Probiotics and the immune response
As the COVID vaccines are rolled out at speed (6.4% of the UK population at the time of writing) throughout the UK, we all have our fingers crossed that these particular vaccines prove effective given the high virulence of the virus, and indeed, the mortality suffered to date. However, we do have some controllable influence of the efficacy of the vaccine through our healthy behaviours, one of which is our gut microbiome, so can probiotics make a difference?
Vaccines and the gut
Vaccines are widely regarded as among the greatest successes of modern medicine, helping to protect entire populations against a wide range of infectious diseases. However, there is considerable variation in the efficacy of vaccines amongst individuals. The magnitude of antibody titers induced in individuals receiving the seasonal influenza vaccine, for example, varies by more than 100-fold.
One factor that influences vaccine efficacy is the human gut microbiome (the large collection of microbes that inhabit the gut). A diverse microbial community, dominated by beneficial bacterial species, supports the health of both the gut and the immune system. A healthy microbiota influences the immune system directly via contact between gut microbes and gut-associated immune cells, as well as indirectly through the production of short-chain fatty acids (SCFAs) and other essential nutrients that impact immunity.
The primary factor influencing the gut microbiota is the diet. The consumption of high-fibre diets and fermented foods, for example, has been shown to significantly improve the health of the microbial community. Fibre-rich diets encourage the growth of beneficial bacteria that support the immune response. Today, we’ll focus on the influence of friendly microorganisms, many of which are commonly found in the gut or dietary supplements known as probiotics, on the gut and immune system.
The microbiota in health and disease
Studies show that an imbalance in the gut microbial community, known as dysbiosis, may be a major factor in the variable efficacy of vaccines. Dysbiosis is generally characterized by a loss of beneficial species, a reduction in microbial diversity, and an increase in potential pathogens. Unfortunately, dysbiosis is all too common. Low-fibre diets contribute to this condition, as do endocrine disruptors in the environment. Chronic conditions such as obesity, diabetes, irritable bowel syndrome, and ageing itself are all associated with a decline in the health of the microbial community. Additionally, the use of medications such as antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors (commonly used for heartburn) can cause a reduction in beneficial microbes.
It’s especially difficult to avoid the harmful effects of antibiotics because most of us receive them multiple times throughout life. A single course of antibiotics can destroy more than 90% of the predominant types of microbes in the gut, including friendly bifidobacteria. Although many are aware of the acute gastrointestinal side effects of antibiotic use, we neglect to consider the long-term impact they have. Studies have shown it can take up six months for the microbiota to fully recover.
Fortunately, supplementation with probiotic microorganisms can help reduce the negative effects of antibiotics, particularly if the probiotics are consumed beginning on the first day of antibiotic treatment. In particular, the probiotic known as Saccharomyces boulardii, is an excellent selection for use alongside an antibiotic because it is a yeast, and thus able to survive the antibiotic bacterial killing powers. By preventing dysbiosis, probiotics can also improve vaccine responses, as discussed below.
The importance of Lactobacillus
The most extensively-studied bacterial probiotics are Lactobacillus and Bifidobacterium species. Lactobacilli are found in many fermented foods, including yoghurt and kefir. Once they are consumed, they reside mainly in the small intestine, while bifidobacteria are found mainly in the colon. People who consume a standard Western diet consisting of highly-processed foods generally have low numbers of lactobacilli, while higher levels are generally found in individuals consuming plant-based diets, fermented foods, or probiotics.
Lactobacillus species display many important features including the ability to enhance both innate (non-specific) and adaptive (specific) immunity. In a remarkable display of this principle, scientists showed that the ingestion of a single dose of a strain of lactobacillus known as L. rhamnosus GG turned on genes related to B cell activation within two hours in healthy volunteers. B cells are responsible for producing antigen-specific antibodies in response to vaccines, and the study shows that L. rhamnosus GG directly impacts this response. Although the probiotic dose used in this study was particularly high, at 885 billion colony-forming units (CFUs), the authors note that a follow-up study with continuous more typical dosing would offer further insights to how the body responds to these friendly bacteria.
Consistent with these findings, animal and human studies have shown that the administration of L. rhamnosus can improve the antibody response to common vaccines as well. In a placebo-controlled study of influenza vaccination, 84% of healthy subjects receiving L. rhamnosus GG developed a level of antibodies considered to be adequate for protection against the H3N2 influenza strain within 28 days after vaccination, versus only 55% of those in the placebo group.
