A study from King’s College London has found that people who drank red wine had an increased gut microbiota diversity (a sign of gut health) compared to non-red wine drinkers as well as an association with lower levels of obesity and ‘bad’ cholesterol.
In a paper published today in the journal Gastroenterology, a team of researchers from the Department of Twin Research & Genetic Epidemiology, King’s College London explored the effect of beer, cider, red wine, white wine and spirits on the gut microbiome (GM) and subsequent health in a group of 916 UK female twins.
They found that the GM of red wine drinkers was more diverse compared to non-red wine drinkers. This was not observed with white wine, beer or spirits consumption.
First author of the study, Dr. Caroline Le Roy from King’s College London said:
“While we have long known of the unexplained benefits of red wine on heart health, this study shows that moderate red wine consumption is associated with greater diversity and a healthier gut microbiota that partly explain its long debated beneficial effects on health.”
The microbiome is the collection of microorganisms in an environment and plays an important role in human health.
An imbalance of ‘good’ microbes compared to ‘bad’ in the gut can lead to adverse health outcomes such as reduced immune system, weight gain or high cholesterol.
A person’s gut microbiome with a higher number of different bacterial species is considered a marker of gut health.
The team observed that the gut microbiota of red wine consumers contained a greater number of different bacterial species compared to than non-consumers.
This result was also observed in three different cohorts in the UK, the U.S. And the Netherlands. The authors took into account factors such as age, weight, the regular diet and socioeconomic status of the participants and continued to see the association.
The authors believe the main reason for the association is due to the many polyphenols in red wine.
Polyphenols are defence chemicals naturally present in many fruits and vegetables.
They have many beneficial properties (including antioxidants) and mainly act as a fuel for the microbes present in our system.
Lead author Professor Tim Spector from King’s College London said: “This is one of the largest ever studies to explore the effects of red wine in the guts of nearly three thousand people in three different countries and provides insights that the high levels of polyphenols in the grape skin could be responsible for much of the controversial health benefits when used in moderation.”
The study also found that red wine consumption was associated with lower levels of obesity and ‘bad’ cholesterol which was in part due to the gut microbiota.
“Although we observed an association between red wine consumption and the gut microbiota diversity, drinking red wine rarely, such as once every two weeks, seems to be enough to observe an effect.
If you must choose one alcoholic drink today, red wine is the one to pick as it seems to potentially exert a beneficial effect on you and your gut microbes, which in turn may also help weight and risk of heart disease.
However, it is still advised to consume alcohol with moderation,” added Dr. Le Roy.
Journal information: Gastroenterology
Provided by King’s College London
Microbiome refers to the collective genomes of the micro-organisms in a particular environment, and microbiota is the community of micro-organisms themselves (box 1).
Approximately 100 trillion micro-organisms (most of them bacteria, but also viruses, fungi, and protozoa) exist in the human gastrointestinal tract1 2—the microbiome is now best thought of as a virtual organ of the body.
The human genome consists of about 23 000 genes, whereas the microbiome encodes over three million genes producing thousands of metabolites, which replace many of the functions of the host,1 3 consequently influencing the host’s fitness, phenotype, and health.2
- Microbiome – the collective genomes of the micro-organisms in a particular environment
- Microbiota – the community of micro-organisms themselves
- Microbiota diversity – a measure of how many different species and, dependent on the diversity indices, how evenly distributed they are in the community. Lower diversity is considered a marker of dysbiosis (microbial imbalance) in the gut and has been found in autoimmune diseases and obesity and cardiometabolic conditions, as well as in elderly people
- Operational taxonomic unit – a definition used to classify groups of closely related organisms. DNA sequences can be clustered according to their similarity to one another, and operational taxonomic units are defined based on the similarity threshold (usually 97% similarity) set by the researcher
- Colonocytes – epithelial cells of the colon
- Germ-free animals – animals that have no micro-organisms living in or on them
- Short chain fatty acids – fatty acids with two to six carbon atoms that are produced by bacterial fermentation of dietary fibres
Studying the gut microbiota
Twin studies have shown that, although there is a heritable component to gut microbiota, environmental factors related to diet, drugs, and anthropometric measures are larger determinants of microbiota composition.4 5
Gut microbes are key to many aspects of human health including immune,6 metabolic5 and neurobehavioural traits (fig 1).7 8
Different levels of evidence support the role of gut microbiota in human health, from animal models9 10 and human studies.4 11 12 1
Animal models can help identify gut microbes and mechanisms, though the degree to which findings translate to humans is unknown.
