Probiotics and Immune Function

PROBIOTICS AND IMMUNE FUNCTION

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Microorganisms represent an essential, functioning component of the mammalian intestinal lumen. While the stomach is sparsely populated by acid-tolerant microbes, post-gastric sites support an increasing microbial population density, which in humans can reach concentrations of up to 10¹¹ bacteria g^-1 of lumen contents in the large intestine. Indeed, the human body contains approximately tenfold as many bacterial cells as somatic cells. Colonization of the human intestinal tract by microorganisms begins perinatally, when a newborn baby first encounters maternal and environmental microbes during and immediately following delivery. As neonatal development continues, there is a succession of colonization of the infant's developing intestinal tract by major groups of bacteria, which, under normal circumstances, begins to stabilize during weaning. A stable intestinal microflora is typically attained post-weaning and during early childhood, and forms an essential component fo the functioning human body. Perturbations of this resident microflora (for example, by external stressors, dramatic alterations of the diet or antibiotic treatment) can lead to a deterioration of physiological function and decline in health, including poor digestion and nutrient assimilation, immune dysfunctions and susceptibility to infection by diarrhoea-causing pathogens.

The intestinal microflora constitutes a metabolically active microbial environment, dominated by a relatively low diversity of genera, which, in the gut of healthy individuals, exist as part of a stable community. Under normal circumstances, these resident gut bacteria cause neither pathogenesis nor inflammation in the host, but instead contribute to health maintenance, by forming a barrier layer against colonization by pathogens and by aiding in nutrient digestion and assimilation. In addition, the resident intestinal microflora plays other important physiological roles in health maintenance: deconjugating potentially damaging oxidative metabolites and toxins in the gut; degrading potentially allergenic food proteins; regulating cholesterol and triglyceride uptake; increasing vitamin biosynthesis; and providing immunosurveillance signals to limit intestinal-tract inflammation. Thus, a stable, properly functioning and active intestinal-tract microflora is essential to the continuance of human health.

Among the most predominant microbes in the human intestinal tract are the Gram-positive lactic acid-producing genera Lactobacillus and Bifidobacterium. Lactobacilli and bifidobacteria are also common fermentative microbes in yoghurt, cheese and soured vegetable foods (such as sauerkraut and suguki). The majority of fermentative microorganisms present in such foodstuffs are susceptible to low stomach pH and bile-salt secretions and cannot survive gastric processing. However, following oral delivery, a few strains are able to survive gastric transit and can persist in the intestinal lumen. These strains are thus able to transiently colonize teh gut by integrating into the existing microflora, and are termed 'probiotics'.

Probiotics can be defined as dietary supplements containing living microbes that are able to persist in (or transiently colonize) the human intestinal tract and impart a beneficial influence on host physiology, such that this effect is able to improve health. This process is particularly important at times when the normal indigenous microflora has been perturbed: at this point, exogenously supplied probiotics of a defined species/strain are able to temporarily colonize the intestinal tract and stabilize the microfloral composition, thus restoring the vital physiological functioning of the microbial community. Thus, the use of probiotics in health improvement relies on the principle that exogenous microbes (from food sources) augment the beneficial physiological effects of the normal (indigenous) gut microflora.

Among the many purported physiological influences of probiotic microorganisms, a large proportion of research attention over the last decade has focused on the interaction of probiotics with the immune system. It is evident that several probiotic strains of the lactic acid bacteria (LAB) are able to influence the immune system and, in many cases, this effect has been linked to a measurable improvement in health. The immune system comprises innate and adaptive components, and these play vital interacting roles in health maintenance, in both regulating and stimulating the body's responses.

