October 2020 Issue
Probiotics and Immune Health
By Carrie Dennett, MPH, RDN, CD
Today’s Dietitian
Vol. 22, No. 8, P. 30
Are we getting ahead of the science?
Research on the role of the gut microbiota in human health is a rapidly evolving area of science. The gastrointestinal tract is the largest interface between us and our external environment, and most of our immune cells reside in the wall of our large intestine. Naturally, this raises questions about the role of probiotics in immune system function.
Probiotics—live microorganisms that, when administered in adequate amounts, confer a health benefit on their host—have been shown to improve aspects of gut health, so it seems like a logical assumption that probiotics can improve our immune health. In fact, there are no shortages of claims stating that probiotics do support immune health, but are those claims supported by science?
Gut Microbiota and Immunity
The human gut microbiota—the population of an estimated 100 trillion microorganisms that live in our intestines—provides us with certain benefits our bodies don’t have on their own, including resistance against infection and maturation of our immune systems.1 It’s known that the gut microbiota and the human immune system have a bidirectional relationship: Our gut microbiota develops and regulates our complex immune system, and in return our immune system maintains the symbiotic relationship between us and our microbial community.1-3
To maintain this relationship and achieve the balance between immune tolerance and immune stimulation (inflammation) that’s key to a healthy, properly functioning immune system, our gut microbes and our immune cells must be able to “talk” to each other. That cross-talk is affected by the health of our intestinal barrier, sometimes referred to as the “mucosal firewall.”1,2
Intestinal Barrier Integrity
The immune system constructs and maintains the intestinal barrier, which consists of a combination of mucus, intestinal epithelial cells, immunoglobulin A (IgA), antimicrobial peptides, and other immune cells. In addition to facilitating communication between our immune system and microbiota, this barrier helps protect the gut microbiota by keeping it contained in the intestines.2
The mucus layer protects the epithelium from digestive enzymes and blocks passage of bacteria—helping to prevent both infectious and inflammatory diseases—while allowing passage of nutrients and fluids. The mucus is mostly made of glycoproteins known as mucins, which are secreted by epithelial cells.1,4
Together, the mucus and epithelial layers act as a physical barrier between gut microbes and the lamina propria, a thin layer of connective tissue that houses several immune cells.1,2,5 The cell-rich lamina propria includes lymphocytes—both T cells and IgA-secreting B cells—macrophages, dendritic cells, mast cells, and various white blood cells, all of which play a role in immune function.6,7
Pathogen Response
Our gut microbes support immune health by directly interacting with pathogenic microbes—creating an inhospitable environment for them by various means—or stimulating our immune systems to do the job.1,2 In turn, a healthy immune system protects the gut microbiota by attacking pathogenic microbes while suppressing inflammatory responses to nonpathogenic foreign substances we ingest, including food.
This is important because inappropriate immune responses to nonpathogenic bacteria or dietary components contribute to several intestinal and autoimmune diseases, including celiac disease, irritable bowel syndrome, inflammatory bowel disease, and food allergies.1,2,4 The immune cells primarily responsible for suppressing inappropriate immune responses are regulatory T (Treg) cells, which are generated from both the thymus gland and the gastrointestinal tract.2
Short-Chain Fatty Acids
One pathway to Treg production is by way of short-chain fatty acids (SCFAs), which are byproducts of microbial fermentation of carbohydrates. The primary SCFAs are acetate, butyrate, and propionate.
SCFAs lower the pH of the intestine, helping to inhibit the growth of certain pathogenic microbes.8 While SCFAs are long known to help regulate immunity, more recent evidence has found that they can induce secretion of cytokines and generation of Treg cells in the intestines.2,9 For example, butyrate directly can decrease secretion of proinflammatory cytokines interleukin 6 and 12 (IL-6 and IL-12) and increase secretion of anti-inflammatory (immunoregulating) cytokine interleukin 10 (IL-10) by dendritic cells. Moreover, both butyrate and propionate can prompt dendritic cells to promote Treg cells.4
The ability of gut microbes to indirectly influence dendritic cells is important because dendritic cells also act as messengers between the innate and adaptive immune systems, either by direct contact with immune cells or by release of both proinflammatory and anti-inflammatory cytokines.4
Innate immunity is our front-line defense system, responding rapidly to the presence of pathogenic microbes and protecting us from infection. This front line, which includes neutrophils, monocytes, macrophages, and natural killer (NK) cells, isn’t specific in recognizing and targeting pathogens. Adaptive immunity, on the other hand, develops more slowly but targets specific pathogens more effectively and has a long-lasting protective memory, enabling better response when pathogens are reencountered.
