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

Abstract

Despite ongoing improvements in regimens to prevent allograft rejection, most cardiac and other types of allografts eventually succumb to chronic vasculopathy, interstitial fibrosis, or endothelial changes, and eventually graft failure. Adaptive immune-mediated damage is considered the primary cause of long-term graft failure, though the events leading to chronic rejection are still poorly understood. Gut microbiota is a known driving force in immune dysfunction. We previously showed that gut microbiota dysbiosis profoundly influences the outcome of vascularized cardiac allografts and subsequently identified biomarker species or ″bacterial determinants″ associated with these differential graft outcomes (anti-inflammatoryBifidobacterium pseudolongum(Bifido) and pro-inflammatoryDesulfovibrio desulfuricans(Desulfo)). In this study, we further detailed the multifaceted immunomodulatory properties of the pro-tolerogenic bacterial species over time, using our clinically relevant model of allogenic heart transplantation. This model simultaneously accounts for the immunomodulatory properties of antibiotics and tacrolimus immunosuppression, in addition to bacterial determinants. We observed thatBifidoinduced an early anti-inflammatory phenotype within 7 days, whileDesulforesulted in a pro-inflammatory phenotype, defined by alterations in leukocyte distribution and lymph node (LN) structure. These effects were further modulated by inhibition of myeloid cell migration by CCR2 inhibition, supporting the notion that bacterial determinants regulate innate immunity which subsequently influences adaptive immunity. Indeed,in vitroresults showed thatBifidoandDesulfoacted directly on primary innate immune cells. However, by 40 days after treatment, these two bacterial determinants were associated with mixed effects in their impact on LN architecture and immune cell composition. These dynamic effects suggest a critical role for early bacterial determinant-triggered immunological events such as innate immune cell engagement and LN architectural changes in the subsequent modulation of pro-tolerant versus pro-inflammatory immune responses in organ transplant recipients.

Bifidobacterium exopolysaccharides: new insights into engineering strategies, physicochemical functions, and immunomodulatory effects on host health

“…For instance, in a study involving mice treated with Bifidobacterium adolescentis ATCC15703, lower levels of pro-inflammatory cytokines such as TNFα, IL-6, IL-1β, IL-18, IL-22, and IL-9 were observed compared to the control group. Conversely, higher levels of the anti-inflammatory cytokine IL-10 and the cytokines IL-4 and IL-5, along with increased regulatory T cells (Tregs), were detected in the colons of colitis mice receiving B. adolescentis ATCC15703 (Gavzy et al, 2023). These findings underscore the strain-specific immunomodulatory effects of probiotic bacteria and highlight their potential therapeutic implications in inflammatory conditions.…”

“…In vitro studies involving the treatment of DCs with Bifidobacterium bifidum PRI1, followed by co-culture with naïve CD4 T cells, have demonstrated enhanced induction of regulatory T cells (Tregs) and production of interleukin-10 (IL-10; Gavzy et al, 2023). These findings underscore the immunomodulatory capabilities of Bifidobacterium EPS, particularly in promoting immune tolerance and anti-inflammatory responses mediated by Tregs and IL-10.…”

“…Murine B. pseudolongum UMB287 MBP-01 EPS increases intestinal Tregs, whereas porcine-derived B. pseudolongum ATCC25526 EPS does not. However, EPS from both strains lead to increased dendritic cells (DCs), mesenteric lymph node (MLN) DCs, and intestinal MLN macrophages (Hickey et al, 2021;Gavzy et al, 2023).…”

“…Cytokines serve as soluble mediators of host defense responses, playing crucial roles in both specific and non-specific mechanisms for eliminating foreign antigens (Ashraf and Shah, 2014). The cell surface components of B. longum strains NCC 2705, ATCC 15707, and BIF53 have been shown to stimulate the production of IL-10 and TNFα in isolated peripheral blood mononuclear cells (Gavzy et al, 2023).…”

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“…Here, we first investigated the age-related trajectories in four well-known probiotics that have beneficial effects on the host. Bifidobacterium, a widely distributed commensal genus within the phylum Actinobacteriota, plays a role in maintaining intestinal homeostasis and alleviating inflammation (Liu et al, 2022;Gavzy et al, 2023), thereby benefiting intestinal health. We observed a consistent decline in the genus Bifidobacterium with advancing age, most pronounced during infancy (Figure 6A), which is consistent with the repeatedly observed decreased trend in elderly people in several studies (Arboleya et al, 2016;Seo et al, 2023).…”