill with specific types of bacteria could positively impact a patient’s response to checkpoint inhibitors.

“I think it’s a provocative finding,” said Dr. Adil Daud, a professor of medicine and director of melanoma clinical research at University of California, San Francisco. “But I still think it’s too early to really conclusively say that probiotics interfere with immunotherapy.”

The trial was too small, and too many variables could have influenced its outcome, he said. Microbiota vary too significantly from person to person, and immunotherapy responses might even vary depending on age, ethnicity, and gender, Daud said. The study was too small to possibly take all of these factors into consideration, he said.

Daud noted that he did have one melanoma patient that he treated with pembrolizumab – an anti-PD-L1 immunotherapy – who actually seemed to benefit from probiotic use. Upon stopping a drug that had proved effective, the patient’s tumor began to grow back. When Daud restarted the pembrolizumab, the patient chose to also take a probiotic from Whole Foods; with the addition of the supplement, the same drug had a lasting effect on keeping the cancer at bay.

“But this is an isolated, n=1 case – so I don’t know how much weight this carries,” Daud said.

Daud tells his patients that, rather than focusing on probiotics, they’d be better served to work on their diet – increasing fiber intake, for instance.

Cohen, the internist at Cambridge Health Alliance, said he “can’t make heads or tails” of the latest study – it’s too small and vague, in his view.

“My two cents would be, this study reminds us that there’s no question that probiotics have a powerful impact on the immune system,” Cohen said. “That, and we have almost no data to demonstrate that these live microorganisms actually improve health.”

Probiotics Linked to Poorer Response to Cancer Immunotherapy in Skin Cancer Patients

By Parker Institute on April 2, 2019

https://www.parkerici.org/2019/04/02/probiotics-linked-to-poorer-response-to-cancer-immunotherapy-in-skin-cancer-patients/

Food and supplements such as probiotics may impact immunotherapy response in cancer patients.

In melanoma patients, taking over-the-counter probiotic supplements was associated with a 70 percent lower chance of response to cancer immunotherapy treatment with anti-PD-1 checkpoint inhibitors, according to a preliminary study from the Parker Institute for Cancer Immunotherapy (PICI) and The University of Texas MD Anderson Cancer Center. The results are being presented today at the American Association for Cancer Research (AACR) 2019 Annual Meeting in Atlanta.

Researchers also found that probiotics were linked to lower diversity in the gut microbiome, previously found to be associated with poorer immunotherapy response.

“These findings about probiotics were a bit surprising to us because the general perception is they make your gut microbiome healthier,” said first author Christine Spencer, Ph.D., a research scientist at the Parker Institute, based in San Francisco. “While more research is needed, our data suggests that may not be the case for cancer patients.”

Probiotics are not regulated by the U.S. Food and Drug Administration.

“Based on our early results, cancer patients and doctors should carefully consider the use of over-the-counter probiotic supplements, especially before beginning immunotherapy treatment,” said senior author Jennifer Wargo, M.D., MMsc, a PICI investigator at MD Anderson.

This is the first clinical study designed to examine the relationships between diet, the gut microbiome and immunotherapy response in cancer patients. In addition to the probiotics findings, the data also show patients who reported eating a high-fiber diet were five times as likely to respond to cancer immunotherapy.

POTENTIAL IMPACT OF THE RESEARCH

The implications of the research are significant because checkpoint inhibitors –  a Nobel Prize-winning type of cancer immunotherapy treatment – only work for 20 to 30 percent of cancer patients. The research bolsters the idea that cancer patients might be able to improve how well immunotherapy treatment works by eating, drinking – or avoiding – certain foods, beverages and supplements.

“Imagine if you could increase the number of patients who benefit from immunotherapy through something as simple as dietary changes. That would be remarkable,” Spencer said. “It’s probably not going to be that simple, as there are many factors at work. But this study does point to diet playing a role in immunotherapy response via the gut microbiome and we hope these findings will spur more studies on this topic in the cancer research community.”

THE MICROBIOME-CANCER IMMUNOTHERAPY CONNECTION

In recent years, scientists have discovered that the trillions of intestinal microbes that make up the gut microbiome exert significant control over the immune system. Cancer immunotherapy drugs such as checkpoint inhibitors work by engaging the immune system to fight off cancer.

In theory then, the makeup of the microbiome could affect the immune system, and in turn, the ability for immunotherapy to work against cancer.

A prior study by Dr. Wargo and Spencer was one of the first to explore that idea. In their 2018 Science paper, they and colleagues at MD Anderson found that a more diverse array of microbes in the gut was associated with better response to checkpoint inhibitors for cancer, and that certain types of bacteria in the Ruminococcaceae family were associated with a better response to anti-PD-1 checkpoint inhibition. Other types of bacteria, such as those in the order Bacteroidales, were linked to a poorer outcome.

