Probiotics: Common Indications and Current Evidence [S.S.]

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Probiotics: Common Indications and Current Evidence [S.S.]

Estimated read time = ~ 14-16 minutes

Introduction & Context

Probiotics can been defined as:

live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.” - International Scientific Association for Probiotics and Prebiotics [ISAPP] 

This criteria is strain-specific, encompassing specific species for which there is evidence from controlled interventions demonstrating an effect. To be classified as a probiotic, a product must:

  1. contain live microbes of viable cells (generally containing a minimum of 1 × 109 colony-forming units, or CFU), and
  2. confer a health benefit

Note that this definition of probiotic does not include fermented foods. 

It can be helpful to understand the organisation of living organisms, and how they are categorised, which is known as ’taxonomy’. The ecosystem of live bacteria that exists symbiotically within the human body (primarily the gut), and indeed outside of it (on the skin), contains trillions of bacteria. Due to its enormous gene-expression is considered an ‘extended genome’, and is highly biologically active. In this regard, it may be helpful to define some terminology:

  • ‘Microbiome’: this ‘extended genome’, i.e., what functions do the bacteria exert;
  • ‘Microbiota’: the composition of bacteria in the gut, i.e., what phyla, species, strains, and in what amounts;
  • ‘Microbes’: microorganisms, which could be bacteria, viruses, fungi, or algae;
  • ‘Bacteria’: highly-adaptable single-cell organisms;
  • ‘Dysbiosis’: when the composition of the microbiota is disturbed, and influences disease.

It can also help to understand the taxonomic organisation of bacteria; a useful analogy is thinking of military organisation from company, to battalion, to brigade, to division. There are four main ‘divisions’ in the human microbiota, known as phyla:

  1. Bacteroidetes
  2. Firmicutes
  3. Actinobacteria
  4. Proteobacteria

The majority of bacteria in humans belong to the Firmicutes and Bacteroidetes divisions, which substantial presence of both Actinobacteria and Proteobacteria. These four divisions are considered the “bacterial core” of the human microbiome. 

Within each phyla, there are abundances of different genus of bacteria (think of genus as the brigade), and each genus is composed of numerous species (think of these as the battalion). Finally, we have specific strains of bacteria within a species (think of these as the company), which have specific characteristics that distinguish them. With only four main ‘divisions’, or phyla, the human microbiota has much less variation at this taxonomic level than other ecosystems, for example soil. However, within each genus and species there is significant inter-individual variance in the relative abundance of species and strains. Therefore, in the human gut, microbial diversity reflects the variability within each major phylum.

The following table may help visualise the taxonomic organisation of the human microbiota:

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Understanding the taxonomic organisation to the microbiota relates to the evidence for the role of probiotics in various disease states, because the evidence suggests that efficacy is strain-specific, and thus formulations with single species or combinations of species may have no significant efficacy.

Probiotics for a Generally 'Healthy Gut’?

The difficulty with this claim is that there is currently no scientific consensus for what a ‘healthy’ gut microbiota may look like based on microbial composition, i.e., there is no ’signature human microbiota’. At the broad level, there is evidence of trends in phyla and genus dominance that are associated with host health, with microbial diversity being a consistent feature of a healthy gut microbiota.

For example, in a comparison between populations in the US, Africa, and South America, the US subjects displayed the least microbial diversity, while the African and South American groups were dominated by the Prevotella genus, reflecting their high plant fibre diets. However, although similar at the genus level, the African and South American groups remained distinguishable at the species level, indicative of the variability in the human microbiota by region and diet. 

The evidence to date in human studies indicates that while probiotics may shift the composition in the upper gastrointestinal tract/small intestine, they only have a limited, transient impact on the composition of the microbiota in the colon/large intestine. This is inconsistent with the biological activity of the microbiota as we know it, as the colon is the predominant site of colonisation for anaerobic bacterial species and the production of metabolic byproducts, for example short-chain fatty acids, that are associated with positive effects from host-diet microbiota interactions.

The ISAPP considered "supporting a healthy gut" to be a core benefit of probiotics, however, this was based on evidence for specific disease state indications, specifically diarrhoea and necrotising enterocolitis. This consideration is distinct from the potential for probiotics to confer benefit in a general sense, however, and given that changes in the human microbiota are driven primarily by the presence or absence of fibre, there is little evidence to recommend probiotic supplementation in generally healthy individuals with no specific indication for use.