With regard to the role that the immune system plays in health maintenance and improvement, the traditional viewpoint has been one of immunity as a defence system against intrinsic (neoplasms and tumours) and extrinsic disease-causing agents (pathogens). However, this definition forms only part of the picture. Through control and orchestration of immune responses, the immune system is also able to regulate inflammatory events and control or limit the development of pathologies. This occurs mainly via the production of modulatory hormones (cytokines) that are able to shape and modify the character of a developing immune or inflammatory reaction. In this context, it should be realized that gut-dwelling microbes are far from passive inhabitants of the intestinal-tract mucosa in an inert immunological sense. Paradoxically, it is the very signals generated by gastrointestinal (GI)-tract microbial interactions with the immune system that probably constitute the beneficial impact of probiotics in health. Clinical use studies have indicated that children raised in environments rich in early-life bacterial exposure (including lactobacilli-containing foods) develop fewer immune dysfunctional diseases than those experiencing more sterile environments. In this case, it has been suggested that early stimulation by 'appropriate' bacterial signals may regulate the development of the immune system, such that immunopathologies (e.g. atopic reactions and mucosal allergies) are limited. Indeed, a recent study has shown that supplementing the diets of newborn babies with the probiotic Lactobacillus rhamnosus (strain GG) can effectively reduce the incidence of atopic eczema during infancy and early childhood, suggesting that augmentation of the neonatal intestinal microflora with exogenous bacteria can provide the bacterial signals necessary to combat allergic sensitization.

There is also more direct evidence that orally delivered probiotic organisms can interact with the immune system to limit pathologies. Further studies on L. rhamnosus GG have indicated that this probiotic can alleviate immune-mediated atopy following oral delivery to infants or to nursing mothers, can partially control immune-mediated inflammatory responses in adults (via regulation of leucocyte inflammatory receptor expression) and can reduce the incidence and severity of infant diarrhoea concomitant with an increase in circulating antibody responses (Tab. 1). Clearly, there is scope to exploit the beneficial effects of probiotics on the immune system, with a view to the development of safe, dietary adjuncts/food-borne alternatives to pharmaceutical intervention for the control of a wide range of human pathologies.

The first point of contact for orally delivered probiotics with intestinal tissues occurs as the microorganisms form lectin-like attachments to epithelial cells of the intestinal tract, as tehy begin to colonize the mucosa. Recent research has shown that human intestinal epithelial cells are immunocompetent and can transcribe cytokine messenger RNA in response to contact with probiotic bacteria. This response is heightened in cells that have been subjected to cytokine activation (e.g. during an inflammatory reaction) and is accompanied by an up-regulation of cell surface receptors.

During the regulation of potential inflammatory events, it now seems that bacterial signalling from the gut microflora plays an important role in the communication between gut epithelial cells and associated intraepithelial lymphocytes. In vitro studies with the CaCo-2 human intestinal epithelial cell line have shown that fermentative (Lactobacillus sakei) and probiotic (Lactobacillus johsonii) species can induce the expression of the anti-inflammatory mediator transforming growth factor (TGF)-β, but not pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-α or interleukin (IL)-1β. Addition of leucocytes to CaCo-2 Lactobacillus co-cultures promotes the production of pro-inflammatory molecules by the epithelial cells, but also induces secretion of the leucocyte-derived anti-inflammatory mediator IL-10. Thus, the picture that emerges is that gut microflora and/or probiotic microbes play an active role in the maintenance of gut homoeostasis by inducing the release of anti-inflammatory mediators and that, under pro-inflammatory conditions, the cross-talk between epithelial cells and leucocytes augments this regulatory role via additional cytokine mediation. In this context, contact between gut-dwelling bacteria and intestinal cells may be considered part of the routine microbial signalling processes of a healthy gut microflora, forming a homoeostatic mechanism for the regulation of intestinal inflammation. Indeed, removal of these routine signals at the gut epithelial surface can lead to a breakdown in these regulatory immune mechanisms and consequently promote aggressive and uncontrolled inflammatory responses.