For all these reasons, lactobacilli are even being considered by the pharmaceutical industry as possible adjuvants for vaccines. In addition to the research with L. rhamnosus GG, numerous studies suggest other common lactobacillus probiotic species have a beneficial impact on vaccine response when consumed on a daily basis, either before or after immunization. In placebo-controlled trials, improved responses (antibody titers) to common vaccines have been seen with L. rhamnosus, L. casei, L. fermentum, L. acidophilus, and L. plantarum.
The importance of Bifidobacterium
Whereas lactobacilli live in the small intestine, bifidobacteria reside in the colon, where the vast majority of the gut microbiota is found. Bifidobacteria normally represent 8–10% of the gut microbiota but a single dose of antibiotic can destroy almost 100% of the population.
One of the many important functions of bifidobacteria is to ferment dietary fibres and produce acetate, a short-chain fatty acid (SCFA) that is used as food by other beneficial bacteria in the colon, helping to restore a more healthful microbial balance overall. SCFAs not only improve gut health, they also support antibody responses. In B cells, SCFAs are involved in many metabolic processes that are necessary to produce energy and the building blocks for antibody production.
Another important immune-related job our bifidobacteria serve is to help increase the activity (aka helper recruiting and killing power) of immune cells, including dendritic cells, helper T cells, and natural killer (NK) cells, all of which are needed to mount an effective response to challenges. It’s perhaps not surprising, then, that gut levels of bifidobacteria often correlate with immune responses to vaccines. A randomized controlled trial showed that adults who consumed a common strain of bifidobacteria known as B. lactis daily for two weeks before a flu vaccine and for four weeks after vaccination had 60% higher vaccine-specific antibody levels compared to a placebo group.
For long-term health, bifidobacteria such as B. lactis, B. bifidum, B. longum and B. breve can be taken in regularly via fermented foods or probiotic supplementation. Dietary supplementation with bifidobacteria also has been shown to help alleviate the dysbiosis associated with ageing and antibiotic use.
The role of Saccharomyces boulardii
S. boulardii, a yeast originally isolated from tropical fruit, is arguably the best-known probiotic for the prevention of dysbiosis due to antibiotics. The administration of S. boulardii to healthy subjects does not alter their microbiota long-term however, as it is only a transient resident. That said, in the case of dysbiosis, S. boulardii has been shown to possibly restore the intestinal microbiota faster.
S. boulardii is genetically related to baker’s yeast (S. cerevisiae), but it has distinct features leading to its classification as a probiotic. For example, S. boulardii also is capable of increasing SCFA levels, and S. cerevisiae does not have this property. Like other yeasts, S. boulardii contains β-glucans, which are known for their immune-modulating effects. Remarkably, bifidobacteria can ferment these yeast beta-glucans, which suggests that S. boulardii actually also serves as a prebiotic to encourage the growth of bifidobacteria.
In recent studies, S. boulardii has been shown to synergize with Lactobacillus and Bifidobacterium species. Supplementation with a combination of S. boulardii and bifidobacteria spp. was shown to enhance cellular immune functions in a synergistic manner and to reduce the hospital stay in children with severe diarrhoea. In a human clinical trial, supplementation with a nutritional formula containing S. boulardii lysate, colostrum-derived lactoferrin, and several other components, was shown to increase NK cell activity in healthy elderly volunteers. A third of the subjects even showed a doubling of NK cell activity after two months of daily supplementation.
S. boulardii also has been shown to influence the production of IL-12, which enables a strong immune response to infections. The ingestion of S. boulardii was recently shown to increase the efficacy of a novel DNA vaccine in an animal model. The authors observed that the use of S. boulardii as immunomodulator represents a new strategy for more efficient DNA vaccines.
What to look for in a probiotic supplement
When it comes to choosing a bacterial probiotic supplement, multispecies preparations including Lactobacillus and Bifidobacterium are often preferred over single strains; however, there are some unique strains such as L. rhamnosus GG, discussed herein, which have been widely studied as a monotherapy in many clinical settings.
Cell numbers (as CFUs) are usually printed on the label of probiotic products, and this is important for efficacy. Since there are more than 10 trillion bacteria in the colon, it has been suggested that at least 10 billion viable probiotic microorganisms reaching the bowel may be necessary to provide a significant effect. Clinical studies support the efficacy of high-potency probiotic formulations that provide 50 billion CFU per dose.
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