Posts

Should everyone take a probiotic? Assessment of evidence of probiotics for healthy people

/in ISAPP Science Blog /by KC

By Prof. Daniel Merenstein MD and Dr. Mary Ellen Sanders PhD

During the ISAPP 2024 meeting, an article titled, “Is there evidence to support probiotic use for healthy people?” was published. The authors concluded, “…we did not find a high level of evidence to support recommendations for other endpoints we reviewed for healthy people. Although evidence for some indications is suggestive of preventive benefits of probiotics, additional research is needed.”

Those in the probiotic field are used to headlines critical of probiotics meant to sensationalize rather than accurately reflect the evidence. But this article takes a careful look at if probiotics should be used by everyone regardless of indication. 

Scientific grounding for the paper

This article is an ISAPP output derived from an ISAPP 2023 discussion group that included academic and industry scientists, including the nine authors. The discussion group aimed to examine the evidence that probiotics are beneficial to healthy people at a population recommendation level.

We assembled probiotic and evidence-based medicine experts to review the literature. We chose preventative indications that we felt had some compelling evidence that healthy people would benefit from probiotics. Thus, we examined the evidence that probiotics could reduce urinary, vaginal, gastrointestinal, and respiratory infections, reduce antibiotic use, and improve risk factors associated with cardiovascular health. Populations included certain groups of individuals, including generally healthy people, those at risk for recurrent urinary and vaginal infections, and children taking antibiotics. We considered that the evidence was too nascent for this exercise for endpoints such as cognitive function, athletic performance, and dental health, and therefore did not review these endpoints. 

The challenges of studying prevention

We undertook this effort to address the common question, “Should everyone take a probiotic?” In fact, there are few recommendations for any intervention for people free of underlying disease. Such interventions must have sufficient evidence of benefit and of relatively little to no risk of harm.

In raising this question for probiotics, we took inspiration from the approach of an organization tasked with evaluating preventive evidence: the United States Preventive Services Task Force (USPSTF). Since an important component of a USPSTF review is potential for harm, it is important to note here that experts considering the safety of probiotics recently concluded that commonly used probiotic strains are safe for use in the general population.

The USPSTF recognizes that preventive measures are difficult and expensive to study. Healthy populations are difficult to define and not uniformly defined across studies. The physiology of healthy people recruited into a study is generally unlikely to change, especially over the short term. So efficacy studies must either be long-term or must identify more accessible endpoints, such as validated biomarkers of disease or reduction of infectious disease, as targets for prevention. Further, the threshold of evidence for recommending any intervention to a healthy population has to be very high, partially due to the potential risk of harm. In a patient with an illness, a risk of harm may be tolerable if the benefit outweighs the risk. But in an asymptomatic individual this threshold is more difficult to determine. 

It is noteworthy that some preventive measures are widely believed by the general public to be effective, but upon scrutiny of the data have been found to lack supporting evidence. For example, for healthy adults younger than 75 years of age, the Endocrine Society recently recommended against Vitamin D supplementation above the current RDA. The USPSTF has concluded that there is insufficient evidence to recommend a daily multivitamin for the prevention of cancer or cardiovascular disease, to screen for skin cancer,  or to screen for speech and language delay disorders in children 5 years or younger or eating disorders in adolescents. Even diet and exercise counseling for the prevention of cardiovascular risk in healthy people received only a level C recommendation. As one would expect for recommendations for healthy people, the USPSTF imposes a high bar for required evidence. This group of experts aimed to apply a similar high bar for evidence on probiotic indications.  