While it has been suggested that routine signalling between resident/probiotic microbes and gut epithelial cells plays a maintenance role for gut homoeostasis, it is arguably direct immunostimulation by an interaction of the microbes with lymphoid foci that has received most research attention. In this situation, the interaction are quite different: microbes traverse the epithelial boundary and contact leucocytes directly (e.g. in the organized capsular foci of Peyer's patches), enabing direct immunoactivation. Evidence for this direct interaction has been obtained experimentally in animal models, and has an important consequence: unlike immunoinflammatory events that take place solely in the common mucosal immune system, immunostimulation via lymphoid foci facilitates ready access of messenger cells to the systemic circulation, via drainage to the mesenteric lymph node and thoracic duct. Thus, the consequence of an interaction between probiotic bacteria and lymphoid foci in the GI tract could include effects on systemic immune responses involving circulating leucocytes. Several Gram-positive bacterial cell-wall components (including lipoteichoic acid, peptiodlycan and muramyl dipeptide) have been shown to bind leucocyte pattern-recognition receptors, including the endotoxin receptor (CD14), Toll 2 and type 1 macrophage scavenger receptor, and this could represent the mechanism by which probiotics are able to stimulate the immune system directly.

Although the primary site of immunological signalling is at the gut mucosal interface, there is evidence that the immunomodulatory effects of probiotics can be expressed systemically. Typically, this is manifested by changes in leucocyte or humoral function, which can be assessed by ex vivo assays. To date, several compartments of the immune system have been identified as affected by probiotic delivery, including lymphocyte function (proliferation, cytokine secretion and cellular cytotoxicity); innate cell defences (e.g. phagocytosis, oxidative radical production, lysosomal enzyme secretion); natural cytocidal function of macrophages and natural killer (NK) cells, and antibody responses (both in terms of total immunoglobulin (Ig) levels and antigen-specific responses (Tab. 1). In addition, there is evidence that oral delivery of probiotics can influence cellular phenotype expression, both at the mucosal interface and systemically, to reflect a state of activation.

The majority of research to characterize probiotic effects on lymphocyte function has utilized animal models for study. Oral delivery of different strains of Lactobacillus has been shown to confer an increased capacity for splenic lymphocytes to proliferate in response to T-cell and B-cell mitogenic stimulation and, in at least one case, this general enhancement of lymphocyte function has also been demonstrated at the local level in lymphoid foci of the intestinal tract (i.e. Peyer's patches). What is not clear at the moment is whether this enhanced capacity for lymphocytes to undergo activation/mitosis is due to increases in population levels (i.e. proportionally more lymphocytes) and/or increases in responsiveness to stimuli (i.e. lymphocytes at a heightened state of preactivation). However, a study by Perdigon et al. has shown that T-helper (CD4+) lymphocyte numbers are increased in the gut-associated lymphoid tissue (GALT) following oral-delivery of Lactobacillus casei, providing evidence that probiotic stimulation can increase the size of lymphocyte populations.

Oral delivery of probiotics has also been shown to increase the capacity of systemic lymphocytes to secrete T-cell cytokines in response to appropriate in vitro stimulation. Some strains of Lactobacillus and Bifidobacterium have been demonstrated to increase the capacity of murine splenic lymphocytes and human peripheral-blood lymphocytes to secrete the cytokine interferon-γ (IFN-γ), following mitogen stimulation in vitro. Clinical studies have confirmed that certain probiotic LAB can induce increased expression of both type I and type II interferons among peripheral blood mononuclear cells (Tab. 2).

A large body of work concerned with definition of probiotic effects on the immune system has focused on innate cell responses. Early studies had shown that oral delivery of L. casei probiotic strains to mice could activate mononuclear phagocytes for increased phagocytic activity and lysosomal enzyme production and that this enhancement could be detected in cells derived from peritoneal exudates. Subsequent studies have confirmed that certain strains of probiotic LAB can prime peritoneal macrophage populations for enhanced phagocytosis, lysosomal enzyme production and free radical oxidant production. Further studies in murine models have reported that probiotic feeding can also enhance the activity of blood-derived phagocytes and that both mononuclear (monocyte) and polymorphonuclear (neutrophil) populations are stimulated by probiotics. Human studies have confirmed this effect in circulating phagocytes of adult subjects including the elderly (Tab. 1).