In humans, observational studies can show cross-sectional associations between microbes and health traits but are limited by the inability to measure causal relations.
The strongest level of evidence is obtained from interventional clinical studies – in particular, randomised controlled trials.
The composition of gut microbiota is commonly quantified using DNA based methods, such as next generation sequencing of 16S ribosomal RNA genes or whole genome shotgun sequencing, which also allow inference of microbiota functions.14 15
Metabolic products of the microbiota are now measurable in stool and serum using metabolomic methods.16
What does the gut microbiota do?
The gut microbiota provides essential capacities for the fermentation of non-digestible substrates like dietary fibres and endogenous intestinal mucus.
This fermentation supports the growth of specialist microbes that produce short chain fatty acids (SCFAs) and gases.17
The major SCFAs produced are acetate, propionate, and butyrate.
Butyrate is the main energy source for human colonocytes, can induce apoptosis of colon cancer cells, and can activate intestinal gluconeogenesis, having beneficial effects on glucose and energy homeostasis.18
Butyrate is essential for epithelial cells to consume large amounts of oxygen through β oxidation, generating a state of hypoxia that maintains oxygen balance in the gut, preventing gut microbiota dysbiosis.19
Propionate is transferred to the liver, where it regulates gluconeogenesis and satiety signalling through interaction with the gut fatty acid receptors 18
Acetate – the most abundant SCFA and an essential metabolite for the growth of other bacteria – reaches the peripheral tissues where it is used in cholesterol metabolism and lipogenesis, and may play a role in central appetite regulation.20
Randomised controlled trials have shown that higher production of SCFAs correlates with lower diet-induced obesity21 and with reduced insulin resistance.22
Butyrate and propionate, but not acetate, seem to control gut hormones and reduce appetite and food intake in mice.21 Gut microbial enzymes contribute to bile acid metabolism, generating unconjugated and secondary bile acids that act as signalling molecules and metabolic regulators to influence important host pathways.23
Other specific products of the gut microbiota have been implicated directly in human health outcomes. Examples include trimethylamine and indolepropionic acid.
The production of trimethylamine from dietary phosphatidylcholine and carnitine (from meat and dairy) depends on the gut microbiota and thus its amount in blood varies between people.
Trimethylamine is oxidised in the liver to trimethylamine N-oxide, which is positively associated with an increased risk of atherosclerosis and major adverse cardiovascular events.24
Indolepropionic acid is highly correlated with dietary fibre intake25 and has potent radical scavenging activity in vitro,26 which seems to reduce the risk of incidence of type 2 diabetes.25
The gut microbiota and obesity
The gut microbiota seems to play a role in the development and progression of obesity.
Most studies of overweight and obese people show a dysbiosis characterised by a lower diversity.31-39
Germ-free mice that receive faecal microbes from obese humans gain more weight than mice that receive microbes from healthy weight humans.4
A large study of UK twins found that the genus Christensenella was rare in overweight people and when given to germ free mice prevented weight gain.4
This microbe and others such as Akkermansia correlate with lower visceral fat deposits.12
Although much of the confirmatory evidence comes from mouse models, long term weight gain (over 10 years) in humans correlates with low microbiota diversity, and this association is exacerbated by low dietary fibre intake.28
Gut microbiota dysbiosis probably promotes diet induced obesity and metabolic complications by a variety of mechanisms including immune dysregulation, altered energy regulation, altered gut hormone regulation, and proinflammatory mechanisms (such as lipopolysaccharide endotoxins crossing the gut barrier and entering the portal circulation29 30; fig 1 ).
