Probiotics: use caution with autoimmune disease

Advances in the science of the microbiome is totally changing our understanding of the microbial flora constituting a crucial component of our biology and the clinical use of probiotics (microorganisms introduced into the body for beneficial purposes). As the picture evolves it has been apparent that the past view greatly oversimplified the potential harms as well as benefits (or absence of them) when probiotics are used. A paper published recently in Advances in Immunology, Friend or foe? Lactobacillus in the context of autoimmune disease, offers evidence that, especially when introduced into a milieu permissive of autoimmunity, commonly used Lactobacillus strains can result in significant harm.

The same strain can act as a beneficial microbe or a pathogen

The L. reuteri strain of Lactobacillus has been noted for benefits in certain applications but can act as a 'pathobiont' when the immune system has lost self-tolerance. The authors state:

Disruption of the delicate balance between beneficial and pathogenic commensals, known as dysbiosis, contributes to a variety of chronic immunologic and metabolic diseases. Complicating this paradigm are bacterial strains that can operate paradoxically both as instigators and attenuators of inflammatory responses, depending on host background. Here, we review the role of several strains in the genus Lactobacillus within the context of autoimmune and other chronic disorders with a predominant focus on L. reuteri. While strains within this species have been shown to provide immune health benefits, they have also been demonstrated to act as a pathobiont in autoimmune-prone hosts.

The consequences can include a disruption of normal immunomodulatory functions and the triggering of local or systemic inflammation leading to autoimmune disease.

Context- and strain-dependent

The ecosystem in which bacteria live strongly influence whether they are helpful or harmful. Geographic, ethnic, cultural and genetic differences in host background along with various nutritional, metabolic and immunologic processes are involved.

What determines whether a bacterium is helpful or harmful is the ecosystem in which the bacteria live and is significantly influenced by host factors and genetic background...Thus, gut commensals cannot be easily classified in a binary fashion, as the contributions each species make may be highly context- and strain-dependent.

Cross-reactivity

Of special concern for autoimmunity is the potential for the immune system to cross-react with self-tissue antigens when exposed to otherwise beneficial bacteria.

Within the context of autoimmune diseases, otherwise beneficial microbes promote autoimmunity through a variety of mechanisms (Ruff & Kriegel, 2015). One increasingly appreciated molecular mechanism is cross-reactivity of homologous components within the bacteria with host proteins targeted in autoimmune patients (Gil-Cruz et al., 2019; Greiling et al., 2018; Ruff et al., 2019; Ruff & Kriegel, 2015).

The authors give examples of cross-reactivity involving otherwise beneficial flora including systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS); and focus further on both the documented beneficial effects and potential harms of the lactobacilli and the role of the host environment.

Thus, systemic, non-gut inflammatory diseases may be worsened by lactobacilli, while in a healthy host, lactobacilli may be beneficial by downregulating inflammation within the gastrointestinal environment.

Translocation across the gut barrier

The largest bulk of immune system tissue in the body is the gut-associated lymphoid tissue (GALT) surrounding the intestines. Penetration of this by bacteria, lipopolysaccharides (LPS), and bacterial metabolites can challenge the immune system triggering local and systemic reactions and loss of immune tolerance. Additionally, bacteria can progress beyond the lymph nodes in the gut in other organs and tissues.

Translocation of bacteria and their metabolites across the gut barrier has been increasingly implicated in the development of inflammatory and metabolic diseases. Physiologic sampling of microbial communities leads to education of the gut immune system and oral tolerance (Fine, Manfredo Vieira, Gilmore, & Kriegel, 2019; Macpherson & Uhr, 2004). Depending on bacterial virulence patterns and host predisposition, however, bacteria may gain access to more distant sites beyond the mesenteric lymph nodes and induce systemic and organ-specific inflammatory immune responses that can lead to autoimmunity (Fine et al., 2019).