“There were different types of microbiome profiles, if you will, that were linked to better or poorer response to checkpoint inhibition,” said Dr. Wargo. “For this new study on the diet, microbiome and immunotherapy, we used profiles of responders as the mark of a “good” microbiome when it comes to immunotherapy response.”

ABOUT THE STUDY

The prospective study involved 113 metastatic melanoma patients who were starting treatment at MD Anderson in Houston. The researchers prospectively evaluated their microbiomes by sequencing their fecal samples to determine the presence and abundance of various bacteria in the gut. Patients were also asked to take a lifestyle survey to report on their diet and use of supplements and medication.

After following patients through treatment, the researchers found several correlations between dietary factors and the gut microbiome. They also evaluated those factors in relation to immunotherapy response in a subset that went on anti-PD-1 checkpoint inhibitors.

KEY FINDINGS

Overall, Parker Institute and MD Anderson researchers found that diet and supplements appear to have an effect on a patient’s ability to respond to cancer immunotherapy, most likely due to changes in the patient’s gut microbiome.

Among the findings:

  • Over-the-counter probiotic supplement use was linked to a 70% lower chance of response to immunotherapy with anti-PD-1 checkpoint inhibitors in a subset of 46 melanoma patients .
  • 42% of all patients reported taking over-the-counter probiotics among those who took the lifestyle survey .
  • Probiotics were linked to lower gut microbiome diversity, previously shown to be associated with poorer response to anti-PD-1 checkpoint inhibitors .
  • Patients eating high-fiber diets were about 5 times as likely to respond to immunotherapy treatment with anti-PD-1 checkpoint inhibitors .
  • Patients eating diets rich in whole grains had more bacteria associated with positive response to checkpoint immunotherapy .
  • Diets high in processed meat and added sugar had fewer bacteria associated with a positive response to checkpoint immunotherapy .
  • “Eating a high-fiber diet has long been shown to have health benefits. In this case, we see signs that it is also linked to a better response to cancer immunotherapy,” Spencer said. “Definitely another good reason to load up on whole grains, vegetables and fruits.”

ADDITIONAL MICROBIOME-CANCER IMMUNOTHERAPY TRIALS UNDERWAY

While this study focused on correlations rather than root cause, other randomized, controlled clinical trials are underway that are designed to directly answer the question of whether one can manipulate the microbiome – through food, fecal transplant or other means – to improve cancer immunotherapy response.

The Parker Institute is now conducting such a trial in collaboration with MD Anderson and Seres Therapeutics. This randomized, placebo-controlled clinical study is evaluating whether a specially designed oral microbiome pill with specific types of bacteria could positively impact a patient’s response to checkpoint inhibitors.

The study is open at MD Anderson and the Angeles clinic. For additional information on this trial (NCT03817125) please visit www.clinicaltrials.gov.

In addition, a team of MD Anderson researchers is planning a prospective randomized study in which cancer patients will be provided with different types of diets. Their gut microbiomes will be sequenced to see if and how they change. The study will also evaluate treatment response to immunotherapy.

Abstract 2838: “The gut microbiome (GM) and immunotherapy response are influenced by host lifestyle factors”

Spencer is presenting the most up-to-date information during the Inflammation and Microbiome poster session that runs from 8 a.m.-12 p.m. EDT, April 2, 2019 at the AACR 2019 Annual Meeting.

Contact Information

For more information or a copy of the poster, please contact Science Communications Manager Shirley Dang, sdang@parkerici.org, 415-930-4385.

Probiotic Safety-No Guarantees

Pieter A. Cohen, MD1,2 December 2018

https://jamanetwork-com/journals/jamainternalmedicine/fullarticle/2702973

1Cambridge Health Alliance, Harvard Medical School, Boston, Massachusetts 2Somerville Hospital Primary Care, Somerville, Massachusetts

JAMA Intern Med. 2018;178(12):1577-1578. doi:10.1001/jamainternmed.2018.5403

For centuries, people have consumed live bacteria in many foods, such as yogurt, cheese, kimchi, and sauerkraut. The mass-marketing of isolated live bacteria for their purported beneficial or “probiotic” properties, however, is a relatively recent phenomenon. The World Health Organization defines probiotics as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.” Yet to be sold as a probiotic supplement in the United States, a live microorganism does not require evidence of efficacy or even safety.

Certain live microorganisms do have well-defined health benefits, and an emerging literature supports the use of select strains of bacteria and yeast to treat specific medical conditions.1 The yeast Saccharomyces boulardii, for example, reduces the rates of antibiotic-associated diarrhea in children and can decrease rates of recurrent Clostridium difficile infections in adults, when combined with antibiotics.1 Most microorganisms used in the production of food, however, do not have proven health benefits, and their safety when sold as probiotic supplements has not been fully established.