Microbiota diversity and health
Lower bacterial diversity has been reproducibly observed in people with inflammatory bowel disease,31 psoriatic arthritis,32 type 1 diabetes,33 atopic eczema,34 coeliac disease,35 obesity,36type 2 diabetes,37 and arterial stiffness,38 than in healthy controls.
In Crohn’s disease smokers have even lower gut microbiome diversity.39
The association between reduced diversity and disease indicates that a species-rich gut ecosystem is more robust against environmental influences, as functionally related microbes in an intact ecosystem can compensate for the function of other missing species.
Consequently, diversity seems to be a generally good indicator of a “healthy gut.”40 41
But recent interventional studies indicate that major increases in dietary fibre can temporarily reduce diversity, as the microbes that digest fibre become specifically enriched, leading to a change in composition and, through competitive interactions, reduced diversity.22
The functional role of the gut microbiome in humans has been shown using faecal microbiota transplantation.42
This procedure is effective in cases of severe drug refractory Clostridium difficile infection and is now routinely used for this purpose around the world.43
For other pathologies, faecal transplants are not yet clinical practice but have been explored.44
For example, transplanting faeces from a lean healthy donor (allogeneic) to recipients with metabolic syndrome resulted in better insulin sensitivity, accompanied by altered microbiota composition, than using autologous faeces.45
Effects of food and drugs on the gut microbiota
Specific foods and dietary patterns can all influence the abundance of different types of bacteria in the gut, which in turn can affect health (table 1).
Examples of foods, nutrients, and dietary patterns that influence human health linked to their effect on the gut microbiota
|Dietary element||Effect on gut microbiome||Effect on health outcomes mediated by gut microbiome||Human observational studies||Human interventional|
|Low FODMAP diet||Low FODMAP diet increased Actinobacteria; high FODMAP diet decreased abundance of bacteria involved in gas consumption58||Reduced symptoms of irritable bowel syndrome56||Yes||Yes|
|Cheese||Increased Bifidobacteria,97 98which are known for their positive health benefits to their host through their metabolic activities.99 Decrease in Bacteroides and Clostridia, some strains of which are associated with intestinal infections98||Potential protection against pathogens.100Increased production of SCFA and reduced production of TMAO99||Yes||Yes|
|Fibre and prebiotics||Increased microbiota diversity and SCFA production 22 101102||Reduced type 2 diabetes22 and cardiovascular disease103||Yes||Yes|
|Artificial sweeteners||Overgrowth of Proteobacteria and Escherichia coli.104Bacteroides, Clostridia, and total aerobic bacteria were significantly lower, and faecal pH was significantly higher47||Induced glucose intolerance105||No||No|
|Polyphenols (eg, from tea, coffee, berries, and vegetables such as artichokes, olives, and asparagus)||Increased intestinal barrier protectors (Bifidobacteria and Lactobacillus), butyrate producing bacteria (Faecalibacterium prausnitziiand Roseburia) and Bacteroides vulgatus and Akkermansia muciniphila.107 Decreased lipopolysaccharide producers (E coli and Enterobacter cloacae).106||Gut micro-organisms alter polyphenol bioavailability resulting in reduction of metabolic syndrome markers and cardiovascular risk markers108||Yes||Yes|
|Vegan||Very modest differences in composition and diversity in humans and strong differences in metabolomic profile compared with omnivore diet in humans50||Some studies show benefit of vegetarian over omnivore diet,109others fail to find a difference110||Yes||Yes|
FODMAP=fermentable oligosaccharides, disaccharides, monosaccharides and polyols; SCFA=small chain fatty acids; TMAO= trimethylamine N-oxide
High-intensity sweeteners are commonly used as sugar alternatives, being many times sweeter than sugar with minimal calories. Despite being “generally recognised as safe” by regulatory agencies, some animal studies have shown that these sugar substitutes may have negative effects on the gut microbiota.46 Sucralose, aspartame, and saccharin have been shown to disrupt the balance and diversity of gut microbiota.46 Rats given sucralose for 12 weeks had significantly higher proportions of Bacteroides, Clostridia, and total aerobic bacteria in their guts and a significantly higher faecal pH than those without sucralose.47 Mice given sucralose for six months had an increase in the expression in the gut of bacterial pro-inflammatory genes and disrupted faecal metabolites.48