In common with studies on the effects no lymphocyte proliferation, it is at present unclear whether oral probiotic delivery enhances phagocytic cell function as a reflection of increased cell numbers and/or increased cellular avidity to phagocytose. It is likely that bacterial signalling will activate a general release of phagocytically active cells into circulation, and this is possibly achieved by microbial stimulation of phagocytic precursor cells. It is important to note that mononuclear phagocytes, in particular, are also capable of secreting immunomodulatory cytokines and that stimulation of these cells by oral probiotics has been shown to increase production of key cytokines, which modify and shape the character of the immune response. Thus, it is possible that phagocyte activation is the first and key event in immune stimulation by probiotics and that enhanced phagocytic capacity is a reliable index of this activation, prior to the initiation of downstream events, such as cytokine-mediated enhancement of leucocyte cytotoxicity and lymphocyte activation.

Studies in murine models have shown that the cytocidal activity of splenic leucocytes can also be increased following delivery of certain strains of probiotics. Systemic priming of mice with viable L. casei (Shirota strain) can enhance ex vivo tumoricidal activity of splenic NK cells and macrophages and can also increase cytocidal activity against cytomegalovirus-infected target T-cells. Oral delivery of L. rhamnosus HN001 or L. casei Shirota to mice has also been shown to increase ex vivo NK-cell tumoricidal activity. In human studies, feeding of L. rhamnosus (strain HN001) or Bifidobacterium lactis (strain HN019) has been demonstrated to up-regulate peripheral blood NK-cell-mediated cytotoxicity against tumour cells (Tab. 1).

Several studies have investigated the ability of probiotics to regulate antibody production. Initial animal studies showed that probiotics were able to potentiate systemic antibody responses to parenterally delivered foreign antigens in mice and that serum levels of IgG and IgM isotypes were elevated. Subsequent studies have indicated that probiotic strains such as L. rhamnosus HN001 or B. lactis HN019 can potentiate antibody responses to both systemically and orally administered T-dependent antigens in mice and that increases in specific antibody titre can be measured in both the serum and intestinal-tract secretions, the latter involving a rise in IgA levels. Since the major GI antibody secretion is derived from plasma cells of the lamina propria, these results suggest that probiotics are able to stimulate the mucosal immune system, possibly via direct interaction with immunocompetent T-cells of the GI tract. Indeed, recent studies in mice have indicated that probiotic LAB are able to increase the mucosal density of IgM- and IgA-secreting plasma cells in both gut epithelial and broncho-alveolar lymphoid tissues.

Under disease conditions, animal studies have also indicated that probiotic delivery can can increase GI tract and systemic antibody responses to bacterial pathogens, including Escherichia coli, Shigella sonnei and Salmonella typhimurium. Clinical studies have demonstrated that the orally delivered probiotic L. rhamnosus GG can also increase the frequency of pathogen-specific and total antibody-secreting cells in children during convalescence from rotavirus diarrhoea. However, in the case of non-infectious diseases, such as atopy, it appears that certain probiotic bacteria are able to exert a regulatory, rather than enhancing, effect on antibody production. Several studies have shown that IgE responses in allergen-primed mice can be attenuated by the oral or systemic delivery of probiotic LAB, suggesting that an ability to regulate immune responses may play an important role. Indeed, in vitro studies by Murosaki et al. have shown that adding L. casei (Shirota strain) to cultures of allergen- reactive murine splenocytes can directly suppress IgE production.

As described previously, probiotics are capable of modulating the immune system via both immunostimulation and immunoregulation, and thus have the potential to have an impact on health status and disease conditions that have an inherent immune component. In the case of immunostimulation, probiotics may provide a boosting of the immune system in key aspects of effector mechanisms that are tailored towards combating infectious diseases or intrinsic pathologies, such as neoplasm development. In addition, the ability of probiotics to stimulate cytokine secretion may provide an important immunoregulatory function for the control of immune dysfunctional conditions, such as chronic inflammation and allergies. Research that has sought to investigate these potential outlets for probiotics in health has drawn on both animal studies and human clinical trials for supportive evidence.