Probiotics and Diarrhoea

The strongest evidence for probiotic efficacy appears to relate to diarrhoea, including:

  • Antibiotic-associated Diarrhoea (AAD)
  • Clostridium difficule-associated Diarrhoea (CDD)
  • Infectious Diarrhoea (ID)
  • Travellers Diarrhoea (TD)

AAD and CDD are associated with pathogenic bacteria infection, particularly following antibiotic use, and there is robust evidence that probiotics, in particular L.casei, S.boulardii, S.thermophilus, S.bulgaricus, L.rhamnosus, and L.acidophilus, prevent AAD. S.boulardii and L.rhamnosus appear to be the most effective species in treatment of AAD, and this efficacy is evident concurrent to antibiotic use. S.boulardii has also evidence of efficacy in reducing the recurrence of CDD.

In relation to Travellers Diarrhoea, both S.boulardii and L.rhamnosus GG have been shown to have a preventative effect, however, the effect differed relative to dose, duration of treatment, and region of travel. In Infectious Diarrhoea, three L.rhamnosus strains in combination formula have been shown to reduce duration of diarrhoea in children, while B.lactis and L.reuteri in combination reduced incidence of ID compared to placebo. 

In addition, infection with Helicobacter Pylori (HPP) has been associated with antibiotic use, and there has been research examining the effects of Lactobacillus alone or in multi-strain formulations on HPP eradication. However, eradication rates are not significantly greater than no intervention, and the evidence supporting probiotics for this indication is weak. 

The fact that the effects of probiotics appear to be not only strain-specific, but condition-specific, suggests that pooling data in the context of meta-analysis may yield misleading results if the included studies investigated different strains in different gastrointestinal conditions. Despite these methodological issues, the cumulative weight of evidence does suggest that specific probiotic strains benefit either occurrence, recurrence, treatment, or a combination thereof, of gastrointestinal infections, in particular various diarrhoea conditions.

Probiotics and Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD) is an umbrella term for two conditions:

  1. Ulcerative Colitis (UC)
  2. Crohn’s Disease (CD)

Both conditions are characterised by low microbial diversity, with low levels of Firmicutes and Bacteroidetes, and low levels of the short-chain fatty acid, butyrate. Another critical characteristic of IBD is vitamin D deficiency, with strong inverse relationships between deficiency and incidence evident in epidemiology, and mechanistic support for an important mediating effect between the Vitamin D Receptor (VDR), microbial activity, and intestinal barrier function.

The probiotic research on both Ulcerative Colitis and Crohn’s Disease reflects the strain-specific and condition-specific issues identified above in relation to GI infections. A formulation, commercially known as VSL#3 and containing several species of Lactobacilli, Bifidobacteria, and Streptococcus, has shown considerable efficacy in remission rates in Ulcerative Colitis specifically, with a 2.4-fold increase in remission compared to placebo from a dose of 3600-billion CFU. However, beneficial effects have not been shown for VSL#3 in relation to Crohn’s Disease. Trials of isolated L.rhamnosus GG or L.johnsonii LA1, and S.boulardii in CD have also yielded largely null results.

The overall body of evidence for probiotic treatment in IBD is faced with the same issues are the general literature for probiotics, namely wide variance in:

  • the strains used
  • the dose
  • the condition itself
  • any concurrent therapies for the specific condition
  • the outcomes

Any benefit evident also appears to be confined to Ulcerative Colitis, while there is scant evidence of any benefit to probiotics in Crohn’s Disease.

While not probiotics, there is an emerging hypothesis that ‘contrabiotics’, that is, substrates which inhibit pathogenic bacteria from adhering the intestinal cell wall, may have a protective effect in Crohn’s Disease. Pathogenic strains of E.coli have been shown experimentally to adhere to mucosal cells in the intestine, precipitating inflammatory and immune responses. Experimental evidence has demonstrated that, at physiologically relevant concentrations, non-starch polysaccharides (a specific type of fibre) found in green plantains and broccoli may inhibit the adherence of E.coli to intestinal cells

Probiotics and Irritable Bowel Syndrome

Irritable Bowel Syndrome (IBS) is characterised by abdominal pain, distension, and altered bowel habits from diarrhoea to constipation. However, these symptoms occur in the absence of any evidence for biochemical, structural, or metabolic abnormalities. Given the latter, IBS is classified as a ‘Functional Gastrointestinal Disorder’, defined as a disorder of the gut-brain axis, involving microbial dysbiosis, visceral hypersensitivity, altered mucosal immune function, and dysregulation of gut signalling. In this respect, IBS relates to the subjective interpretation and reporting of symptoms by an individual, and psychosocial factors strongly influence the condition. Unlike, for example, IBD, where outcomes can be assessed as clinical endpoints such as remission, in IBS the outcomes are  ultimately an experiential change in physiological function.

