Opinion Article

Probiotics: A Guide for Healthcare Professionals 

Dr Sarah Jarvis, GP

Introduction

As a healthcare professional, I frequently have conversations with my patients about probiotics – not uncommonly initiated by them. It feels as if probiotics have been around forever, yet the term itself was officially defined less than 25 years ago by an Expert Consultation of the Food and Agricultural Organization of the United Nations and the World Health Organization (FAO/WHO 2001).

In 2014, an article based on an Expert Panel of the International Scientific Association for Probiotics and Prebiotics published what has become the widely accepted global definition of probiotics - “Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.” (Hill, 2014).

Within a generation, the focus of probiotic research has moved from gastrointestinal disorders and diseases (irritable bowel syndrome (Dale 2019), diverticular disease (Lahner 2016), inflammatory bowel disease (Estevinho 2024) to wider physical disease such as type 2 diabetes (Ayesha 2023), obesity (Tome-Castro 2021), coronary heart disease, and mental health (Merkouris et al 2024).

Mechanism of action of probiotics

• Probiotics exert their positive effect on human health through a variety of mechanisms (Vanderpool 2008). For example, they can:
• Inhibit the growth of pathogens by competing for nutrients and attachment sites at the intestinal epithelium.
• Strengthen the epithelial tight junctions and preserve mucosal barrier function (Rao 2013, Zakostelska 2011).
• Modulate host cell signalling pathways, including Akt, mitogen-activated protein kinases, and nuclear factor-kappa B to mediate intestinal epithelial functions.
• Produce antimicrobial substances, such as short chain fatty acids, which support maintenance of intestinal homeostasis and block pathogenic bacterial effects.
• Regulate innate and adaptive immune responses by interacting with immune cells such as dendritic cells, macrophages, natural killer cells, and T and B cells. 

Safety of Probiotics

The Agency for Healthcare Research and Quality carried out a comprehensive review on the safety of probiotics for both the general public and for special populations (AHRQ 2011). Among the 387 studies which documented the presence or absence of specific adverse events, there was no increased risk associated with the use of probiotics. This included gastrointestinal (GI) events, infection or other adverse or serious adverse effects.

Of note, in randomised controlled trials (RCTs) in medium-risk and critically ill participants, there was no statistically significant increase in adverse events compared to the control groups with similar characteristics. Case studies suggested that participants with compromised health were most likely to experience adverse events associated with probiotics.

They did note that RCTs did not routinely monitor for infections, reporting mainly on GI side effects. The trials which included adverse event monitoring were of short-term duration.

Generally, critically ill patients in intensive care units, critically sick infants, postoperative and hospitalized patients and patients with immune-compromised complexity were the most at-risk populations. 

A more recent review (Merenstein 2023) commented on the wide variety of products marketed as probiotics and the differences between them, as well as the expanding use of probiotics into vulnerable populations. They examined potential safety issues related to probiotic strain, product quality, or probiotic administration. 

The review concluded that “Issues related to safety pertaining to formulation of probiotic products include the need to establish purity, potency (the quantity of live microbes delivered), and composition of the final product.” They also note that “The manner in which the probiotic is given or taken must also be safe. This constitutes safe administration of a properly designed product to the intended host.”

Are all probiotics the same?

What to Look for

In the same way that safety data differs between probiotics, not all probiotics have the same evidence for efficacy. 

ISAPP guide to choosing a probiotic reminds consumers that “Not all products labelled “probiotic” are true probiotics” (ISAPP 2018). It is recommended that consumers consider:

·        Scientific evidence for the product.

·        Specific trial evidence for the condition they are interested in.

·        Colony forming units (CFUs) for each dose, mostly ranging from 100 million to 50 billion or more CFU/dose.

·        Safety (special consideration for pregnant women, infants, people with compromised immune systems, or people with short bowel syndrome, although they make the point that for healthy people, probiotics are generally safe to consume).

·        Labelling, which according to FAO/WHO 2001 should include:

1.     Genus, species and strain designation for each probiotic strain in the product.

2.     Minimum viable numbers of each probiotic strain at the end of the shelf-life, expressed as CFU count for each serving.

3.     Proper storage conditions.

4.     Suggested dose or serving size to deliver the effective dose of probiotics related to any health benefit communicated on the label.

5.     Company contact information.

Beyond the Strain: Other Aspects to Consider

Global Guidelines from the World Gastroenterology Organisation (World Gastroenterology Organisation 2023) recommend that clinicians should only be recommending probiotics with in vivo RCTs evidence for the patient’s individual condition. They consider that the optimal dose of probiotics is both strain- and product-dependent. 

Formulation, storage and instructions for consumption can all affect the viability and efficacy of a product. For example, an in vitro study comparing eight commercially available probiotic preparations showed significant differences in terms of their viability when exposed to a simulation of conditions in the stomach (Fredua-Agyeman 2015). Of note, the investigators concluded that:

In general, liquid-based products tested tended to have improved survival compared with the freeze-dried products tested.

Results from tests in the fed state in porcine gastric fluid suggested that food greatly affects viability.

Most current guidelines (ISAPP 2018, FAO/WHO) consider only bacterial strain(s) and CFU. However, this may well not reflect clinical effectiveness if viability is not proven. Thus, it is essential to ensure that any product has robust in vivo RCTs in a particular disease area before recommending it to patients for that condition.

Summary Table

This table gives a summary of clinical conditions in which there are meta-analyses looking at the use of probiotics.