There is clear evidence that certain probiotic LAB strains are able to potentiate pathogen-specific antibody responses, both in animal models and in humans. Yasui et al. have demonstrated that mice immunized with influenza vaccine and fed Bifidobacterium breve (strain YIT4064) as a probiotic developed enhanced virus-specific antibody responses and showed greater protection against respiratory challenge than non-probiotic-fed mice. In addition, some studies have confirmed an increase in innate and lymphoid cell-mediated events in pathogen-infected mice, which may contribute to enhanced disease resistance. Shu et al. have recently shown that the probiotic B. lactis HN019 could enhance pathogen-specific antibody responses in S. typhimurium-infected mice, as well as promoting increased peritoneal cell phagocytosis and splenic lymphoproliferative potential; correlation analyses indicated that elevated immune function in probiotic-fed mice corresponded with reduced pathogen translocation in these mice and promoted enhanced survival. Other strains of bifidobacteria (such as B. breve) have been shown to increase murine antibody titres in nursing dams and to provide increased protection to weanling mice against rotavirus. Recent studies have confirmed this phenomenon in weanling piglets that have been fed B. lactis HN019, which exhibit enhanced cellular and humoral immunity and increased protection against naturally acquired weanling diarrhoea.

In human studies, the probiotic L. rhamnosus GG has been shown to promote recovery from both rotavirus and non-bloody diarrhoea in children and infants, by reducing virus shedding as well as the duration and intensity of diarrhoeal disease (Tab. 2). Two studies have demonstrated a concomitant rise in the frequency of antibody-secreting plasma cells in the circulation of probiotic-fed children, strongly suggesting that enhanced humoral immunity plays a role in reducing convalescence time by aiding viral elimination. Studies using B. breve have shown that oral administration of this probiotic to hospitalized children can also support a reduction in both the incidence of diarrhoea and of viral shedding, concomitant with elevated titres of anti-rotavirus IgA antibody in the stools.

Several studies in animal models have investigated the effects of probiotic administration on immune responses and tumour regression. Initial studies had indicated that systemically delivered LAB cells could potentiate ex vivo leucocyte tumoricidal and lymphoproliferative responses and could limit the growth of both primary and secondary tumours at several tissue sites in vivo. More recent studies have focused on the use of orally delivered probiotics and anti-tumour immunity. L. casei Shirota has received a great deal of research attention. Orally delivered L. casei Shirota was shown to reduce the establishment and growth of inoculated syngeneic sarcoma cells in BALB/c mice, concomitant with an increased lymphoproliferative response and capacity to secrete the cytokine IL-2 by splenic T-cells in these animals. Furthermore, growth of secondary tumours was inhibited in probiotic-fed mice following tumour resection, again linked to enhanced lymphocyte
responsiveness. Lactobacillus plantarum (strain L- 137) has also been shown to retard the growth of implanted P3881D tumour cells in syngeneic DBA/2 mice, and in this case the mechanism was suggested to be a systemic elevation of the pro-cellular-immunity cytokine IL-12, favouring anti-tumour cellular immune responses.

Additional studies on L. casei Shirota have indicated that this strain may also have anti-carcinogenic effects related to enhanced immune activity. Takagi et al. have recently demonstrated that mice fed the probiotic developed fewer systemic tumours following injection of the hydrocarbon carcinogen 3- methylcholanthrene and that lymphoproliferative responses and the IL-2- secreting activity of splenic T-cells were retained, while the comparative immune responses in non-probiotic-fed mice declined markedly during tumour development. In similar studies, probiotic-containing yoghurt has been shown to limit intestinal-tract tumour development in mice injected with the carcinogen 1,2-dimethylhydrazine, and this reduction was associated with enhanced infiltrations of CD4+ T lymphocytes into the intestinal tissues in these mice. Other strains of Lactobacillus have also been shown to limit the incidence and mean developmental size of colonic adenocarcinomas in Sprague–Dawley rats fed 1,2-dimethylhydrazine, although associated immune responses were not investigated in these studies. A further anti-cancer mechanism of probiotics involves the deconjugation of potentially mutagenic enzymes in the gut lumen, although this mechanism is not thought to have an immune component.