Meeting the strict criteria for an effective preventative measure

We reviewed data for indications where there were compelling studies on essentially healthy individuals showing some benefit from probiotics. But we wanted to determine if it was plausible that this body of evidence would meet a USPSTF-level of evidence for a recommendation for all healthy people. We recognized that there is sufficient evidence of efficacy to consider using specific probiotics for some indications for certain people. For example, evidence reviews have found that certain probiotics can be effective to prevent necrotizing entercolitis, reduce incidence of antibiotic associated diarrhea, reduce crying time in breast-fed colicky infants, improve therapeutic effectiveness of antibiotics to treat bacterial vaginosis, reduce risk for Clostridioides difficile infections, treat acute pediatric diarrhea, and manage symptoms of constipation. However:

Sufficient evidence of benefit to support the recommendation that “everyone should take a probiotic” is not yet available.

At ISAPP 2024 (held July 9-11), we heard from experts about the promise of probiotics for our skin as we age, for social anxiety, for immune function in children and for helping undernourished kids thrive. Those who understand the evidence level for probiotics recognize the proven and potential role for probiotics in health. Our paper does not change that. There is evidence for many individuals to take daily probiotics due to conditions they have. Interestingly, after our discussion group, the FDA approved a qualified health claim that can be used on yogurt. The claim relates to the impact of yogurt on the risk of developing diabetes. Allowed language for this claim includes:

  • “Eating yogurt regularly, at least 2 cups (3 servings) per week, may reduce the risk of type 2 diabetes. FDA has concluded that there is limited information supporting this claim.” 
  • “Eating yogurt regularly, at least 2 cups (3 servings) per week, may reduce the risk of type 2 diabetes according to limited scientific evidence.”

This claim relied on evidence of correlative associations in humans. For our analysis, we required a higher level of evidence from randomized, controlled trials. Further, this claim applies to yogurts that may or may not contain added probiotics in addition to the yogurt starter cultures. However, it is an important preventative endpoint and supports the idea that healthy people may benefit from probiotic-containing foods.  

Evidence to date suggests that with additional investment in well-designed research, the future may see probiotics reach the high standard of evidence needed for preventative recommendations in healthy people.

 

Further Reading

Do probiotics really benefit healthy people? from NewsMedical

The American College of Gastroenterology recommends against use of probiotics for primary or secondary prevention of C. difficile

/in Uncategorized /by KC

By Prof. Daniel Merenstein MD, Georgetown University School of Medicine and Prof. Eamonn Quigley MD FRCP FACP MACG FRCPI,  Houston Methodist Hospital and Weill Cornell Medical College

The American College of Gastroenterology (ACG) recently published ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. This review considers probiotics for prevention of CDI. The ACG’s recommendations regarding probiotics and C. difficile infection (CDI) are:

  1. We recommend against probiotics for the prevention of CDI in patients being treated with antibiotics (primary prevention) (conditional recommendation, moderate quality of evidence).
  2. We recommend against probiotics for the prevention of CDI recurrence (secondary prevention) (strong recommendation, very low quality of evidence).

The ACG guidelines take a different approach to the evidence relating to probiotics than that of the American Gastroenterological Association (AGA) or the Cochrane Collaboration. The most recent Cochrane review on prevention of C. difficile-associated diarrhea (CDAD) concluded in brief, “moderate certainty evidence suggests that probiotics are effective for preventing CDAD”. In the AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders, the recommendation was:

In adults and children on antibiotic treatment, we suggest the use of S. boulardii; or the 2-strain combination of L. acidophilus CL1285 and Lactobacillus casei LBC80R; or the 3-strain combination of L acidophilus, Lactobacillus delbrueckii subsp bulgaricus, and Bifidobacterium bifidum; or the 4-strain combination of L. acidophilus, L. delbrueckii subsp bulgaricus, B. bifidum, and Streptococcus salivarius subsp thermophilus over no or other probiotics for prevention of C difficile infection. (Conditional recommendation, low quality of evidence.)

In both the AGA and ACG guidelines the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used. How, then, did they come to such different conclusions and recommendations?

