As an infectious diseases physician, I was trained at a time when most bacteria were considered to be public enemy number 1. It was very much a “them” versus “us” perspective. Fast-forward to 2018, and we are now talking about probiotics or good bacteria. It seems that now the conversation has shifted to “them” and “us.”
Not everyone is enamored with probiotics. Just last month, the New York Times ran an article entitled ‘The Problem With Probiotics’ (1). The article describes the multi-billion dollar probiotic market as ‘wishful thinking’ and ‘imprecision in marketing’.
Sounds like the perfect time to review the science behind probiotics.
What are Probiotics?
To understand probiotics, we have to first talk about the microbiome or microbiota.
Microbiota (or the microbiome) refers to a collection of microbes that naturally inhabit any particular space. It is a huge and complex ecosystem. Over 100 trillion microorganisms make up our microbiome which means that our personal genes are outnumbered 100:1 by the microbiome gene pool (2).
Essentially, we could just see ourselves as scaffolding for these trillions of bugs which is a very humbling thought. In reality, it is a little more complex than that and these bacteria are not just passive tenants. These bacteria actually affect our health and well-being.
Symbiosis refers to a healthy relationship between us and our microbiome which in turn is believed to promote human health and wellness.
Dysbiosis refers to an imbalance in the bacteria in our microbiome which is believed to induce disease states.
Probiotics are microbes that confer health benefits. Bifidonacterium and Lactobacillus are the most widely recognized probiotic bacteria. The history of the oral consumption of micro-organisms producing a protective effect on the gut flora began a very long time ago with fermented foods (3).
Nowadays, probiotics can be consumed as foods eg yogurt, drinks, food supplements or drugs.
Just a little more terminology to get out of the way, before we delve into the science.
Prebiotics are non-viable foods like oligosaccharides that stimulate the growth of gut bacteria and as such can confer health benefits.
Synbiotics is the term used to describe the combined use of probiotics and prebiotics.
By definition, the terms “prebiotics” and “probiotics” are health claims because they allude to health benefits.
Consumption of probiotics has doubled in the USA since the turn of the century (4) The probiotic industry exceeds $4 billion per year currently (5). People with a college education are the main consumers of probiotics (4).
Probiotic use is not restricted to the community setting and it is now estimated that up to 3% of hospitalized patients also now receive probiotics (6). In some hospitals, probiotics are automatically prescribed along with antibiotics for certain conditions.
There are over 3000 probiotics for sale on Amazon (although it is totally confusing for buyers as there is a bewildering array of products and a shortage of unbiased reliable information on how to select a product). Go marketing.
Under the current regulatory framework, there is no requirement for proof of safety or efficacy for probiotics when they are sold as food supplements (7).
Is There any Research?
There are 20,000 studies and 2156 clinical trials on probiotics. When other commuters on my train hang out on Instagram or play Candy Crush, I like to relax with PubMed. Sad but true.
I can honestly say that I have never seen as many meta-analyses and systematic reviews on any other topic as I have seen on probiotics. There are even meta-analyses of meta-analyses.
I have also never seen so many recent papers. As you will notice, many of these papers we will discuss were published in 2018 and we will even look at some 2019 papers which have not even been published yet.
Do Probiotics Help in Treatment for NAFLD?
One of the hottest topics in medicine right now is NASH/NAFLD (non-alcoholic steatohepatitis/non-alcoholic fatty liver disease). Currently, we have a limited understanding of these liver diseases and how best to manage them.
I only recently learned that NAFLD is the most common chronic liver disease in children. There is a growing interest in the possible therapeutic role of probiotics for these liver conditions (8).
One systematic review of 3 trials looking at probiotics, prebiotics or both (synbiotics) in the treatment of NAFLD in adult patients showed that 2 studies showed that probiotics showed favorable improvements as compared to the control groups while 1 study showed improvements in both the probiotic and control arms of the study (9).
A 2013 review of 4 trials involving 134 patients with NAFLD/NASH showed that probiotics can reduce abnormal liver blood tests (amino transferase) and total cholesterol while improving insulin resistance (10).
