The mammalian intestine harbors a remarkable number of microbes and their components and metabolites, which are fundamental for the instigation and development of the host immune system. The intestinal innate and adaptive immunity coordinate and interact with the symbionts contributing to the intestinal homeostasis through establishment of a mutually beneficial relationship by tolerating to symbiotic microbiota and retaining the ability to exert proinflammatory response towards invasive pathogens. Imbalance between the intestinal immune system and commensal organisms disrupts the intestinal microbiological homeostasis, leading to microbiota dysbiosis, compromised integrity of the intestinal barrier, and proinflammatory immune responses towards symbionts. This, in turn, exacerbates the degree of the imbalance. Intestinal adaptive immunity plays a critical role in maintaining immune tolerance towards symbionts and the integrity of intestinal barrier, while the innate immune system regulates the adaptive immune responses to intestinal commensal bacteria. In this review, we will summarize recent findings on the effects and mechanisms of gut microbiota on intestinal adaptive immunity and the plasticity of several immune cells under diverse microenvironmental settings.

https://downloads.hindawi.com/journals/jir/2019/4735040.pdf

Gut Microbiota Modulation on Intestinal Mucosal Adaptive Immunity.

Disruption of the intestinal microbiota occurs frequently in allogeneic hematopoietic cell transplantation (allo-HCT) recipients and predisposes them to development of graft-versus-host disease (GvHD). In a prospective, single-center, single-arm study, we investigated the effect of donor fecal microbiota transplantation (FMT) on symptoms of steroid-refractory or steroid-dependent, acute or late-onset acute intestinal GvHD in 15 individuals who had undergone allo-HCT. Study participants received a fecal suspension from an unrelated healthy donor via nasoduodenal infusion. Donor FMT was well tolerated, and infection-related adverse events did not seem to be related to the FMT procedure. In 10 of 15 study participants, a complete clinical response was observed within 1 month after FMT, without additional interventions to alleviate GvHD symptoms. This response was accompanied by an increase in gut microbial α-diversity, a partial engraftment of donor bacterial species, and increased abundance of butyrate-producing bacteria, including Clostridiales and Blautia species. In 6 of the 10 responding donor FMT recipients, immunosuppressant drug therapy was successfully tapered. Durable remission of steroid-refractory or steroid-dependent GvHD after donor FMT was associated with improved survival at 24 weeks after donor FMT. This study highlights the potential of donor FMT as a treatment for steroid-refractory or steroid-dependent GvHD, but larger clinical trials are needed to confirm the safety and efficacy of this procedure.

Donor fecal microbiota transplantation ameliorates intestinal graft-versus-host disease in allogeneic hematopoietic cell transplant recipients

Chronic stress disrupts immune homeostasis while gut microbiota-derived metabolites attenuate inflammation, thus promoting resilience to stress-induced immune and behavioral abnormalities. There are both peripheral and brain region-specific maladaptations of the immune response to chronic stress that produce interrelated mechanistic considerations required for the design of novel therapeutic strategies for prevention of stress-induced psychological impairment. This study shows that a combination of probiotics and polyphenol-rich prebiotics, a synbiotic, attenuates the chronic-stress induced inflammatory responses in the ileum and the prefrontal cortex promoting resilience to the consequent depressive- and anxiety-like behaviors in male mice. Pharmacokinetic studies revealed that this effect may be attributed to specific synbiotic-produced metabolites including 4-hydroxyphenylpropionic, 4-hydroxyphenylacetic acid and caffeic acid. Using a model of chronic unpredictable stress, behavioral abnormalities were associated to strong immune cell activation and recruitment in the ileum while inflammasome pathways were implicated in the prefrontal cortex and hippocampus. Chronic stress also upregulated the ratio of activated proinflammatory T helper 17 (Th17) to regulatory T cells (Treg) in the liver and ileum and it was predicted with ingenuity pathway analysis that the aryl hydrocarbon receptor (AHR) could be driving the synbiotic's effect on the ileum's inflammatory response to stress. Synbiotic treatment indiscriminately attenuated the stress-induced immune and behavioral aberrations in both the ileum and the brain while in a gut-immune co-culture model, the synbiotic-specific metabolites promoted anti-inflammatory activity through the AHR. Overall, this study characterizes a novel synbiotic treatment for chronic-stress induced behavioral impairments while defining a putative mechanism of gut-microbiota host interaction for modulating the peripheral and brain immune systems.

Microbiota metabolites modulate the T helper 17 to regulatory T cell (Th17/Treg) imbalance promoting resilience to stress-induced anxiety- and depressive-like behaviors

Effects of polysaccharides from bee collected pollen of Chinese wolfberry on immune response and gut microbiota composition in cyclophosphamide-treated mice

Associations of the gut microbiome and clinical factors with acute GVHD in allogeneic HSCT recipients.