Hundreds of small studies whose results are spun as favorable, creative advertising, and enthusiasm for the microbiome have contributed to increased popular and professional interest in commercial probiotics. Between 2002 and 2012 consumption of probiotic supplements more than doubled in the United States.2 Consumption is highest among college-educated adults, with 3.5% reporting the use of probiotic supplements within the past 30 days.2 Probiotics are frequently prescribed by clinicians as well; a survey of 145 US hospitals found that 2.6% of patients had received probiotics during their hospitalizations.3

Although preliminary evidence supports the use of specific strains of probiotics in certain clinical settings, such as preventing C difficile and antibiotic-associated diarrhea, widespread use, particularly among people who are healthy, has greatly outpaced the science. Probiotics are promoted to assist healthy adults, adolescents, and children to maintain normal intestinal function and to sustain cardiovascular, respiratory, immunologic, reproductive, and even psychological health.4 Despite the advertised indications, there are no large, long-term clinical trials proving that probiotics offer clinical benefits for people who are already healthy.4 The lack of robust evidence does not limit US manufacturers’ ability to promote supplements to improve health. There are few restrictions on structure and/or function claims, such as “boosts digestive health” or “supports the immune system,” on supplement labels, and information about potential adverse effects is not required. As a result, consumers are unlikely to appreciate that probiotic supplements may also present risks, such as opportunistic infections and allergic reactions.5,6

Probiotic supplements, given the inherent infective qualities of the microorganisms they contain, may pose risks to certain people. Serious adverse events, such as fungemia and bacteremia, have been described in dozens of case reports, especially among immune-compromised individuals. However, as a result of a lack of structured reporting of adverse events in most probiotic clinical trials, and a lack of effective systems to detect postmarketing harm from supplements, the actual rates of opportunistic infections from probiotic supplements are not known.5-7

Poor-quality probiotic supplements raise additional safety concerns. Although the US Food and Drug Administration (FDA) has established current good manufacturing practices for all dietary supplements, including that firms conduct all manufacturing operations in accordance with adequate sanitation principles, manufacturers are often not compliant with them. For example, the FDA inspected 656 facilities producing a wide variety of dietary supplements in fiscal year 2017 and found violations in more than half of the inspected facilities. These violations were not trivial: Most commonly, companies had failed to establish the identity, purity, strength, or composition of their final product. The FDA also requires that supplements be tested for contaminants; nonetheless, studies have found commercial probiotics that contain live microorganisms not listed on their labels.6 These contaminants can pose life-threatening risks as was tragically illustrated by the death of an 8-day-old premature infant from fulminant gastrointestinal mucormycosis.8 Epidemiologists at the Centers for Disease Control and Prevention eventually traced the source of the infection to fungal contamination of a probiotic supplement used to treat the infant.8

Full compliance with FDA manufacturing standards for supplements would help to prevent products from containing contaminants and incorrect species of bacteria, but still would not ensure the safety of probiotic supplements. The FDA’s requirements do not address the unique risks that probiotics may pose, such as the potential to introduce new genes into consumers’ microbiomes.6 Of particular concern are genes that may confer antibiotic resistance. Bacteria sold as probiotics, like all bacteria, may have intrinsic as well as acquired resistance to antibiotics. Intrinsic resistance refers to each strain’s typical resistance pattern. These qualities are not easily transferrable to other bacteria in the human gut; thus, they pose health risks only in instances in which individuals develop opportunistic infections from the probiotic and require treatment. Intrinsic resistance to antibiotics may, in fact, be a desirable trait as probiotics may be administered concomitantly with antibiotics to prevent diarrhea or other conditions, and resistance to the administered antibiotic could enhance the probiotic’s efficacy.

In contrast, atypical or acquired resistance patterns in probiotics may signal the presence of a mobile gene capable of transferring antibiotic resistance to pathogenic bacteria. This has been established under experimental conditions both in vitro and in rodent models. For example, in vitro the probiotic Lactobacillus plantarum M345 can transfer erythromycin resistance genes to Listeria monocytogenes. To date, however, only limited resources-and to my knowledge just 1 study involving 7 subjects-have been dedicated to determining whether such transfers might occur in the human intestine.9

Until more data are available regarding the transfer of probiotic genes in humans, modern manufacturing techniques should be used to ensure that mobile resistance genes are not contained in the probiotics consumed by millions of people in the United States. Standards designed to decrease exposure to mobile resistance genes have been implemented in Canada and several European countries. The FDA, however, does not require these safeguards in the United States. In fact, in 2005, the agency permitted the sale of infant formula that included a probiotic strain with a potentially transferrable tetracycline resistance gene.