There is some emerging data to support a potential role for probiotics in NASH/NAFLD.
Do Probiotics Improve Mental Illness?
Welcome to the world of psychobiotics and nutritional psychiatry.
The gut-brain axis is a bidirectional connection between nerves in the gut and the brain which suggests that gut health can influence mental health and vice versa. There are multiple mechanisms by which the microbiome is believed to affect mental health including:
- directly affecting levels of neurotransmitters such as serotonin
- affecting the stress response and steroid levels
- production of metabolites such as short chain fatty acids and tryptophan which affects the CNS and
- affecting the immune system and inflammatory messengers which interact with the brain (11).
A 2016 review from Canadian researchers on probiotics in depression and anxiety found 10 relevant randomized trials (12). They concluded that ‘Despite methodological limitations of the included trials and the complex nature of gut-brain interactions, results suggest the detection of apparent psychological benefits from probiotic supplementation’.
Another 2016 systematic review and meta-analysis of randomized controlled trials in depression (this time from China) found that probiotics significantly reduced the depression score (13).
The benefits were seen in healthy patients and people with major depression. The effects were most noticeable in the under 60-year-old population but not in the over 65-year-old population.
It seems strange that two meta-analyses, both done the same year, would have similar but different results but I guess the overall take-home message is the same.
One year later, Wallace and colleagues looked at the literature for probiotics in depressive symptoms. They found ten studies relating to mood anxiety and cognition (14). They concluded that the majority of the studies found positive results but that no studies addressed the issue of sleep.
They postulated that probiotics could act by modulating the activity of the neurotransmitter serotonin or via modulating inflammatory pathways. They also found a wide range of variables in terms of strength of dosing, strains, and duration which makes it hard to make specific recommendations.
This article was subsequently corrected because of an error that was noted in one of the tables. However, the error turned out to be a minor typo which did not change the bottom line
In 2018, researchers identified 10 clinical trials of 1349 patients which compared probiotics to placebo for depressive symptoms (15). Oddly the majority of these studies were conducted in healthy people. Taking the data as a whole, they found no benefits of probiotics over placebo for depression.
On sub-analysis, they found that probiotics resulted in significant improvements in mood in people with mild to moderate depression but not in healthy people. The bottom line for the study authors was that probiotics had an insignificant effect on mood and that future studies should be conducted on people with actual mood issues.
The issue of probiotics and mental well-being in healthy people is very interesting.
Let’s look at a meta-analysis which addresses an issue that would describe the mental health of many of my friends – “Probiotics and Subclinical Psychological Symptoms in Healthy Participants” (16).
This 2017 review from Australia found 7 relevant studies and concluded that probiotic use could have a positive effect on psychological symptoms of depression, anxiety, and perceived stress in healthy human volunteers.
I think that this is a really important finding. All too often, healthy people with perceived stress end up on antidepressants and anti-anxiety pills as part of the “medicalization of human despair.”
At this stage, I have seen enough data to come up with my bottom line here.
There is very definitely some gut-brain connection and some link between the state of our microbiome and our mental health. The specifics of what is needed for a certain diagnosis in a specific population needs fine-tuning and further research.
Do Probiotics Help Improve Skin Health?
Huang and colleagues from China looked at probiotics in atopic dermatitis in children (17). The results were hard to interpret in any meaningful way. Some strains of probiotics had favorable effects eg Lactobacillus fermentum and Lactobacillus salivarius. The effects were more favorable in Asia as opposed to Europe.
A 2018 systematic review and meta-analysis of probiotic use for the prevention of atopic dermatitis in infants and children looked at 25 individual studies (18). Overall, compared with controls, probiotic treatment reduced the risk of atopic dermatitis.
On closer examination, the results were a little more complex. Probiotics had to be taken before and for 6 months after delivery to afford protective benefits. Use of probiotics either before or after delivery was not enough.