Altered microbial composition compared to healthy controls is a characteristic of IBS, with patients exhibiting an increased Firmicutes:Bacteroidetes ratio. This is significant as it means that there are reduced levels of Bacteroidetes species, which specialise in the degradation of short-chain carbohydrates, known collectively as ‘FODMAPs’ (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols). Reduced levels of these specialised bacteria may contribute to IBS symptoms, however, this is difficult to establish cause-and-effect relationships with as the primary dietary intervention for IBS, the Low-FODMAP Diet, also results in reduced populations of these fibre-degrading bacteria. 

The evidence for probiotic supplementation in IBS is inconsistent, again reflective of issues relating to strain, single or multi-formulas, dose, duration of treatment, and outcome assessment. While certain analyses have found greater efficacy in multi-strain formulas, others have found a greater magnitude of effect from single-strain probiotics. The underlying reason for this discrepancy in effect remains unclear, as various single-strains have been shown to exert beneficial effects on IBS symptoms.

Interestingly, analysis based on dose has suggested that lower doses of 10 × 109 10 × 1010 may be the range at which benefits are observed, and that higher doses may aggravate dysbiosis or cause over-fermentation of carbohydrate. The efficacy of lower doses has been shown in other analyses. The strains which may confer benefit in IBS are predominantly Lactobacillus and Bifidobacterium genus, however, there is significant variance in the strains used, typifying a major limitation of attempts to synthesise the evidence for probiotics into coherent recommendations.

At this juncture, the evidence for probiotic supplementation in IBS is mixed, with an overall trend toward a beneficial effect compared to placebo evidence in controlled interventions. However, the magnitude of this effect is inconsistent, and it appears certain subgroups benefit more than others, although defining characteristics of responders vs. non-responders have yet to be elucidated. 

Probiotics and Food Allergy & Intolerance

Food allergy denotes an Immunoglobulin-E mediated reaction that is:

  • immediate (0-2hrs)
  • not dose-dependent
  • reproducible each time a culprit food is consumed

A recent meta-analysis of published randomised controlled trials up to 2015 found that supplementation with Lactobacillus and/or Bifidobacterium strains prenatally and postnatally reduced risk of food sensitisation, and significantly reduced risk for atopic sensitisation. Although in relation to the latter, only two studies tested food allergens. Interestingly, the effects were not observed when probiotics were provided either prenatally or postnatally alone, and benefits particularly noted in children delivered via cesarean-section. However, a limitation of the included studies - and consequently the results from the perspective of food hypersensitivity as an outcome - is that lack of food allergy confirmed through oral food challenge, which is the gold standard for assessing food allergy. Nonetheless, given the critical period of infancy from birth delivery method, to feeding method, to food sensitisation during weaning, on the gut microbiota, there is sufficient evidence to date to support further research into the potential for prenatal and postnatal probiotic supplementation to reduce allergy risk in children.

Another interesting study in children with confirmed peanut allergy found that supplementing the strain L.rhamnosus CGMCC1.3724 alongside oral immunotherapy led to significant desensitisation in the probiotic group in response to a peanut food challenge (82.1% unresponsive), compared to placebo (3.6% unresponsive). Four-year follow-up found a significant difference in the numbers of participants from the intervention group able to continue eating peanuts compared to the placebo group (67% vs. 4%), suggesting a legacy benefit from combined immunotherapy and probiotic supplementation.

A study in children with confirmed cow’s milk allergy found that the addition of the probiotic strain L.rhamnosus GG to an extensively hydrolysed casein formula reduced incidence of allergic symptoms, including rhino-conjunctivitis, eczema, and asthma, over 3-years, compared to the formula alone. However, it is important to state that these trials provide preliminary evidence and and lack the robustness and replication necessary to make recommendations for probiotic supplementation in food allergy prevention or treatment.