Food additives, such as emulsifiers, which are ubiquitous in processed foods, have also been shown to affect the gut microbiota in animals.49 Mice fed relatively low concentrations of two commonly used emulsifiers—carboxymethylcellulose and polysorbate-80—showed reduced microbial diversity compared with mice not fed with emulsifiers. Bacteroidales and Verrucomicrobia were decreased and inflammation promoting Proteobacteria associated with mucus was enriched .49
Other areas of concern include the side effects of popular restrictive diets on gut health. These include some strict vegan diets, raw food or “clean eating” diets, gluten-free diets, and low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diets used to treat irritable bowel syndrome.
Vegans are viewed by some as healthier than omnivores. A study of 15 vegans and 16 ominvores found striking differences in serum metabolites generated by the gut microbes but very modest differences in gut bacterial communities.50 A controlled feeding experiment of 10 human omnivores randomised to receive either a high fat and low fibre diet or a low fat and high fibre for 10 days found very modest effects on gut microbiome composition and no difference in short chain fatty acid production. Together these data support a greater role for diet influencing the bacterial derived metabolome than just the short term bacterial community.50
Animal and in vitro studies indicate that gluten-free bread reduces the microbiota dysbiosis seen in people with gluten sensitivity or coeliac disease.51 52 But most people who avoid gluten do not have coeliac disease or proved intolerance, and a recent large observational study showed an increased risk of heart disease in gluten avoiders, potentially because of the reduced consumption of whole grains.53 One study showed that 21 healthy people had substantially different gut microbiota profiles after four weeks on a gluten-free diet. Most people showed a lower abundance of several key beneficial microbe species.54
The low FODMAP diet has been shown in six randomised controlled trials to reduce symptoms of irritable bowel syndrome.55 56 It is associated with a reduced proportion of Bifidobacterium in patients with irritable bowel syndrome, and responsiveness to this diet can be predicted by faecal bacterial profiles.57 Low FODMAP diets lead to profound changes in the microbiota and metabolome, the duration and clinical relevance of which are as yet unknown.58 59
In addition to diet, medication is a key modulator of the gut microbiota composition. A large Dutch-Belgian population study showed that drugs (including osmotic laxatives, progesterone, TNF-α inhibitors and rupatadine) had the largest explanatory power on microbiota composition (10% of community variation).13 Other studies have shown major effects of commonly prescribed proton pump inhibitors on the microbial community, which could explain higher rates of gastrointestinal infection in people taking these drugs.60 Antibiotics clearly have an effect on gut microbes, and low doses are routinely given to livestock to increase their growth and weight. A large proportion of antibiotic use in many countries is for agriculture—particularly intensive farming of poultry and beef.61 Several observational human studies as well as many rodent studies have pointed to an obesogenic effect of antibiotics in humans even in tiny doses found in food.61 But humans have very variable responses to antibiotics, and intervention studies have not shown consistent metabolic consequences.62 Pesticides and other chemicals are commonly sprayed on foods, but, although levels can be high, solid evidence for their harm on gut health and the effects of organic food is currently lacking.63
Insufficient clinical evidence exists to draw clear conclusions or recommendations for these or other dietary preferences based on gut microbiota. But future studies of food additives, drugs, and the safety and efficacy of dietary modifications must take into account these advances and their effect on the gut microbiota. This is becoming clear in patients with cancer treated with immunochemotherapy, bone marrow recipients, and patients with autoimmune disorders on biologics, where small changes in their microbiota can cause major changes in their response.64Moreover, animal experiments have shown the protective effects of phytoestrogens on breast cancer depend on the presence of gut microbes (such as Clostridium saccharogumia, Eggerthella lenta, Blautia producta, and Lactonifactor longoviformis) that can transform isoflavones into the bioactive compounds.65
Box 2 summarises our current knowledge on the interactions between gut microbiota, nutrition, and human health.