Interestingly, psychological stress can compromise the gut barrier sufficient to permit translocation. This makes sense considering the central role of vagal outflow to the gut in the maintenance of barrier integrity.

Different probiotics may exert local and distant pro-inflammatory or protective effects depending on the host background and environment.

Translocation of lactobacilli can be induced by psychological stressors as was shown in a murine social disruption model (Lafuse et al., 2017).

Even a single dose of most antibiotics can do similarly.

Chemical stressors such as antibiotics also promote translocation of gut commensal bacteria across the colonic epithelial to the mesenteric lymph nodes, which is associated with gut inflammation (Knoop, McDonald, Kulkarni, & Newberry, 2016). Interestingly, only those oral antibiotics that promote gut commensal translocation predispose hosts to increased inflammation in vivo, and a single dose of most antibiotics tested was sufficient for bacterial translocation (Knoop et al., 2016). Furthermore, systemic administration of antibiotics, in this case ceftriaxone, disrupts mucosal homeostasis and facilitates the translocation of enterococci and lactobacilli into systemic tissues (Chakraborty et al., 2018). Thus, both oral and systemic administration of certain antibiotics can facilitate translocation of lactobacilli and enterococci across the gut barrier.

The authors also mention the effect of chemotherapy on the gut barrier leading to translocation and its consequences.

Diet and short-chain fatty acids

Short-chain fatty acids (SCFAs) produced in healthy amounts and proportions by the metabolism of a diversity of fiber by a diverse and healthy gut microbial ecology are important for immune, metabolic and GI health. Insufficiency of SCFAs can result in the passage of lactobacilli into the bloodstream and distal tissues.

Diet can alter the composition of the gut microbiome and affect barrier function; in particular, dietary fiber strengthens the gut barrier (Schroeder et al., 2018)....In human patients with SLE, Lactobacillus species including L. reuteri were enriched in a subset of patients who carried a decreased abundance of Clostridiales and other taxa capable of producing short-chain fatty acids (SCFAs) (Zegarra-Ruiz et al., 2019). In addition to a dysbiotic gut with an imbalance of lactobacilli versus Clostridiales, patients with SLE were also shown to carry Lactobacillales DNA in the blood stream (Ogunrinde et al., 2019; Zegarra-Ruiz et al., 2019), suggesting lactobacilli may also translocate in humans to tissues. Consistent with this notion, Lactobacillus signals are detectable in human livers besides enterococci (Manfredo Vieira et al., 2018)...Bacterial translocation, therefore, occurs in the setting of a weakened gut barrier that depends on environmental factors such as a poor diet and host genetic background.

Required: a personalized approach

The authors list many beneficial effects of probiotics in the right biological context. But their documentation of the potential adverse effects is a necessary corrective for the oversimplification and unrestricted use of probiotics that has become mainstream. They conclude:

Gut commensals and lactobacilli in particular have complex effects on the host depending on bacterial strain-level attributes, host genetics, and environmental factors. Diet, medication, and other environmental influences have profound effects on these commensal bacteria and thereby on the pathogenesis of immune-mediated diseases...Within the gut microbiome, there is no straight-forward distinction between “friend and foe,” which was exemplified by Lactobacillus species under different host and environmental contexts as reviewed here. This paradigm supports the need to a personalized health care approach in order to developing new therapies centered around the human microbiome. Further research will need to delineate the implications for human health in individual subjects, including the potential danger of taking unrestricted probiotics that contain certain Lactobacillus strains. They may promote immune disease in a predisposed host or cause even frank bacteremia in critically ill patients (Yelin et al., 2019; Zegarra-Ruiz et al., 2019). More generally, unrestricted use of probiotics cannot be recommended in light of the varied effects of the gut microbiota on predisposed subjects. Instead, recommendations tailored to patient subsets based on their gut microbiota and genetic background are most likely the safest and most efficacious way forward.

For more on the importance of SCFAs see Gut microbiome, SCFAs, mood disorders, ketogenic diet and seizures.