No longitudinal clinical trials have yet been undertaken to determine the potentially protective effects of immunoactive probiotics in the reduction of tumour incidence/development. However, a few studies have investigated the ability of probiotic LAB strains to retard tumour growth in cancer patients. L. casei Shirota was shown to reduce the recurrence of superficial bladder cancer in adult patients following resection and also to delay the onset of tumour recurrence (Tab. 2). Although associated cellular immune parameters were not reported in these studies, work in adult colon-cancer patients has shown that oral L. casei Shirota delivery can enhance circulating NK-cell activity, suggesting that tumour limitation may be the result of enhanced immunoactivity imparted by the probiotic. In contrast, however, a recent study has reported that L. casei Shirota does not enhance NKcell tumoricidal activity in healthy adult subjects.

The immune system plays an essential role in the regulation of inflammatory-type diseases, and consequently a dysfunction of the immune system can lead to exacerbation of disease. Due to their potential for immune regulation, it has been suggested that probiotics offer potential for the alleviation of several immuno-inflammatory diseases. Perhaps most attention has been given to the ability of probiotics to regulate allergic/atopic responses. In animal studies, L. casei Shirota has been shown to reduce cutaneous anaphylaxis in allergen-sensitized mice following dermal challenge. Both L. casei Shirota and L. plantarum L-137 have been shown to exhibit anti-allergy properties in mice, reportedly due to their ability to induce high-level systemic expression of IL-12, which can downregulate allergic responses. Indeed, some strains of lactobacilli have been shown to elevate systemic levels of IL-12 following oral delivery, suggesting that this is a major mechanism by which probiotics effect anti-allergy-type immunoregulation.

In human studies of allergic disease, there is longitudinal evidence that consumption of probiotic-supplemented yoghurt over a period of 1 year can lower the circulating levels of IgE and reduce nasal allergies in elderly subjects (Tab. 2). Wheeler et al. have shown that shorter-term consumption of probiotics (i.e. 1 month) by adult allergy sufferers can generate a trend towards reduced peripheral blood eosinophil counts and increased IFN-γ-secreting activity of lymphocytes, suggesting that probiotic-induced anti-allergy immune regulation may be effective in humans also. A report by Pelto et al. demonstrated an alternative mechanism for the ability of L. rhamnosus GG to limit hypersensitivity responses in subjects with cows’-milk allergy, namely, that the probiotic can prevent the up-regulation of pro-inflammatory receptors on leucocytes (a response that normally precedes GI tract inflammation in milk-sensitive subjects). Other potential mechanisms by which probiotics might limit food-hypersensitivity responses include their ability to stabilize the gut intestinal barrier against macromolecular sensitization and/or the enzymatic hydrolysis of potentially allergenic macromolecules. In the latter case, an additional mechanism may be the generation of immunoregulatory peptides from milk substrates by the enzymatic action of probiotics, since Sutas et al. have shown that milk or casein hydrolysed with L. rhamnosus GG invokes lower levels of pro-allergy immune responses in antigen-stimulated peripheral blood lymphocytes from milk-sensitive subjects than do intact macromolecules.

In addition to anti-allergy immunoregulation, several studies have suggested that probiotics could be used to combat inflammatory-type diseases. There is some evidence that dietary consumption of immunoregulating LAB might assist in combating autoimmune diseases, including juvenile chronic arthritis, although the potential mechanism for this is uncertain. A recent report has shown that a diet rich in lactobacilli could decrease subjective symptoms of arthritis among rheumatoid patients, although whether this effect was a result of anti-inflammatory immune regulation is uncertain. The potential use of probiotics to augment the routine immune signalling events of the gut microflora, as a means of restoring vital anti-inflammatory immunoregulatory control mechanisms, has recently gained a great deal of attention as a promising means of combating inflammatory bowel disease. However, definitive proof for the effectiveness of this mechanism remains to be obtained.