Consensus and uncertainties
What we know
- Probiotic supplementation has several beneficial effects on human health
- The microbes in our gut influence and human energy metabolism22 23 24 25 26 27 28 2930 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
- Diet and medication have a strong influence on gut microbiota composition
- Microbiota composition influences response to chemotherapy and immunotherapy96
- Microbiome composition defines glucose response to foods and can be used to personalise diet94
- Dietary fibre intake influences gut microbiota composition and is related to better health86 87 104
What we don’t know
- Are natural probiotics in food better than probiotic supplements? Should we take them preventively?
- Can microbes influence food choices and appetite?
- Do low dose antibiotics in food affect human health?
- What is the effect of pesticides in food on the gut microbiome? Is organic food better for the gut microbiota?
- Should all new drugs and food chemicals be tested on the gut microbiota?
Manipulating the gut microbiota through diet
Changes to the gut microbiota can occur within days of changing diet; remarkable differences were found after African Americans and rural Africans switched diets for only two weeks.66Increased abundance of known butyrate producing bacteria in the African Americans consuming a rural African diet caused butyrate production to increase 2.5 times and reduced synthesis of secondary bile acid.66 Another study comparing extreme shifts between plant and animal protein based diets showed these changes after only five days.67 But healthy microbiota are resilient to temporal changes by dietary interventions, meaning that homeostatic reactions restore the original community composition, as recently shown in the case of bread 68
Prebiotic foods and dietary fibre
Most national authorities define dietary fibre as edible carbohydrate polymers with three or more monomeric units that are resistant to the endogenous digestive enzymes and thus are neither hydrolysed nor absorbed in the small intestine.69 A subset of dietary fibre sources is fermentable, which means that they serve as growth substrates for microbes in the distal bowel.70 Some non-digestible carbohydrates have been referred to as “prebiotics,” which are defined as food components or ingredients that are not digestible by the human body but specifically or selectively nourish beneficial colonic micro-organisms (box 3).71 The prebiotic concept has been criticised for being poorly defined and unnecessarily narrow,72 and some scientists prefer the term “microbiota accessible carbohydrates,”11 which are essentially equivalent to fermentable dietary fibre in that they become available as growth substrates for gut microbes that possess the necessary enzymatic capacity to use them.70
What are prebiotics and probiotics?
Dietary amounts of protein, saturated and unsaturated fats, carbohydrates, and dietary fibre influence the abundance of different types of bacteria in the gut. The microbiota can also be modified by adding live micro-organisms to food or by periods of fasting.
- Probiotics are live bacteria and yeasts that, when administrated in a viable form and in adequate amounts, are beneficial to human health. They are usually added to yoghurts or taken as food supplements.