In relation to intolerances, there is some evidence of benefit to specific probiotic strains for lactose intolerance (LI) symptoms, a condition characterised by lack of the lactase enzyme required to digest milk sugars. In particular, B.animalis has shown to ameliorate LI symptoms in response to lactose challenge in subjects with confirmed LI. Other strains of both the Lactobacillus and Bifidobacterium species, in addition to S.boulardii, have not demonstrated efficacy in treatment of LI symptoms. 

Necrotising enterocolitis (NEC), late-onset sepsis (LOS), and feeding intolerance, are all issues that contribute significantly to risk of long-term neurodevelopment disorders, and mortality, in pre-term infants. A strain-specific analysis on the effects of probiotics in pre-term infants found a preventative effect against NEC. Indeed, a robust and substantial body of evidence supports probiotic supplementation for the reduction of mortality, NEC, LOS, and feeding intolerance, in pre-term infants. This is one area where the recommendations for probiotic supplementation would be considered strong and persuasive having regard to the evidence.

Probiotics and Obesity

There has been a distinct trend of overreach on the available literature in relation to the microbiome and obesity to suggest a cause-effect relationship. While alterations in microbial composition are evident in obesity, in particular increased concentrations of Firmicutes and decreased populations of Bacteroidetes. Evidence from comparative studies suggests, however, that this composition is a consequence of diet, not a cause of obesity, i.e., diet causes obesity and the microbiota shifts in response to diet. A more accurate characterisation of the role of the microbiota may be that the altered composition in turn exacerbates the negative effects of increasing adiposity by promoting intestinal inflammation, and potentially contributing to insulin resistance and altered fat metabolism. However, the majority of the proposed mechanisms remain derived from animal models. 

Confining our analysis to human intervention studies, therefore, there is scarce data to support an effect of probiotic supplementation itself in the treatment of obesity. Certain trials have found reductions in visceral fat mass and abdominal adiposity, without significant changes in absolute body weight, from strain-specific probiotic supplementation, however, diets have not been controlled in these studies and thus it is not possible to attribute any effects to the addition of probiotics alone independent of dietary changes.

Thus, notwithstanding interesting findings in rodents, these translational models have yet to translate to significant magnitudes of effect in human obesity. Given the more established role of energy restriction and dietary modifications to reduce adiposity, there is little evidence to support probiotics as a specific intervention for obesity, particularly having regard to the fact that the increased ratio of Firmicutes to Bacteroidetes that characterises obesity is known to reverse with dietary interventions (increased fibre) and reductions in adiposity.

Probiotics and Neurological Health

Emerging understanding of the bi-directional communication between the central and enteric nervous systems has generated interest into the role of the intestinal microbiota as a factor modulating the gut-brain relationship. Research in rodents has shown that probiotics modulate stress responses, mediated via the hypothalamic-pituitary-adrenal (HPA) axis, with reductions in anxiety and depressive behaviours evident from these translation models.

There is some degree of translation emerging in human research. A four-week study assessing emotional reactivity measured by functional magnetic resonance imagining (fMRI) and providing three strains of probiotics in a fermented milk product, found changes in activity of emotional attention brain networks in response to negative visual stimuli, effects not observed with the control (a non-fermented milk product) or the no-intervention group.

A number of RCTs in humans have found reductions in ratings of depression. However, many of these studies are conducted in otherwise healthy subjects and use different depression rating scales (in addition to the different strains and doses utilised), and it is difficult to extrapolate any benefit to patients with depression. There is a body of literature now accumulating specifically examining probiotics in the treatment of depression and anxiety, with the weight of this evidence in favour of a benefit to probiotics compared to placebo. However, the majority of trials are not conducted in participants with clinically diagnosed depression and/or anxiety. The fact that the majority of trials are conducted in clinical populations undergoing medical treatment makes cause-effect inferences difficult, given that the improvement in depression and anxiety may reflect improvement in the specific medical condition and prognosis. However, when stratifying studies based on clinical depression, there does appear to be an effect of probiotic supplementation compared to placebo.

Thus, future research should focus on clinical depression and anxiety, as although the current evidence is suggestive of benefit, it is a weak pool of evidence that remains preliminary. That fact that there do appear to be differences at the genus level in the microbiota of patients with depression compared to healthy controls provides additional support for the potential of interventions targeting bacterial composition and activity in the gut. 