It is clear, from the foregoing discussions, that there is significant evidence, both experimental and clinical, to indicate that certain strains of probiotic organisms can modulate the immune system of the host. The two major impacts that have been demonstrated so far include immunostimulation and immunoregulation. Immunostimulation involves an elevation of immune function(s) to a heightened state of responsiveness, and may provide an important role in conditions where an elevation of immune function is not achievable by conventional means or in boosting responses among individuals with sub-optimal immunity. Experimentally, several strains of Lactobacillus and Bifidobacterium have been shown to boost humoral antibody responses to experimentally administered T-cell-dependent antigens. In human studies, Lactobacillus GG has been shown to enhance the humoral immune response to orally administered rotavirus and Salmonella typhi vaccines, while B. breve enhances IgA antibody responses to poliomyelitis vaccine, thus providing evidence of the potential use of probiotics as oral adjuvants to boost immune responses at the gut mucosal surface. Future uses of probiotics may be expanded to their use as oral adjuvants to promote immune responses against vaccines that currently can only be administered parenterally – for example, to boost circulating antibody responses to orally administered influenza vaccine.

A further role for immune-stimulating probiotics is their use in boosting immune function in individuals with suboptimally functioning immunity. Lactobacillus GG has already been mentioned as an oral immunostimulator to enhance antibody responses in children combating rotavirus infection, and probiotics may prove very useful in this context of boosting immunity among malnourished children or infants with poorly developed sensitization. At the other end of the age spectrum, probiotics may prove useful in boosting immunity among elderly subjects. Studies have shown that senescence of the immune system can predispose the elderly to infectious and non-infectious diseases and that a decline in immune function with age can contribute to decreased life expectancy. Immunosenescence is characterized by a suboptimal functioning of the cellular immune system in particular, mainly involving T-cell-mediated responses but also some NK-cell and phagocyte functions. In this respect, it has been demonstrated that L. rhamnosus (strain HN001) and B. lactis (strain HN019) are both effective at boosting cellular immune function among healthy middle-aged and elderly subjects. Thus, certain probiotic strains may offer benefit to elderly consumers by stimulating the very compartments of the immune system that are adversely affected by ageing.

The immunoregulatory role of probiotics has probably received the greatest degree of attention in experimental research. A large proportion of this work has thus far focused on probiotic LAB, which induce the anti-allergy cytokines IL-12 and IFN-γ, for their potential use in preventing atopic responses and combating allergies. Yet there is still only limited clinical evidence that orally delivered probiotics are effective at combating allergic symptoms among at-risk groups. In contrast, there is gathering clinical evidence that certain probiotic strains can be used effectively in neonatal and paediatric care to provide the necessary bacterial signals which, in early life, enable the immune system to develop appropriately and to avoid allergic
sensitization.

Other potential uses of immunoregulatory probiotics (e.g. in controlling inflammatory diseases at the gut surface) have only recently begun to attract research attention, partly because the microbial : gut mucosal signalling mechanisms are only beginning to be understood by microbiological researchers. A recent pilot study showed promising preliminary results for the use of L. rhamnosus GG as a dietary supplement to reduce clinical indices of GI-tract inflammation in children with Crohn’s disease. As research starts to define the interactions of the gut microflora and the immune system in the maintenance of health, so it is likely that new avenues for dietary intervention will become the focus of research efforts.

For both immunostimulatory and immunoregulatory roles, contemporary research has already identified a few promising strains of immunoactive probiotics (predominantly LAB) and these strains either are currently being commercialized or are near commercialization. An on-going need for research in this area is for continued safety monitoring, particularly among individuals with pre-existing health conditions. For example, among patients with active autoimmune conditions, probiotic strains that stimulate cellular immune function must receive particular and thorough attention to avoid the potential for disease exacerbation; moreover, the safety of probiotics in subjects with deficient immune systems (e.g. acquired immune deficiency syndrome (AIDS) patients) should be considered. That aside, the essential requirement in all of these cases is not only that the probiotic under consideration is effective at influencing immunity but that it influences the immune system in the appropriate manner and, moreover, that this action contributes in a meaningful way to health improvement. In the former case, this suggests that well-designed and appropriate clinical trials are conducted to determine the impact of any probiotic on the immune system and that this research is conducted on the target population (with regard to demographics, etc.). In the latter case, where an effect of probiotics on the immune system has already been demonstrated, there remains the need to correlate immunoactivity with health improvement. In many cases (e.g. boosting of anti-tumour immunity) such evidence will only come from longitudinal/cross-sectional studies of significant duration. Nevertheless, major progress in the use of defined probiotics for health improvement is likely to become apparent in the coming decade.