The ACG guideline stated,  “a meta-analysis of 19 RCTs that concluded that probiotics were helpful at prevention of CDI in hospitalized patients if given close to start of antibiotics, with a 70% lower risk if probiotics were started within 2 days but falling to a 30% risk reduction if probiotics were started after 2 days of antibiotic therapy”. But then they did not take timing of probiotic administration into account as they assessed the evidence. Instead, they use the negative PLACIDE trial to override all other evidence for primary prevention. The PLACIDE trial was a well-done trial, but participants started their probiotic treatment 3- 7 days after antibiotics. Thus, it would seem that the ACG guideline’s conclusion could favor probiotics as long as they can be started within 2 days of the antibiotic and not recommend against probiotic use.

The ACG guideline objects to combining data on different probiotic strains in meta-analyses in order to provide evidence in favor of probiotics: “Evidence to support probiotics for this indication comes mainly from meta-analyses that pool data from small trials of different probiotic formulations and methodologies.” This is true, but the Cochrane review found thirty-nine studies (8,672 participants) that met their eligibility criteria and it is noteworthy that several different probiotics were found to be effective. The Cochrane number needed to treat (NNT) to prevent CDI is 42. However, if the ACG thought this was driven by too many negative trials, they could have qualified their recommendation. The Cochrane review found in subgroup analyses that probiotics are most effective (NNT=12) among trials with a CDI baseline risk >5%. But to conclude there is no benefit of probiotics for primary CDI is not supported by the evidence.

It is puzzling that ACG insists that the probiotic literature be pooled in a strain-specific manner, yet they support conclusions on fecal microbial transplant (FMT) even though FMT interventions are much more heterogeneous than probiotics in regard to composition and mode of administration. They recommend FMT for treatment of C. difficile based on only three double-blinded randomized clinical trials (here, here and here), only one of which was positive. The positive FMT study was conducted at two sites and compared donor stool (heterologous) versus patient’s own stool (autologous) administered by colonoscopy. Overall, 91% of patients in the FMT group achieved clinical cure compared with 63% in the control group. At site #1, the cure rate with donor FMT was 90.0% (CI, 51.8% to 98.7%) versus 42.9% with autologous FMT, whereas in site #2 the cure rate was essentially identical between the two groups. At site #2, donor FMT cure rate was 91.7% (CI, 57.2% to 98.9%) compared with 90.0% (CI, 51.8% to 98.7%) after autologous FMT. We mention this to question the consistency of evidence standards that the ACG guideline authors impose. They admonish pooled data from small trials of different probiotic formulations and methodologies yet ignore heterogeneity in FMT interventions. The data reviewed for probiotics was primarily from double-blinded randomized trials, while for FMT they rely on case series, uncontrolled studies or retrospective studies.

The authors go on to state, “… high quality evidence to support probiotics for most conditions is scarce.” How do they define “scarce” and “most conditions”? As mentioned, Cochrane found thirty-nine studies (8,672 participants) for prevention of CDAD. Under “summary of evidence”, the authors address issues such as size of the market, regulatory oversight, product cost and quality control problems with commercial products, all of which may reflect practical concerns with some probiotic products in the marketplace, but have nothing to do with available evidence. Furthermore, it is the only intervention where the financial value of the industry and cost of interventions is mentioned. Why are the size of the market or costs for FMT or drugs not just as relevant to this review? Cost is discussed throughout the recommendation but without performing or citing a formal cost analysis or cost-effectiveness analysis, even though there are approaches for doing so to inform evidence-based decision-making (here).

The authors indict probiotics for concerns about safety, citing not the thorough review sponsored by AHRQ and conducted by the RAND corporation that looked at 622 studies and found no statistically significant increased relative risk of the overall number of experienced adverse events (RR 1.00; 95% confidence interval [CI]: 0.93, 1.07, p=0.999), but by referring to a review article that cites case reports of blood infections and refers to one study with microbiota, not clinical, endpoints done in Israel on one commercial product. The data actually show that for well characterized, clinically tested probiotics with high levels of quality control the evidence for infectious complications in non-vulnerable populations is virtually nil. ACG does not mention that FMT was shut down due to safety concerns as soon as the pandemic started.