- Prebiotics are defined as a substrate that is selectively used by host micro-organisms conferring a health benefit. Although all compounds considered prebiotics are microbiota accessible carbohydrates or fermentable dietary fibre, the reverse is not true. The prebiotic concept is an area of current debate70
- Synbiotics contain a mixture of prebiotics and probiotics
Consuming resistant starches has been shown to enrich specific bacterial groups (Bifidobacterium adolescentis, Ruminococcus bromii, and Eubacterium rectale) in some people.74 75 The taxa enriched differ depending on the type of resistant starches and other dietary fibres,75 indicating that shifts are dependent on the carbohydrate’s chemical structure and the microbes’ enzymatic capacity to access them. Microbes need also to “adhere” to a substrate and tolerate the conditions generated from fermentation (such as low pH).76
The effect of microbiota accessible carbohydrates on the gastrointestinal microbiome composition can be substantial, with specific species becoming enriched to constitute more than 30% of the faecal microbiota.75 77 Thus, microbiota accessible carbohydrates provide a potential strategy to enhance useful minority members of the microbiome. These changes only last as long as the carbohydrate is consumed, and they are highly individual, which provides a basis for personalised approaches. Many short term feeding trials with purified dietary fibres or even whole plant based diets either have no effect on microbiota diversity or reduce it,22 but can still have clinical benefits, potentially through metabolites such as small chain fatty acids.22 67
Low fibre intake reduces production of small chain fatty acids and shifts the gastrointestinal microbiota metabolism to use less favourable nutrients,78 leading to the production of potentially detrimental metabolites.79 80 Convincing evidence shows that the low fibre Western diet degrades the colonic mucus barrier, causing microbiota encroachment, which results in pathogen susceptibility81and inflammation,82 providing a potential mechanism for the links of Western diet with chronic diseases. Two recent studies showed that the detrimental effects of high fat diets on penetrability of the mucus layer and metabolic functions could be prevented through dietary administration of inulin.83 84 Overall, these findings, together with the role of butyrate in preventing oxygen induced gut microbiota dysbiosis,19 provide a strong rational to enrich dietary fibre consumption to maintain intact mucosal barrier function in the gut.85
Considerable observational evidence shows that fibre intake is beneficial for human health. Two recent meta-analyses found clear links between dietary fibre and health benefits in a wide range of pathologies,86 87 and a recent intervention study found dietary fibres significantly reduced insulin resistance in patients with type 2 diabetes, with clear links to the shifts in the microbiota and beneficial metabolites (such as butyrate).45
Probiotics are live micro-organisms that, when administered in adequate amounts, confer a health benefit on the host).88 Probiotics (mostly Bifidobacterium and Lactobacillus species) can be included in a variety of products, including foods, dietary supplements, or drugs.
There are concerns that most microbe supplements are unable to establish themselves in the gut and fail to exert an effect on the resident community.89 90 But probiotics can affect health independently of the gut microbiota through direct effects on the host; for example, through immune modulation or the production of bioactive compounds. The therapeutic effect of probiotic supplementation has been studied in a broad range of diseases.