When it comes to eczema, a Cochrane review found 39 randomized controlled trials involving 2599 study subjects (19). They found no benefit in terms of patient-rated eczema symptoms, quality of life or physician assessment scores.
This led the investigators to conclude that the use of probiotics in eczema is currently not evidence-based.
Probiotics have not been shown to improve skin health.
Do Probiotics Improve Digestive Health?
A 2018 meta-analysis looked at 11 published articles relating to 2977 people who participated in studies relating to the role of probiotics in the prevention of travellers diarrhea (20). The probiotic strain, Saccharomyces boulardii, showed a protective effect against travellers diarrhea.
Another 2018 meta-analysis found 11 studies on Helicobacter pylori which taken together only showed a minimal effect on H pylori eradication (21).
The data on Clostridium difficile diarrhea is more robust (22). Data from an international consortium involving almost 7000 study participants found that there was moderate quality evidence that probiotics prevent Clostridium diarrhea especially in people taking 2 or more antibiotics in hospitals.
A review is currently underway to look at the available evidence on probiotics in gastrointestinal disease from the Cochrane group (23). At the time of writing, that review article was still underway.
When it comes to digestive health, probiotics have the best track record for Clostridium difficile infection.
Do Probiotics Reduce Inflammation & Boost Immunity?
A paper has been accepted for publication in 2019 which specifically looks at the role of probiotics as immunomodulators (24). Unfortunately, I do not know what the paper will say.
A 2018 review looked at 9 trials of 895 patients with cows’ milk allergy (25). The study focused on the pediatric population. The current management of food allergies involves identification of the offending allergen, avoidance of the allergen and alleviation of symptoms if allergic people encounter their trigger allergen.
The data was confusing. At best, it might be concluded that there was “moderate” evidence that probiotics could help with allergy symptoms and ‘low level’ evidence that probiotics could help children with cows milk allergy tolerate cows milk.
One of the most interesting features of the study was not the results. One of the articles reviewed was written in the Polish language and the researchers used Google translate to translate the paper to English.
Another systematic review examined the efficacy of probiotics for inflammatory bowel disease (26). There are two main forms of inflammatory bowel disease: ulcerative colitis and Crohns Disease.
The researchers initially found over 12000 possible papers but reduced that down to 22 eligible and relevant trials. The review found that probiotics may help with ulcerative colitis but not Crohns Disease.
The data on probiotics in inflammation and immunity is inconclusive at this time.
Do Probiotics Treat Diseases in Children?
There is growing interest in the use of probiotics in children. I have been at a number of talks which suggested a possible role for probiotics in the prevention of respiratory tract infections in kids. Ask any mother of a school-age child with asthma if this of interest and I can guarantee you that the answer will be an overwhelming, “yes please.”
One systematic review of the literature found 21 trials with 6603 study participants relating to the topic of using probiotics to prevent coughs, colds, and sniffles (27). The review found no convincing evidence to support probiotics for this indication.
Meanwhile, a 2016 review of 23 trials involving 6269 children found that probiotics significantly reduced the number of respiratory tract infections and number of days absent from school leading these authors to conclude that probiotics are a feasible way to reduce respiratory tract infections in children (28).
There is no consensus among the meta-analysis on the value of probiotics in children.
Do Probiotics Help Lower Blood Pressure?
A 2014 meta-analysis of collated data from 7 studies of probiotics and BP involving 543 participants (29).
The authors found that probiotic use significantly reduced both systolic and diastolic blood pressure as compared to control groups. The effect was most noticeable in people with a high baseline blood pressure and when the probiotics were taken for at least 8 weeks.
There is evidence to support a role for probiotics in hypertension.
Do Probiotics Reduce Risk of Diabetics?
There are 5 meta-analysis published on probiotics and type 2 diabetes (30). Of these, 4 involve adults and 1 involves adults and children. Data from a total of 2501 people took part in these studies.
Overall the meta-analysis find that probiotics can cause significant reductions in fasting blood sugar but there is no consensus on the effect of probiotics on insulin levels.