B and T lymphocyte cells are the primary players in the adaptive immune system. B cells secrete antibodies, and T cells have different roles through their subtypes: T helper cells (Th or CD4+ cells) and cytotoxic T cells (CD8+).
Probiotics and Immunity
So that’s what our endogenous—or native—gut microbes can do for our immune systems. But what about probiotic bacteria and other microbes people ingest through supplements, foods, and beverages?
Similar to endogenous gut microbes, probiotics have been shown to have immunomodulatory properties through direct and indirect pathways. Through direct pathways, probiotics can increase activity of macrophages and NK cells or modulate the secretion of immunoglobulins and cytokines. Through indirect pathways, probiotics can enhance the gut epithelial barrier, alter mucus secretion, and successfully compete with and exclude pathogenic bacteria.1
Direct Mechanisms
Similar to endogenous gut microbes, different probiotics can be classified as proinflammatory or anti-inflammatory, according to their capacity to stimulate or regulate immune and nonimmune cells.10 Ideally, the immune system is stimulated when it needs to fight against pathogens, and regulated when there’s no actual threat.
Proinflammatory probiotic species induce IL-12 and NK cell immunity and have the ability to act against infection and cancer cells, as well as against allergies.7,11,12 Anti-inflammatory probiotics can induce IL-10 and Treg production,11 which can decrease risk of allergy, inflammatory bowel disease, autoimmune diseases, and other inflammatory responses.12 By modulating the immune response and inducing the development of Treg cells, probiotics may help preserve intestinal homeostasis.10
For example, consumption of a strain of Bifidobacteria infantis by healthy human volunteers resulted in an increased proportion of Treg cells in the blood. Consumption of B infantis by patients with psoriasis, individuals with chronic fatigue syndrome, and those with ulcerative colitis experienced reduced levels of serum proinflammatory biomarkers such as C-reactive protein, which was possibly mediated by increased numbers of Treg cells.4
Certain probiotics, including several species of Lactobacillus and Bifidobacterium, may influence NK T cells, a group of cells that share characteristics of both T cells and NK cells and play a role in several aspects of immunity. However, the consequences of this in humans are unclear.4,12 These probiotics may also stimulate production of IgA, IL-10, transforming growth factor beta, and IL-6 in the epithelial cells, mucosa, and/or the lamina propria.12
Indirect Mechanisms
The tight junctions between epithelial cells are a key factor in the integrity of the gut barrier. When the proteins that make up the tight junctions become dysregulated, the gut barrier is compromised, and leaky gut may develop.1,13 Various nutrients can regulate tight junction proteins, and some probiotics may have similar capability.1 For example, research has shown several specific probiotic strains, including E coli Nissle 1917, B infantis from a VSL#3 cocktail, and several Lactobacillus strains were able to positively alter the regulation of tight junction proteins. Most studies were conducted in animals or lab settings, but Lactobacillus plantarium has shown positive effects when tested on human subjects.1,6
Specific probiotic bacterial strains, including some from the Lactobacillus family, have been shown to regulate mucin expression, and therefore indirectly regulate the immune system by supporting a healthy mucus layer. Most of the supporting studies have been in vitro, with some overlap with the probiotic strains shown to help regulate tight junction proteins. One of these is VSL#3.1,4
In addition, certain probiotic microbes can induce metabolism of vitamin A into retinoic acid by dendritic cells—important for immune health—at least in in vitro and animal models, and Lactobacillus rhamnosus can induce development of a dendritic enzyme that in turn induces development of mucosal Treg cells.4
When human endogenous gut microbes are able to occupy all functional niches in the microbiota, they effectively crowd out any pathogenic bacteria. But when some of these niches are left open, supplementing with probiotics can potentially fill those voids and prevent or reduce invasion and colonization by pathogenic bacteria.
Probiotics also may alter the intestinal environment by producing SCFAs, lactic acid, bacteriocins (protein-based toxins produced by one bacterial species to inhibit the growth of a closely related bacterial strain), reactive oxygen species (which can regulate T cell immune response), and other metabolites, which could inhibit growth of pathogenic microbes.11,12 Because select probiotics protect against pathogenic bacteria and help ensure the survival of endogenous microbes, this also has an indirect effect on immune function. Several Lactobacillus strains have been identified as having these properties.1
Probiotics and COVID-19
While “boosting immunity” was of interest long before the coronavirus pandemic hit, now it’s a holy grail. While certain probiotics have been shown to reduce the risk of viral infections, it’s important to remember that they haven’t been studied specifically for COVID-19 prevention or treatment.
