A Gut Instinct on Leukaemia: A New Mechanistic Hypothesis for Microbiota-Immune Crosstalk in Disease Progression and Relapse

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Abstract

Despite significant advances in the treatment of Chronic Myeloid and Acute Lymphoblastic Leukaemia (CML and ALL, respectively), disease progression and relapse remain a major problem. Growing evidence indicates the loss of immune surveillance of residual leukaemic cells as one of the main contributors to disease recurrence and relapse. More recently, there was an appreciation for how the host’s gut microbiota predisposes to relapse given its potent immunomodulatory capacity. This is especially compelling in haematological malignancies where changes in the gut microbiota have been identified after treatment, persisting in some patients for years after the completion of treatment. In this hypothesis-generating review, we discuss the interaction between the gut microbiota and treatment responses, and its capacity to influence the risk of relapse in both CML and ALL We hypothesize that the gut microbiota contributes to the creation of an immunosuppressive microenvironment, which promotes tumour progression and relapse.

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Role of the microbiota in immunity and inflammation.

Yasmine Belkaid, Timothy Hand (2014)

The microbiota plays a fundamental role on the induction, training, and function of the host immune system. In return, the immune system has largely evolved as a means to maintain the symbiotic relationship of the host with these highly diverse and evolving microbes. When operating optimally, this immune system-microbiota alliance allows the induction of protective responses to pathogens and the maintenance of regulatory pathways involved in the maintenance of tolerance to innocuous antigens. However, in high-income countries, overuse of antibiotics, changes in diet, and elimination of constitutive partners, such as nematodes, may have selected for a microbiota that lack the resilience and diversity required to establish balanced immune responses. This phenomenon is proposed to account for some of the dramatic rise in autoimmune and inflammatory disorders in parts of the world where our symbiotic relationship with the microbiota has been the most affected. Copyright © 2014 Elsevier Inc. All rights reserved.

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Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation

Nicholas Arpaia, Clarissa Campbell, Xiying Fan … (2014)

Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T (Treg) cells expressing transcription factor Foxp3 play a key role in limiting inflammatory responses in the intestine 1 . Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory Th17 cells 2-6 , the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we hypothesized that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We found that a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg cell numbers upon provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells as the observed phenomenon was dependent upon intronic enhancer CNS1, essential for extrathymic, but dispensable for thymic Treg cell differentiation 1, 7 . In addition to butyrate, de novo Treg cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of HDAC inhibition, but not acetate, lacking this activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.

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Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

Seth Rakoff-Nahoum, Justin Paglino, Fatima Eslami-Varzaneh … (2004)

Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.