We searched the Cochrane library of systematic reviews for “probiotic*”, yielding 39 studies, and searched Medline for “systematic review” or “meta-analysis” and “probiotic*”, yielding 31 studies. We included information on systematic reviews of randomised controlled trials published in the past five years where the main treatment was probiotics (not dietary supplements in general). Only studies that focused on comparisons of probiotics with a control group, that contained at least some moderate or high quality randomised controlled trials in the estimation of the authors of the systematic review, which resulted in a total of 22 systematic reviews (table 2 ). The analysis of 313 trials and 46 826 participants showed substantial evidence for beneficial effects of probiotic supplementation in preventing diarrhoea, necrotising enterocolitis, acute upper respiratory tract infections, pulmonary exacerbations in children with cystic fibrosis, and eczema in children. Probiotics also seem to improve cardiometabolic parameters and reduced serum concentrationof C reactive protein in patients with type 2 diabetes. Importantly, the studies were not homogeneous and were not necessarily matched for type or dose of probiotic supplementation nor length of intervention, which limits precise recommendations. Emerging areas of probiotic treatment include using newer microbes and combinations, combining probiotics and prebiotics (synbiotics),91 and personalised approaches based on profiles of the candidate microbes in inflammation, cancer, lipid metabolism, or obesity.92 Stable engraftment of a probiotic Bifidobacterium longum, for example, has been shown to depend on individualised features of the gut microbiota, providing a rationale for the personalisation of probiotic applications.93
Summary of systematic reviews analysing the role of probiotics on clinical outcomes
|Outcome||Reference||No of studies/participants||Evidence of benefit?||Results/conclusions|
|Clostridium difficileassociated diarrhoea in adults and children||Goldenberg et al (2017)111||39/9955||Yes||Moderate quality evidence that probiotics are safe and effective for preventing C difficileassociated diarrhoea. (RR 0.30, 95% CI 0.21 to 0.42)|
|Necrotising enterocolitis||Al Faleh et al (2014)112Rees et al (2017)113||17/5338||Yes||Enteral supplementation of probiotics prevents severe necrotising enterocolitis (RR 0.43, 95%CI 0.33 to 0.56) and all cause mortality in preterm infants (RR 0.65, 95% CI 0.25 to 0.81)|
|Antibiotic associated diarrhoea in children||Goldenberg et al (2015)114||26/3898||Yes||Moderate evidence of a fall in the incidence of antibiotic associated diarrhoea in the probiotic v control group (RR 0.46, 95% CI 0.35 to 0.61; I2=55%, 3898 participants)|
|Probiotics for preventing acute upper respiratory tract infections||Hao et al (2015)115||12/3720||Yes||Probiotics were better than placebo in reducing the number of participants experiencing episodes of acute upper respiratory tract infections, the mean duration of an episode , antibiotic use, and related school absence (12 trials, 3720 participants including children, adults, and older people)|
|Urinary tract infections||Schwenger et al (2015)116||9/735||No||No significant benefit for probiotics compared with placebo or no treatment|
|Prevention of asthma and wheeze in infants||Azad et al (2013)117||6/1364||No||No evidence to support a protective association between perinatal use of probiotics and doctor diagnosed asthma or childhood wheeze|
|Prevention of eczema in infants and children||Mansfield et al (2014)||16/2797||Yes||Probiotic supplementation in the first several years of life did have a significant impact on development of eczema (RR 0.74, 95% CI 0.67 to 0.82)|
|Prevention of invasive fungal infections in preterm neonates||Agrawal et al (2015) 119||19/4912||Unclear||Probiotic supplementation reduced the risk of invasive fungal infections (RR 0.50, 95% CI 0.34 to 0.73, I2=39%) but there was high heterogeneity between studies. Analysis after excluding the study with a high baseline incidence (75%) showed that probiotic supplementation had no significant benefits (RR 0.89, 95% CI 0.44 to 1.78)|
|Prevention of nosocomial infections||Manzanares et al (2015)120||30/2972||Yes||Probiotics were associated with a significant reduction in infections (RR 0.80, 95%CI 0.68 to 0.95, P=0.009; I2=36%, P=0.09). A significant reduction in the incidence of ventilator associated pneumonia was found (RR 0.74, 95% CI 0.61 to 0. 90, P=0.002; I2=19%)|