In the United States, live bacteria, yeast, and other microorganisms may be sold as food, dietary supplements, or drugs, with differing regulatory requirements for each category. A better approach would be to create a consistent regulatory framework under which all probiotic-type microorganisms could be safely marketed to improve health. High-quality microorganisms with a long track record of safety should be accurately labeled and readily available to consumers, and labels should only advertise health claims if robust clinical evidence has demonstrated efficacy. Such a framework would require new laws, and Congress would seem unlikely to tackle probiotics in the foreseeable future.

The FDA has recently released a draft guidance that, if implemented, would give firms the option of listing the number of colony forming units in the Supplement Facts label.10 The agency should go further and require manufacturers, as Canadian authorities already do, to provide the specific strain or strains, and the number of live microorganisms per serving, on every bottle of probiotic supplements. This should be a routine part of ingredient disclosure. The FDA should also revise its current good manufacturing practices for live microorganisms and include additional safety testing, such as identifying and eliminating potentially transferrable antibiotic resistance genes, for all bacterial strains prior to marketing, as is currently required in Canada. In the meantime, the underdeveloped regulatory framework in the US and inadequate compliance of manufacturers with the existing laws and regulations remain substantial problems. Consumers and physicians should not assume that the label on probiotic supplements provides adequate information to determine if consuming the live microorganism is worth the risk.

Corresponding Author: Pieter A. Cohen, MD; Somerville Hospital Primary Care, 236 Highland Ave, Somerville, MA 02143 (pcohen@challiance.org).

Published Online: September 17, 2018. doi:10.1001/jamainternmed.2018.5403

Conflict of Interest Disclosures: Dr Cohen reports a research collaboration with NSF International and research funding from Consumers Union.

Additional Contributions: Robert Bonomo, MD, Case Western Reserve University; Rachael Bedard, MD, Mt Sinai Hospital; and Michael Hochman, MD, University of Southern California provided thoughtful comments on earlier versions of the manuscript. They were not compensated.

References

  1. Parker EA, Roy T, D’Adamo  CR, Wieland  LS.  Probiotics and gastrointestinal conditions: an overview of evidence from the Cochrane Collaboration.  Nutrition. 2018;45:125-134.e11. doi:10.1016/j.nut.2017.06.024
  2. Kantor  ED, Rehm  CD, Du  M, White  E, Giovannucci  EL.  Trends in dietary supplement use among US adults from 1999-2012.  JAMA. 2016;316(14):1464-1474. doi:10.1001/jama.2016.14403
  3. Yi  SH, Jernigan  JA, McDonald  LC.  Prevalence of probiotic use among inpatients: a descriptive study of 145 U.S. hospitals.  Am J Infect Control. 2016;44(5):548-553. doi:10.1016/j.ajic.2015.12.001
  4. Khalesi  S, Bellissimo  N, Vandelanotte  C, Williams  S, Stanley  D, Irwin  C.  A review of probiotic supplementation in healthy adults: helpful or hype?  [published online March 26, 2018].  Eur J Clin Nutr. doi:10.1038/s41430-018-0135-9
  5. Hempel  S, Newberry  S, Ruelaz  A,  et al.  Safety of probiotics used to reduce risk and prevent or treat disease.  Evid Rep Technol Assess (Full Rep). 2011;200(200):1-645.
  6. Sanders ME, Akkermans LMA, Haller  D,  et al.  Safety assessment of probiotics for human use.  Gut Microbes. 2010;1(3):164-185. doi:10.4161/gmic.1.3.12127
  7. Bafeta  A, Koh  M, Riveros  C, Ravaud  P.  Harms reporting in randomized controlled trials of interventions aimed at modifying microbiota: a systematic review.  Ann Intern Med. 2018;169(4):240-247. doi:10.7326/M18-0343
  8. Vallabhaneni  S, Walker  TA, Lockhart  SR,  et al; Centers for Disease Control and Prevention (CDC).  Notes from the field: fatal gastrointestinal mucormycosis in a premature infant associated with a contaminated dietary supplement-Connecticut, 2014.  MMWR Morb Mortal Wkly Rep. 2015;64(6):155-156.
  9. Egervärn M, Lindmark H, Olsson  J, Roos  S.  Transferability of a tetracycline resistance gene from probiotic Lactobacillus reuteri to bacteria in the gastrointestinal tract of humans.  Antonie Van Leeuwenhoek. 2010;97(2):189-200. doi:10.1007/s10482-009-9401-0
  10. Food and Drug Administration. Draft guidance for industry: policy regarding quantitative labeling of dietary supplements containing live microbials: guidance for industry. https://www.federalregister.gov/documents/2018/09/07/2018-19367/policy-regarding-quantitative-labeling-of-dietary-supplements-containing-live-microbials-draft. Accessed September 7, 2018.

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