Strain-specific alterations in gut microbiome and host immune responses elicited by tolerogenic Bifidobacterium pseudolongum

Abstract

The beneficial effects attributed to Bifidobacterium are largely attributed to their immunomodulatory capabilities, which are likely to be species- and even strain-specific. However, their strain-specificity in direct and indirect immune modulation remain largely uncharacterized. We have shown that B. pseudolongum UMB-MBP-01, a murine isolate strain, is capable of suppressing inflammation and reducing fibrosis in vivo. To ascertain the mechanism driving this activity and to determine if it is specific to UMB-MBP-01, we compared it to a porcine tropic strain B. pseudolongum ATCC25526 using a combination of cell culture and in vivo experimentation and comparative genomics approaches. Despite many shared features, we demonstrate that these two strains possess distinct genetic repertoires in carbohydrate assimilation, differential activation signatures and cytokine responses signatures in innate immune cells, and differential effects on lymph node morphology with unique local and systemic leukocyte distribution. Importantly, the administration of each B. pseudolongum strain resulted in major divergence in the structure, composition, and function of gut microbiota. This was accompanied by markedly different changes in intestinal transcriptional activities, suggesting strain-specific modulation of the endogenous gut microbiota as a key to immune modulatory host responses. Our study demonstrated a single probiotic strain can influence local, regional, and systemic immunity through both innate and adaptive pathways in a strain-specific manner. It highlights the importance to investigate both the endogenous gut microbiome and the intestinal responses in response to probiotic supplementation, which underpins the mechanisms through which the probiotic strains drive the strain-specific effect to impact health outcomes.

Early immunomodulatory program triggered by pro-tolerogenicBifidobacterium pseudolongumdrives cardiac transplant outcomes

“…A. muciniphila reached peak abundance at week 2, followed by a stable, reduced level through week 6. In our previous study 31 , A. muciniphila was enriched in the gut microbiota in Bifido MD gavaged mice, despite its overall low abundance. Lachnospiraceae and Ruminococcus , obligate anaerobes within Clostridiales with diverse fermentative capabilities, were highly variable following SBT (Fig.…”

“…In comparing Bifido ATCC and MD immunologic effects over longer time periods of 40 and 60 days, we found their immunologic effects on allografts and LN to be highly similar (Fig. 5d) , despite some short-term strain-specific in vitro differences 31 .…”

“…Since Bifido MD is murine-tropic with improved anti-inflammatory capacity in vitro 31 , subsequent transplant experiments were carried out using the Bifido MD strain. We compared Bifido MD SBT to Desulfo or control PBS gavage in animals receiving allogeneic cardiac transplants.…”

“…We previously showed that Bifido MD and Bifido ATCC elicited strain-specific differential effects on innate immune cell activation, tolerogenic LN architecture, and host transcriptome profiles 31 . In this study, murine-isolated Bifido MD elicited early pro-tolerant immune changes in terms of allogeneic T cell differentiation while histologic allograft changes were observed over longer periods.…”

“…We previously demonstrated that both the gut microbiota as a whole or the responsible single bacteria ( Bifido or Desulfo species) can profoundly influence the outcomes of vascularized cardiac allografts 30 . Oral gavage with a single anti-inflammatory strain of Bifidobacterium pseudolongum ( Bifido ), enriched in pregnant mouse (representing immune suppression) gut microbiome, resulted in significant improvement in long-term allograft survival, prevention of inflammation and fibrosis in the grafts, and balanced anti-inflammatory and homeostatic cytokine response from dendritic cells (DCs) and macrophages (MΦ) 30,31 . On the other hand, the single pro-inflammatory strain of Desulfovibrio desulfuricans ( Desulfo ), enriched in colitic mouse (representing immune inflammation) gut microbiome, triggered a greater inflammatory cytokine response in vitro 30 .…”