Back in 2005, a randomized, double-blinded, placebo-controlled intervention study supplemented 479 healthy adults aged 18 to 67 with daily vitamin and mineral supplements, with or without specific lactobacilli and bifidobacteria probiotic strains. After three months, when looking at incidences of the common cold, participants who received the probiotics recovered almost two days sooner, on average, and had reduced severity of symptoms. The probiotic group also had larger increases in CD8+ and CD4+ cells.14
A 2015 Cochrane review of randomized controlled trials comparing probiotics with placebo to prevent acute upper respiratory tract infections (URTIs) concluded that probiotics were better than placebo in reducing the number of participants experiencing episodes of acute URTI and average duration of an episode of acute URTI, as well as reducing antibiotic use and cold-related school absence. The authors say this suggests probiotics may be more beneficial than placebo for preventing acute URTIs, with the caveat that the quality of the available evidence was low or very low.15
Given that some orally administered probiotic strains have been shown to reduce the incidence and severity of viral URTIs, some public health experts are pushing for them to be used with COVID-19 patients, especially since many drugs are being deployed that have little data specific to COVID-19. It also has been suggested that the government should fund probiotic trials as well as drug trials.16
However, other experts emphasize that the rationale for using probiotics in COVID-19 is derived from indirect evidence. In a July letter in The Lancet Gastroenterology and Hepatology, the authors wrote, “Blind use of conventional probiotics for COVID-19 is not recommended until we have further understanding of the pathogenesis of SARS-CoV-2 and its effect on gut microbiota. It is likely that a novel and more targeted approach to modulation of gut microbiota as one of the therapeutic approaches of COVID-19 and its comorbidities will be necessary.”17
In a guidance document on the use of probiotics and prebiotics for COVID-19, the board of the International Scientific Association for Probiotics and Prebiotics reiterates that not all evidence that probiotics can reduce the incidence and duration of URTIs is of high quality, and more trials are needed to confirm these findings as well as determine the optimal strain(s), dosing regimens, and time and duration of intervention. “Further, we do not know how relevant these studies are for COVID-19, as the outcomes are for probiotic impact on upper respiratory tract infections, whereas COVID-19 is also a lower respiratory tract infection and inflammatory disease,” they wrote. “We reiterate, currently no probiotics or prebiotics have been shown to prevent or treat COVID-19 or inhibit the growth of SARS-CoV-2.”18
Future Directions
The field of immunology is pivoting away from a lymphoid tissue–centric view of the immune system and increasing research to further understand the role of the microbiota. However, to date most studies on probiotics have focused on the effects on human metabolism, not on human immune response.12
While it’s clear that gut health plays a major role in immune system function, it’s too soon to recommend probiotics as a go-to for enhancing immunity. Research has shown that probiotics have immune system–modulating activity through various mechanisms, yet it’s with specific strains, not just with a random off-the-shelf probiotic supplement or brand of yogurt. Demonstrating an effect on immune health requires studies of specific probiotic strains with defined immunological endpoints. If, say, a specific strain of lactobacilli is shown to improve immune health, those results can’t be extrapolated to other probiotics or strains of microbes in fermented foods that haven’t been specifically identified as probiotic.
This is an area where it’s easy for consumers, as well as dietitians and other health care providers, to get ahead of the science and take actions or make recommendations that aren’t evidence based. While this is an exciting area of science—and one with increased urgency, given the coronavirus pandemic—it’s important to be able to articulate to patients and consumers the difference between where the science is and where it may be going.
“The complexity of this issue rests with the fact that to make the claim that probiotics can improve or support immune health, you need to have both mechanistic data, from human studies, and clinical endpoint data,” says Mary Ellen Sanders, PhD, owner of Dairy & Food Culture Technologies, a probiotic consulting business in Centennial, Colorado. “There are many studies showing impact on what are considered to be positive immune markers, but unless there is a measurable impact on some meaningful clinical endpoint, who cares? None of us cares if our natural killer cell activity is increased. We care if we aren’t as likely to get sick or can get better faster.”
— Carrie Dennett, MPH, RDN, CD, is the nutrition columnist for The Seattle Times, owner of Nutrition By Carrie, and author of Healthy for Your Life: A Holistic Guide to Optimal Wellness.
References
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17. Mak JWY, Chan FKL, Ng SC. Probiotics and COVID-19: one size does not fit all. Lancet Gastroenterol Hepatol. 2020;5(7):644-645.
18. International Scientific Association for Probiotics and Prebiotics board of directors. ISAPP provides guidance on use of probiotics and prebiotics in time of COVID-19. International Scientific Association for Probiotics and Prebiotics website. https://isappscience.org/isapp-provides-guidance-on-use-of-probiotics-and-prebiotics-in-time-of-covid-19/. Published May 1, 2020.