Probiotics and Skin

Recent interest in probiotics in the field of dermatology has largely been based on a hypothesis of a “gut-skin-brain-axis”. However, a critical distinction must be made between the human gut microbiome and the skin microbiome, which are distinct and not equivalent. Nonetheless, there is emerging research based on the hypothesis that probiotic supplementation delivered to the gut may benefit skin conditions. An intervention in psoriasis patients with the strain B.infantis 35624 led to improvement in inflammatory markers, but there was no assessment of disease severity in the study.

Intestinal-borne dermatoses results in skin erythema and papular-pustular rash, and an intervention with the strain E.coli Nissle 1917 found significant reductions in both after one month of supplementation. However, this is an intestinal-borne condition with extra-intestinal manifestation, and it is difficult to extrapolate the results from this specific condition to infer a general benefit to probiotic supplementation on the skin microbiome.

A recent meta-analysis including 39 trials and 2599 total participants of probiotic supplementation in atopic dermatitis found no evidence of benefit to probiotics compared to no intervention. There is novel evidence suggesting topical probiotics may modulate the skin microbiome, however, this is nascent research and no interventions have yet been tested in relation to specific dermatological conditions. Currently, the use of probiotics for dermatological conditions lacks any good evidence.

Conclusions

The role of probiotics in health and disease remains an emerging area of scientific inquiry, complicated by our still emerging understanding of the complexity of this ecosystem. The major limitation of synthesising the evidence-base into cogent recommendations is the significant variance in the strains utilised, the condition, the dose and duration of the intervention. It may be more helpful to think at a broader level of whether there is a benefit accruing to the class of probiotics as a whole. From this perspective, it does appear that for certain conditions there is a clear benefit - diarrhoea from different infectious causes and NEC/LOS/feeding intolerance in pre-term infants being cases in point.

The wider literature could be best described as suggestive, preliminary, and in some cases positive but requiring more refined research to build on the available data. There does not appear to be any compelling reason in the literature for otherwise healthy individuals to supplement with probiotics, and general advice in this respect remains focused on diet, and incorporation of fermented foods and prebiotic fibres (which are selectively fermented by beneficial bacteria, in particular the Bifidobacterium species, and help to increase populations of these bacteria). 

Summary of Key Points:
  1. Evidence suggests that efficacy of probiotic supplementation is both strain-specific and condition-specific.
  2. There is no consensus on what a "healthy" gut microbiome is, but microbial diversity is consistently seen as important.
  3. Probiotics only seem to have a very limited and transient impact on the microbiota in the colon. Thus supplementing with probiotics doesn't seem to cause lasting shifts in the microbiome.
  4. Based on current evidence, there is little to no reason to recommend probiotic supplementation to healthy individuals for the purposes of "general health" or "gut health".
  5. Certain strains of probiotics have been shown to be efficacious in treating various diarrohoea conditions.
  6. Specific probiotic strains have shown efficacy for patients with Ulcerative Colitis.
  7. There is mixed evidence for the use of probioitics in those with IBS, but there is a trend towards a beneficial impact.
  8. There is some preliminary evidence suggestive of potential benefit in certain allergies (peanut and cow's milk) and lactose intolerance.
  9. There is strong evidence of benefit of probiotic supplementation in preventing mortality, necrotising enterocolitis, late-onset sepsis and feeding intolerance, in pre-term infants.
  10. There is little evidence to support probiotics as an intervention for obesity.
  11. There is evidence that suggests a benefit of probiotics in the treatment of depression and anxiety. However, this is largely still preliminary and the evidence lacks robustness.
  12. Currently there is no real evidence to support the use of probiotics for skin conditions.

Statement Author: Alan Flanagan, PhD (c)
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Alan is the Research Communication Officer here at Sigma Nutrition. Alan is currently pursuing his PhD in nutrition at the University of Surrey, UK, with a research focus in chrononutrition. Alan previuosly completed a Masters in Nutritional Medicine at the same institution.

Originally a lawyer by background in Dublin, Ireland, Alan combines an investigative and logical approach to nutrition together with advocacy skills to communicate the often complicated world of nutrition science, and is dedicated to guiding healthcare professionals and the lay public in science-based nutrition.