In summary, we are not convinced that the authors have justified their recommendation against the use of probiotics in relation to CDI prevention. They fail to clarify why the results of their GRADE evaluation of probiotic evidence for prevention of C. difficile resulted in totally different conclusions compared to the AGA document, which found evidence sufficient for conditional recommendation of four probiotic preparations. Further,  the review of evidence for probiotics, whether in terms of efficacy or safety, should be addressed in a manner consistent with other interventions considered and editorializing on issues such as market size, profits and product cost, in the absence of an objective approach using appropriate instruments, should be avoided.

ISAPP collaborates with NEC Society to help parents understand the role of probiotics in reducing the risk of necrotizing enterocolitis

/in Consumer Blog, News /by KC

By Dr. Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

To date, over 50 clinical trials on probiotics and necrotizing enterocolitis have been published. Medical organizations have considered the trials completed to date and have provided guidance (ESPHGAN) and recommendations (American Gastroenterological Association) for implementing probiotics in clinical practice.

As important as the science on this issue are the perspectives from parents of babies who have suffered from NEC or are at risk of developing the disease. Such parents consistently point to the need for credible and balanced educational materials about this condition. Recently, ISAPP has been fortunate to work with the NEC Society to develop materials that will help inform parents.

See the new ISAPP infographic Probiotics and Necrotizing Enterocolitis: What Parents Should Know.

Disponible también en español. Информация также доступна на русском языке.

Also, a recent ISAPP blog Probiotics to Prevent Necrotizing Enterocolitis: Moving to Evidence-Based Use by Dr. Ravi Patel MD, a neonatologist on the NEC Society’s Scientific Advisory Council, summarizes the state of the science supporting this use, including both controlled efficacy trials and post-implementation surveys.

The NEC Society is a nonprofit organization – the only US group dedicated to NEC – with the stated mission of “building a world without necrotizing enterocolitis (NEC) through research, advocacy, and education.” They advocate for families affected by NEC by bringing together critical stakeholders to improve understanding, prevention, and treatment for NEC. Jennifer Canvasser founded the NEC Society in 2014 after her son, Micah, died from complications of NEC just before his first birthday. Micah was born at 27-week’s gestation, placing him at increased risk of NEC. Despite Micah’s risk factors and his parents asking the care team to consider offering Micah probiotics, he was not treated with probiotics. Although it is impossible to know if probiotics could have changed Micah’s course, his parents feel that more could have been done to better protect Micah from the devastation of NEC. Micah’s photo is featured in the new infographic co-created by ISAPP and the NEC Society.

“It is vital for healthcare providers to support NICU parents in understanding the protective and risk factors associated with NEC,” Canvasser shared. “Parents are the most important members of their baby’s care team. For parents to effectively engage and contribute, they need to be supported in accessing and understanding important information related to their child’s health. This new resource on probiotics and NEC will help to ensure that NICU parents are informed and feel encouraged to ask questions so they can best advocate for their child.”

The NEC Society intends to use the new infographic as a resource available to NICU parents and providers. It will be downloadable from the websites of both the NEC Society and ISAPP, and it will be shared via both social media platforms. Once in-person events are possible again, print versions will be made available. ISAPP will also work with the NEC Society’s Scientific Advisory Council to explore how we can further disseminate this resource to NICUs.