There is a lack of clarity on the preferred strains of probiotics for diabetes but it is likely necessary to take the probiotics for a minimum of 8 weeks to see clinically meaningful results.
A systematic review from researchers in Spain looked at the effects of probiotics and synbiotics for obesity, diabetes, insulin resistance and non-alcoholic liver disease (31). The ambitious review concluded that the data on probiotics and synbiotics for these diseases was generally positive but also often contradictory.
They suggested that the inconsistency in the results might be due to the small number of patients studied, the use of different doses of and strains of probiotics and synbiotics.
Probiotics may help people with type 2 diabetes.
Finally, do Probiotics Help With Weight Loss?
A 2015 systematic review of the medical literature found 4 randomized controlled trials that directly compares probiotics to placebo for weight loss (32). Extensive number crunching showed no report significant effect of probiotics on body weight or body mass index.
The authors of the study do caution the reader that there were too few studies and too few data points to draw any meaningful conclusions.
That same year, another meta-analysis of 25 trials found that probiotics reduced body weight and body mass index (33). This body of work concluded that 8 weeks was necessary for meaningful results and that multiple species of probiotics were necessary to see benefits.
It is not possible to reconcile the results from the meta-analyses on probiotics for weight loss.
Are Probiotics Safe?
There is no legal requirement for proof of safety prior to the sale of a probiotic food supplements in the USA. Many probiotics are classified as ‘Generally Regarded As Safe’ by the FDA (34). Generally safe is debatable.
Studies have found that commercial probiotics can contain live microorganisms. The CDC reported the really tragic case of a premature infant who died of a fungal infection associated with a contaminated probiotic supplement (35).
A 2014 systematic review of the safety of probiotics found an overall good safety profile. However, they did find cases of bacterial infections, fungal infections and especially in the intensive care/critically ill patient population (36).
Four types of mechanisms behind adverse effects of probiotics were identified in a 2002 report jointly released by the World Health Organization (WHO) and the Food and Agriculture Organization (FAO) of the United Nations
- Systemic infections eg fungal or bacterial infections
- Deleterious metabolic activities eg increased oxygen demand in the gut leading to bowel ischaemia.
- Excessive immune stimulation in susceptible individuals.
- Gene transfer of antibiotic resistance from probiotic bacteria and other bacteria in the gut (37).
On reading the individual studies and meta-analyses, the data on probiotics for some conditions look promising.
On the other hand, it has to be said that there are so many limitations when it comes to the science of probiotics.
Firstly, there are so many different strains and doses of probiotics used in the studies that it is hard to make meaningful cross-study comparisons.
Secondly, the studies come from different countries which means that the study participants have different genetics and different microbiomes.
A 2017 high-level review of meta-analyses (a meta-analysis of meta-analysis) discounted much of the science around probiotics.(30). The review was carried out by a team of Italian investigators. They considered recommendations for probiotics in C. difficile diarrhea and respiratory tract infections as being evidence-based and reasonable.
They would not stand over the results of other meta-analyses for the following conditions: metabolic disease, IBS, constipation, IBD, chemotherapy-associated diarrhea, ventilator-associated pneumonia, NAFLD, liver encephalopathy, periodontitis, depression, vaginosis, urinary tract infections, pancreatitis, incidence of ventilator-associated pneumonia, hospital infection and stay in ICU, mortality of post-trauma patients and/or necrotising enterocolitis in premature infants.
What about healthy people? Can probiotic supplementation help there? A review by Khalesi and colleagues found improvements in the immune, gastrointestinal, and female reproductive health systems in healthy adults (38). However, there was no evidence of long-term benefits in this population.
My take-home message here is that the health of our microbiome affects our overall health. Probiotics may/not help. At the rate of publication of papers on probiotics, we are on a steep learning curve on this topic.
In the meantime, ensuring a healthy microbiome by minimizing unnecessary antibiotic use and indiscriminate exposure of our microbiome to anti-bacterials seems like a smart thing to do.