 A Practical Guide to Choosing Probiotics

Reassure patients that for the majority who are not immunocompromised or critically ill, probiotics have a good safety and tolerability profile.

Explain to the patient that strain, disease/condition and viability are all important in determining whether a probiotic is likely to have a clinically relevant effect for an individual patient.  This means that product as well as strain may determine efficacy.

Look for: 

·        CFUs for each dose

·        Genus, species and strain designation for each probiotic strain in the product

·        Confirmatory clinical trials for the individual product which prove efficacy of the individual product for the patient’s condition

Advise the patient to use the product at the dose recommended, and to ensure both storage and dosing instructions (e.g. storage temperature, taken with or without food) are followed closely.

There is limited guidance on the recommended duration of treatment. For IBS, NICE Clinical Knowledge Summaries (NICE 2023) recommends that for people who choose to take an over-the-counter probiotic supplement, healthcare professionals should advise that they do so for at least twelve weeks and discontinue if there is no improvement in symptoms.

References

AHRQ Publication No. 11-E007 April 2011. Safety of Probiotics to Reduce Risk and Prevent or Treat Disease. https://www.ncbi.nlm.nih.gov/books/NBK56091/pdf/Bookshelf_NBK56091.pdf

Ayesha I et al. Probiotics and Their Role in the Management of Type 2 Diabetes Mellitus (Short-Term Versus Long-Term Effect): A Systematic Review and Meta-Analysis. Cureus.  2023 Oct 9;15(10):e46741. https://pubmed.ncbi.nlm.nih.gov/38022046/ 

Dale H et al. Probiotics in Irritable Bowel Syndrome: An Up-to-Date Systematic Review. Nutrients 2019 Sep 2;11(9):2048. https://pubmed.ncbi.nlm.nih.gov/31480656/

Estevinho M et al. Efficacy and safety of probiotics in IBD: An overview of systematic reviews and updated meta-analysis of randomized controlled trials. United European Gastroenterol J. 2024 Sep;12(7):960-981. https://pubmed.ncbi.nlm.nih.gov/39106167/ 

FAO/WHO. Health and Nutrition Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria. Report of a Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria October 2001. http://www.fao.org/3/a-a0512e.pdf

Fredua-Agyeman, M; Gaisford, S; (2015) Comparative survival of commercial probiotic formulations: tests in biorelevant gastric fluids and real-time measurements using microcalorimetry. Beneficial Microbes , 6 (1) pp. 141-151. https://pubmed.ncbi.nlm.nih.gov/25351484/ 

Hill C et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews Gastroenterology & Hepatology 2014; 11: 506–514. https://www.nature.com/articles/nrgastro.2014.66

ISAPP Probiotic Checklist: making a smart selection. 2018. https://isappscience.org/wp-content/uploads/2019/04/Probiotic-Checklist-Infographic.pdf

Lahner E et al. Probiotics in the Treatment of Diverticular Disease. A Systematic Review. J Gastrointestin Liver Dis. 2016 Mar;25(1):79-86. https://pubmed.ncbi.nlm.nih.gov/27014757/

Merenstein D et al. Emerging issues in probiotic safety: 2023 perspectives. Gut Microbes 2023; 15 (1). https://pubmed.ncbi.nlm.nih.gov/36919522/ 

Merkouris E et al. Probiotics' Effects in the Treatment of Anxiety and Depression: A Comprehensive Review of 2014-2023 Clinical Trials. Microorganisms. 2024 Feb 19;12(2):411. https://www.mdpi.com/2076-2607/12/2/411

NICE (National Institute for Health and Care Excellence) 2023. https://cks.nice.org.uk/topics/irritable-bowel-syndrome/management/management/ 

Rao R, Samak G. Protection and Restitution of Gut Barrier by Probiotics: Nutritional and Clinical Implications. Curr Nutr Food Sci. 2013 May 1;9(2):99–107. https://pmc.ncbi.nlm.nih.gov/articles/PMC3864899/

Snydman D. The safety of probiotics. Clin Infect Dis. 2008 Feb 1:46 Suppl 2:S104-11. https://pubmed.ncbi.nlm.nih.gov/18181712/ 

Tome-Castro X et al. Probiotics as a therapeutic strategy in obesity and overweight: a systematic review. Benef Microbes. 2021 Feb 24;12(1):5-15. https://pubmed.ncbi.nlm.nih.gov/33459204/ 

Vanderpool C et al. Mechanisms of probiotic action: Implications for therapeutic applications in inflammatory bowel diseases. Inflamm Bowel Dis. 2008 Nov;14(11):1585-96. https://pubmed.ncbi.nlm.nih.gov/18623173/

World Gastroenterology Organisation (WGO) global guidelines: Probiotics and prebiotics. 2023 Feb. https://www.worldgastroenterology.org/UserFiles/file/guidelines/probiotics-and-prebiotics-english-2023.pdf 

Wu H et al. Potential Benefits of Probiotics and Prebiotics for Coronary Heart Disease and Stroke. Nutrients. 2021 Aug 21;13(8):2878. https://pubmed.ncbi.nlm.nih.gov/34445037/

Zakostelska Z et al. Lysate of Probiotic Lactobacillus casei DN-114 001 Ameliorates Colitis by Strengthening the Gut Barrier Function and Changing the Gut Microenvironment. PLoS One. 2011 Nov 22;6(11):e27961. https://pmc.ncbi.nlm.nih.gov/articles/PMC3222668/