|Treatment of rotavirus diarrhoea in infants and children||Ahmadi et al (2015)121||14/1149||Yes||Probiotic supplementation resulted in a mean difference of −0.41 (CI 95% −0.56 to −0.25; P<0.001) in the duration of diarrhoea. Probiotics exert positive effect on reducing the duration of acute rotavirus diarrhoea compared with control|
|Prevention and treatment of Crohn’s disease and ulcerative colitis||Saez Lara et al (2015)122||14/821 ulcerative colitis|
8/374 Crohn’s disease
|Yes||The use of probiotics and/or synbiotics has positive effects in the treatment and maintenance of ulcerative colitis, whereas in Crohn’s disease clear effectiveness has only been shown for synbiotics (no meta- analysis was performed)|
|Pulmonary exacerbations in children with cystic fibrosis||Ananathan et al (2016)123||9/275||Yes||Significant reduction in the rate of pulmonary exacerbation (two parallel group randomised controlled trials and one crossover trial: RR 0.25, 95% CI 0.15 to 0.41; P< 0.00001)|
|Type 2 diabetes (fasting glucose, glycated haemoglobin test)||Akbari et al (2016)124||13/805||Yes||Probiotics significantly reduced fasting blood glucose compared with placebo (8 studies; standardised mean difference −1.583; 95% CI −4.18 to 4.18; P = 0.000). Significant reduction in HbA1c was also seen (6 studies; SMD −1.779; 95% CI, −2.657 to −0.901; P = 0.000)|
|Type 2 diabetes (insulin resistance, insulin levels)||Zhang et al (2016)125||7/425||Yes||Probiotic therapy significantly decreased homeostasis model assessment of insulin resistance (HOMA-IR) and insulin concentration (WMD: −1.08, 95% CI −1.88 to −0.28; and weighted mean difference −1.35mIU/L, 95% CI -−2.38 to −0.31, respectively|
|Necrotising enterocolitis in pre-term neonates with focus on Lactobacillus reuteri||Athalye-Jape et al (2016)126||6/1778||Yes||Probiotic reduced duration of hospitalisation (mean difference = −10.77 days, 95% CI −13.67 to −7.86; in 3 randomised controlled trials), and late onset sepsis (RR 0.66; 95% CI, 0.52 to 0.83; 4 RCTs) were reduced in the|
|Reduction of serum concentration of C reactive protein||Mazidi et al (2017)127||19/935||Yes||Significant reduction in serum C reactive protein after probiotic administration with a WMD −1.35 mg/L, (95% CI −2.15 to −0.55, I2 65.1%)|
|Cardiovascular risk factors in patients with type 2 diabetes||Hendijani et al (2017)128||11/641||Yes||Probiotic consumption significantly decreased systolic blood pressure (−3.28 mm Hg; 95% CI −5.38 to −1.18), diastolic (WMD −2.13 mm Hg; 95% CI −4.5 to 0.24), low density lipoprotein cholesterol (WMD 8.32 mg/dL; 95% CI −15.24 to −1.4), total cholesterol (WMD −12.19 mg/dL; 95% CI −17.62 to −6.75) and triglycerides(WMD −24.48 mg/dL; 95% CI −33.77 to −11.18) compared with placebo|
|Reduction of total cholesterol and low density lipoprotein cholesterol||Wu et al (2017)129||15/976||Yes||Lactobacillus consumption significantly reduced total cholesterol by 0.26 mmol/L (95% CI −0.40 to −0.12) and LDL-C by 0.23 mmol/L (95% CI, −0.36 to −0.10)|
|Depressive symptoms||Wallace, and Milev (2017)79,130||6/1080||Yes||No quantitative analysis was performed. Most studies found positive results, and the authors conclude that compelling evidence shows that probiotics alleviate depressive symptoms|
|Vulvovaginal candidiasis in non-pregnant women||Xie et al (2018)131||10/1656||Yes||Probiotics increased the rate of short term clinical cure (RR 1.14, 95% CI 1.05 to 1.24, low quality evidence) and mycological cure (RR 1.06, 95% CI 1.02 to 1.10, low quality evidence) and decreased relapse rate at one month (RR 0.34, 95% CI 0.17 to 0.68, low quality evidence)|
|Chronic periodontitis||Ikram et al (2018) 132||7/220||Yes||The overall mean difference for gaining clinical attachment level gain between probiotics and placebo was significant (weighted mean difference 1.41, 95% CI 0.15 to 2.67, P=0.028)|
RR=risk ratio, SBP systolic blood pressure, DBP= diastolic blood pressure, TC= total cholesterol, TG=serum triglycerides, SMD=standardised mean difference, WMD=weighted mean difference’ CI=confidence interval