Our findings show that oral administration of B. infantis 35624 modulates the cytokine milieu across both gastrointestinal and non-gastrointestinal inflammatory disorders and healthy subjects. B. infantis 35624 significantly reduced plasma CRP levels in all patient groups, plasma TNF-α in the non-gastrointestinal disorders, psoriasis and CFS, while non-statistically significant trends toward a reduction in levels of IL-6 were seen in patients with CFS and UC. Furthermore, B. infantis 35624 altered responses to inflammatory stimuli in ex vivo cultures from healthy volunteers.
Chronic inflammatory diseases such as UC, CFS and psoriasis are characterized by an over-production of pro-inflammatory cytokines. C-reactive protein (CRP) is an acute phase protein synthesized by hepatocytes and adipocytes in response to increased peripheral pro-inflammatory cytokines, such as TNF-α and IL-6,13,14
and the serum or plasma level is a useful and clinically relevant indicator of systemic pro-inflammatory activity in multiple inflammatory states.15
In this study, plasma CRP was significantly elevated in all conditions investigated compared with healthy controls. These elevated levels of CRP concur with the results of previous studies conducted in CFS,16,17
and UC patients.22
In standard clinical laboratories the median value of plasma CRP for healthy subjects is < 1mg/L.23-25
Ultrasensitive assays have associated low-grade inflammation (CRP > 2.4 mg/L) with increased risk for coronary artery disease,26
while levels of CRP from 10‒1000 mg/L are associated with overt inflammatory and infectious disorders.25
Interestingly, B. infantis
35624 significantly reduced plasma CRP levels in all three inflammatory conditions examined. Regarding the significance of changes in CRP following treatment, the best illustration is provided by studies in heart disease where very small increments in CRP (1–2 mg/L) were associated with substantial increases in risk for coronary events.27
The effect of other microbes on CRP levels has been quite variable. Studies have shown that microbial treatment reduced CRP levels in the serum or plasma in ulcerative colitis28-30
while others noted an increase in serum CRP levels in a non-gastrointestinal condition eczema dermatitis31,32
or no effect in both gastrointestinal33
and non-gastrointestinal conditions.31,34,35
This suggests that not all commensal microbes can induce this effect in humans.
TNF-α and IL-6 are pro-inflammatory cytokines which are elevated in a variety of inflammatory conditions and involved in transcriptional regulation of CRP.25,36
They are not employed in clinical practice but both of these cytokines have been targeted by aggressive anti-cytokine biologic agent therapy in the treatment of autoimmune diseases.37,38
The attenuation of CRP following B. infantis
35624 treatment in this study is consistent with the reduction in circulating levels of both of those pro-inflammatory cytokines. In general, reduction in inflammatory markers, such as those seen in this study would be regarded as indicative of clinical remission and of a lower risk of relapse.22,39,40
Patients with CFS, psoriasis and UC had higher baseline TNF-α levels compared with healthy controls. These findings are in agreement with other studies.22,41-43
Following eight weeks of treatment with B. infantis
35624, a significant attenuation of TNF-α was observed for CFS and psoriasis patients; no such effect was noted with placebo treatment. A trend toward decreased TNF-α in the UC group was also observed, but this did not reach statistical significance, perhaps due to the shorter treatment time (i.e., 6 weeks). These data implicate TNF-α in the pathophysiology of inflammatory conditions and support the use of specific and well selected therapeutic microbes in alleviating the inflammatory component of such conditions, despite the often conflicting literature.34,35,44-47
Plasma IL-6 levels were significantly higher in CFS, psoriasis and UC patients compared with healthy controls, which is consistent with the findings of previous studies in psoriasis,42,48
Though previous studies have indicated that certain therapeutic microbes could significantly reduce IL-6 levels in both patients with gastrointestinal inflammatory disorders and healthy controls,44,51-53
plasma IL-6 levels were only marginally decreased following B. infantis
35624 administration in this study. These data reinforce the hypothesis that individual elements of the microbiota influence specific components of the host immune response and not all members of the microbiota, or even not all members of the same species, exert an identical effect.
Overall, 70% of all of the individuals with UC, CFS or psoriasis fed B. infantis 35624 for 6–8 weeks showed marked decreases in all three biomarkers. Despite the limitations of post hoc analysis, this finding supports the concept of B. infantis 35624 acting centrally, perhaps through increased numbers of regulatory T cells, to minimize pro-inflammatory activity in vivo. Furthermore, in the ex vivo studies, secretion of IL-6 and TNF-α from LPS-stimulated peripheral blood mononuclear cells (PBMCs) was significantly reduced by B. infantis 35624 feeding in healthy controls compared with placebo-fed controls.
There are limitations to this study: first, the n value for each clinical condition studied is relatively low; collectively, however, the message is consistent. While the numbers included were sufficient to demonstrate statistical significance for objectively measured biomarkers, larger patient populations would be required to demonstrate clinical efficacy. Second, only one daily dose of this microbe was studied and a dose-dependent anti-inflammatory effect was, therefore, not demonstrated. It is noteworthy in this respect, that many naturally occurring and even biologic agents, such as anti-TNF-α strategies, do not exhibit clear dose-response profiles.
In conclusion, oral administration of a single microbial agent, B. infantis 35624, was sufficient to reduce systemic inflammatory biomarkers in both gastrointestinal and extra-intestinal inflammatory disorders. This is consistent with the hypothesis that certain elements of the enteric microbiota can induce mucosal immunoregulatory responses that can exert an effect systemically.