Restoring Specific Lactobacilli Levels Decreases Inflammation and Muscle Atrophy Markers in an Acute Leukemia Mouse Model

Abstract

The gut microbiota has recently been proposed as a novel component in the regulation of host homeostasis and immunity. We have assessed for the first time the role of the gut microbiota in a mouse model of leukemia (transplantation of BaF3 cells containing ectopic expression of Bcr-Abl), characterized at the final stage by a loss of fat mass, muscle atrophy, anorexia and inflammation. The gut microbial 16S rDNA analysis, using PCR-Denaturating Gradient Gel Electrophoresis and quantitative PCR, reveals a dysbiosis and a selective modulation of Lactobacillus spp. (decrease of L. reuteri and L. johnsonii/gasseri in favor of L. murinus/animalis ) in the BaF3 mice compared to the controls. The restoration of Lactobacillus species by oral supplementation with L. reuteri 100-23 and L. gasseri 311476 reduced the expression of atrophy markers (Atrogin-1, MuRF1, LC3, Cathepsin L) in the gastrocnemius and in the tibialis, a phenomenon correlated with a decrease of inflammatory cytokines (interleukin-6, monocyte chemoattractant protein-1, interleukin-4, granulocyte colony-stimulating factor, quantified by multiplex immuno-assay). These positive effects are strain- and/or species-specific since L. acidophilus NCFM supplementation does not impact on muscle atrophy markers and systemic inflammation. Altogether, these results suggest that the gut microbiota could constitute a novel therapeutic target in the management of leukemia-associated inflammation and related disorders in the muscle.

Muscle wasting: The gut microbiota as a new therapeutic target?

“…Lactobacilli beneficial effect seems to be bacterial strain-or species-dependent. Indeed, administration of L. acidophilus NCFM to leukemic mice with cachexia did not reduce systemic inflammation and muscle atrophy markers (Bindels et al, 2012). Whether the anti-atrophy effect of specific lactobacilli are directly dependent on their immunomodulatory properties remains to be determined.…”

“…Levels of caecal Lactobacillus spp., a bacterial genus known for its immunomodulatory properties, were decreased. Lactobacilli species were differentially affected: L. reuteri and L. gasseri/johnsonii were decreased whereas L. murinus/animalis remained unaffected (Bindels et al, 2012). Interestingly, restoring gut lactobacilli by oral supplementation with L. reuteri 100-23 and L. gasseri 311476 reduced the levels of systemic inflammatory cytokines, such as interleukin (IL)-6, IL-4 and monocyte chemoattractant protein (MCP)-1.…”

“…Probiotics, as defined by the Food and Agriculture Organization of the United Nations, are live microorganisms, which, when administered in adequate amount, confer a health benefit on the host (Delzenne and Cani, 2011). For example, we described earlier how specific lactobacilli given as oral probiotics may arouse full interest in cancer cachexia, at least in mice (Bindels et al, 2012). In a double-blind randomized controlled trial, ready-to-use therapeutic food was administered to Malawian children with severe acute malnutrition.…”

The intestinal microbiota, energy balance, and malnutrition: emphasis on the role of short-chain fatty acids

“…In a mouse model for leukemia-induced cachexia, a decrease in Lactobacillus reuteri and L. gasseri was shown compared to healthy controls. Interestingly, supplementation of these Lactobacillus species resulted in a reduction in atrophy markers and inflammatory cytokines [78].…”

Unlocking the wasting enigma: Highlights from the 8th Cachexia Conference

“…A microbial signature common in both mouse models including the Entero‐bacteriaceae family/Escherichia genus, Lactobacillus genus and Parabacteroides goldsteinii/ASF 519 species were presented. Interestingly, a highly significant negative correlation was found between the level of lactobacilli in the cecal content and the atrophy marker expression in the gastrocnemius muscle (Atrogin‐1, MurF1, LC3 and Cathepsin L) 9. Moreover, they impressively demonstrated that cancer cachexia was associated with profound alterations of the gut microbiota in two animal models.…”