Read more about the efforts of the NEC Society here:

Head of the Herd: Jennifer Canvasser, Founder and Director, Necrotizing Enterocolitis (NEC) Society

Family Reflections: harnessing the power of families to improve NEC outcomes

10 Things All Parents of NICU Babies Need to Know

9 Things You Need to Know About Necrotizing Enterocolitis

Probiotics to Prevent Necrotizing Enterocolitis: Moving to Evidence-Based Use

/in ISAPP Science Blog /by KC

By Ravi Mangal Patel, MD, Msc, Associate Professor of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta. rmpatel@nullemory.edu Twitter: @ravimpatelmd

Necrotizing enterocolitis (NEC) is one of the most lethal neonatal diseases, yet most people have never heard about it. The disease primarily affects preterm infants and is characterized by the development of intestinal inflammation. Clinically, the disease often manifests with an infant developing feeding intolerance or abnormal abdominal exam findings. The diagnosis is confirmed by abdominal x-ray or ultrasound. One of the key diagnostic radiographic findings is pneumatosis, which is air in the lumen of the bowel caused by gas-producing bacteria.

Dr Ravi Mangal Patel

NEC accounts for 1 out of every 10 deaths in US neonatal intensive care units. Among extremely preterm infants (those born at 22-28 weeks’ gestation) in the US, NEC is the most common single cause of death between 2 weeks and 2 months of age. Many infants with NEC undergo surgery to remove diseased bowel and those who recover and survive are at risk for long-term neurodevelopmental impairment and short bowel syndrome.

Decades of research into NEC have identified several key risk factors, including formula feeding, inconsistent feeding, abnormal intestinal oxygenation and [gut microbiota] dysbiosis. Studies have shown that dysbiosis, or abnormal intestinal colonization, is an important antecedent risk factor for the development of NEC. These studies have found that infants who develop NEC have an increase or bloom in the relative abundance of proteobacteria, compared to those who do not develop NEC. These proteobacteria, which contain a lipopolysaccharide coating, may lead to inflammation through their interaction with Toll-like receptor 4.

Given the role of dysbiosis in NEC, efforts to intervene by provision of probiotics to prevent NEC is a rational and extensively studied intervention, with over 63 randomized trials enrolling ~15,000 infants to date. The aforementioned meta-analysis, along with several others (Table 1), show probiotic supplementation results in large magnitude reductions in the risks of NEC and death and more modest reductions in the risks of late-onset sepsis. However, there is more limited data on extremely preterm infants and the quality or certainty of evidence for probiotics for the prevention of NEC was low in a recent Cochrane review.

 

Source: https://doi.org/10.1053/j.sempedsurg.2017.11.008

In the United States, an increasing number of centers have begun to routinely provide probiotics, with the greatest increase in use beginning in 2015. Observational studies evaluating routine probiotic use show benefits that are similar in magnitude to those from randomized trials, supporting the external validity of the results from the trials. This includes a large recent evaluation of probiotic use in the United States. Around the world, probiotic use is highly variable, from 100% of NICUs in New Zealand, 68% of NICUs in Germany, to 12% in the UK, 21% in Canada and 14% in the United States. Some of the variability in clinical use may be related to the uncertainty regarding the quality of commercially available probiotic products and need for clarity regarding strain-specificity of effects. There are many considerations both for and against routine use of probiotics to prevent NEC (Table 2). Current probiotic dietary supplements do not undergo FDA’s premarket review and approval requirements for safety and effectiveness or have to meet manufacturing and testing standards for drugs, and the potential risks were highlighted by a case of an infant death from a contaminated supplement. There is currently no FDA-approved live biotherapeutic product to prevent NEC.

Source: doi: 10.1016/j.earlhumdev.2019.05.009

Recent recommendations and guidance from ESPHGAN and the AGA also demonstrate that some medical organizations recognize the strength of the data in support of probiotic use to prevent NEC. It has been over two decades since the first study demonstrating the benefit of probiotic supplementation to prevent NEC in preterm infants. Now, more than ever, the evidence continues to accumulate regarding the beneficial effects of probiotic use in preterm infants as a compelling strategy to reduce the risks of both NEC and death. Therefore, considering the balance of potential risks and benefits including data from both randomized trials and routine implementation studies, my opinion is that the cumulative evidence to date supports routine probiotic use to prevent NEC and death in preterm infants.