Animal models have indicated that intestinal microbiota influence acute graft-versus-host disease (aGVHD) by modulating immune homeostasis. But, in humans, the mechanism by which the microbiota induces aGVHD remains unclear. In this study, we investigated the relationship between the intestinal microbiota and T cell subsets in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) to explore the mechanism by which microbiota induced aGVHD. Based on aGVHD, this study was categorized into two groups: grades II-IV aGVHD (aGVHD group, n = 32) and grade 0-I aGVHD (non-aGVHD group, n = 49). The intestinal microbiota was detected by 16S rRNA gene sequencing, and the T cell subsets and histone 3 (H3) acetylation in CD4+ T cells in the peripheral blood was assayed by flow cytometry at the time of engraftment. The aGVHD group had greater low microbial diversity than the non-aGVHD group (56.3 versus 24.5%, p = 0.004). The bacterial community was depleted of Clostridia (e.g., the Lachnospiraceae and Ruminococcaceae families) and enriched for Gammaproteobacteria (e.g., the Enterobacteriaceae family) in the aGVHD group compared with the non-aGVHD group. The relative abundance of Lachnospiraceae and Ruminococcaceae was positively correlated with the Treg/Th17 ratio counts (r = 0.469 and 0.419; p < 0.001 and <0.001, respectively), whereas Enterobacteriaceae was negatively correlated with the Treg/Th17 ratio (r = -0.277; p = 0.012). The level of acetylated H3 in CD4+ T cells was not only correlated with Lachnospiraceae/Ruminococcaceae, but also with the Treg/Th17 ratio (r = 0.354; p = 0.001). In conclusions, our results suggest that decreased Lachnospiraceae and Ruminococcaceae and increased Enterobacteriaceae, correlate with a Treg/Th17 imbalance, which might be through acetylated H3 in CD4+ T cells. These findings suggest that intestinal microbiota might induce aGVHD by influencing the Treg/Th17 balance.

/pdf/intestinal-microbiota-at-engraftment-influence-acute-graft-32vmjab90r.pdf

Intestinal Microbiota at Engraftment Influence Acute Graft-Versus-Host Disease via the Treg/Th17 Balance in Allo-HSCT Recipients.

Intestinal Microbiota Can Predict Acute Graft-versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

Background: The intestinal microbiome plays an important role in the development of acute graft-versus-host disease (aGVHD). However, it is not well known whether the intestinal microbiota at neutrophil engraftment could predict the occurrence and grades of aGVHD. 

Methods: We collected stool and blood samples from 141 patients undergoing allogeneic hematopoietic stem cell transplantation. The microbiota, the inflammatory factors and T lymphocyte subsets were detected at pre-conditioning, day 0 and day 15 post-transplantation. The abundance of bacterial that could predict aGVHD and diversity were included in accumulated intestinal microbiota (AIM) score.  

Findings: We found microbiota diversity was associated with conditioning (P = 0.017, day 0 and P = 0.045, day 15) and β-lactam antibiotics (P = 0.004, day 15). Treg/Th17 ratio was positively correlated with microbial diversity (r = 0.216, P = 0.010), while it was negatively correlated with levels of TNF-α, IL-17A, IL-1β and LPS in plasma (r = -0.226, -0.225, -0.335, -0.291; P = 0.007, 0.010, < 0.001, < 0.001, respectively) at day 15. The accumulated intestinal microbiota (AIM) score at day 15 could be a predictor for the development of aGVHD (II-IV aGVHD: AUC = 0.75, P < 0.001; III-IV aGVHD: AUC = 0.84, P < 0.001). AIM score was also correlated with aGVHD grades (r = 0.481, P < 0.001).  

Interpretations: These findings suggest intestinal microbiota and conditioning might induce aGVHD by inflammatory factors and influence Treg/Th17 balance. The constitution of the intestinal microbiota at neutrophil engraftment may predict the development and grades of aGVHD.  

Funding: This work was funded by the National Natural Science Foundation of China (Nos. U1401221, 81770190, 81870144, 81600141, 81700176, and 81470349), the National primary research plan (Nos. 2017YFA105500 and 2017YFA105504). Science and Technology Major Planning Project of Guangdong Province (2014B020226004), Natural Science Foundation of Guangdong Province (No.2016A030310390), and Medical Science and Technology Planning Project of Henan Province (201403227). 

Declaration of Interest: The authors declare no competing financial interests.

Ethical Approval: This study was approved by the ethical committee of the Nanfang Hospital, Southern Medical University, China. After approval of the study, the consent of the participants was signed for biospecimen collection and analysis. This study was conducted in accordance with the Declaration of Helsinki.

Intestinal Microbiota Can Predict aGVHD Following Allogeneic Hematopoietic Stem Cell Transplantation

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Intestinal Microbiota at Engraftment Influence Acute Graft-Versus-Host Disease via the Treg/Th17 Balance in Allo-HSCT Recipients.

Intestinal Microbiota Can Predict Acute Graft-versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

Intestinal Microbiota Can Predict aGVHD Following Allogeneic Hematopoietic Stem Cell Transplantation