As important is considering the parent voice regarding probiotic use. The NEC Society is a non-profit focused on NEC that has worked to incorporate the voice of the patient-family in clinical decisions.

Disclosures: Dr. Patel serves on the data-safety monitoring board of the Connection Study, which is a trial examining the use of an investigational probiotic to decrease the risk of NEC.

For further information, see this seminar by Dr. Patel: Practical Consideration for Probiotics in the NICU

GG + BB-12 don’t reduce antibiotic use in an elderly, institutionalized population

/in Consumer Blog, ISAPP Science Blog /by KC

By Mary Ellen Sanders, PhD, ISAPP Executive Science Officer

Close to two years ago, a team convened by ISAPP conducted a meta-analysis showing that probiotics may reduce number of antibiotic prescriptions, with evidence primarily in children (ISAPP-initiated systematic review and meta-analysis shows the association of probiotic consumption with reduced antibiotic prescriptions). A recent study suggests that this outcome likely does not extend to elderly care home residents.

A newly published randomized, placebo-controlled trial tested a combination product comprising two well-studied probiotic strains, Lacticaseibacillus (formerly known as Lactobacillus) rhamnosus GG and Bifidobacterium animalis subsp lactis BB-12, administered at ~1.5 × 1010 per day to institutionalized residents 65 years of age or older to test if this treatment reduced antibiotic administration. The study showed no reduction in antibiotic use compared to the control. Further, the probiotic was not associated with improvement in secondary endpoints, which included many that probiotics are hypothesized to mitigate, including incidence of common infections, duration of infections, C. difficile infection, antibiotic associated diarrhea, hospitalizations, or presence of antibiotic resistant microbes in fecal samples.

Other endpoints suggested that the probiotic group fared worse than the placebo group. Statistically significant differences were found between the probiotic and placebo groups for antibiotics administered for lower respiratory tract infections and well-being scores at 3 months.

This was a well-controlled, comprehensively reported study.  Some factors to consider in interpreting these results:  The population was elderly (mean age = 85.3 years) and infirmed (66% lacked capacity to consent and 63 of 310 randomized subjects died prior to conclusion of the study). Stool culture at 3 months showed L. rhamnosus present in 84% of intervention group compared to 37% of placebo group, although the groups were matched for this factor at baseline. This suggests some cross-contamination between the placebo and intervention groups may have occurred. As the authors state, exposure of the placebo group to the probiotic “would dilute any between-group differences in outcomes.” A higher number of C. diff positive subjects were assigned to the probiotic group than the placebo group (7.2% vs 0%, respectively).

Overall, this study provides evidence that L. rhamnosus GG + B. lactis BB-12 are not effective prophylactically in a population of elderly care home residents.

 

probiotics for healthy people infographic

ISAPP releases new infographic: “Probiotics for Healthy People”

/in featured, News /by Mary Ellen Sanders

November 20, 2017. Probiotics are most commonly studied with for populations with a specific condition—frequent examples include diarrhea, irritable bowel syndrome, and pouchitis. But what kind of evidence exists on probiotics for healthy people?

A new ISAPP infographic gives an overview of what we know about the use of probiotics in healthy individuals. The resource was developed by ISAPP’s Science Translation Committee and approved by  the ISAPP board of directors.

“Studying health benefits in healthy people is a challenge. But there is evidence that probiotics can provide dietary management of some digestive conditions that don’t reach the level of diagnosed disease as well as prevent of some common infectious diseases and. These, and other benefits, are of value to healthy people,” says ISAPP’s Executive Science Officer, Dr. Mary Ellen Sanders. The new infographic  emphasizes it is not necessary to take probiotics to be in good health, but they may serve as a useful addition to a healthy lifestyle.

Research investigating how probiotics can affect healthy individuals through their microbiomes is ongoing in laboratories around the world, and ISAPP continues to track the latest findings.