Microbe-mediated intestinal NOD2 stimulation improves linear growth of undernourished infant mice

Abstract

The intestinal microbiota is known to influence postnatal growth. We previously found that a strain of Lactiplantibacillus plantarum (strain Lp WJL ) buffers the adverse effects of chronic undernutrition on the growth of juvenile germ-free mice. Here, we report that Lp WJL sustains the postnatal growth of malnourished conventional animals and supports both insulin-like growth factor–1 (IGF-1) and insulin production and activity. We have identified cell walls isolated from Lp WJL , as well as muramyl dipeptide and mifamurtide, as sufficient cues to stimulate animal growth despite undernutrition. Further, we found that NOD2 is necessary in intestinal epithelial cells for Lp WJL -mediated IGF-1 production and for postnatal growth promotion in malnourished conventional animals. These findings indicate that, coupled with renutrition, bacteria cell walls or purified NOD2 ligands have the potential to alleviate stunting.

Peptidoglycan-induced modulation of metabolic and inflammatory responses

“…In contrast, NOD1 signaling negatively influences metabolic disease. The protective role for NOD2 and recognition of peptidoglycan fragments in metabolic disease is also supported by experiments in a mouse model of malnutrition that found that oral gavage with live Lactiplantibacillus plantarum or cell wall isolates enhanced the weight gain and growth of the mice in a NOD2-dependent manner despite the nutrient restriction [86] . Using tissue-specific knockout mice, the impact of L. plantarum was determined to be mediated by NOD2 expression in intestinal epithelial cells (IEC), and IEC-specific MyD88 −/− mice still showed increased growth and weight gain in response to L. plantarum ruling out a role of TLR signaling [86] .…”

“…The protective role for NOD2 and recognition of peptidoglycan fragments in metabolic disease is also supported by experiments in a mouse model of malnutrition that found that oral gavage with live Lactiplantibacillus plantarum or cell wall isolates enhanced the weight gain and growth of the mice in a NOD2-dependent manner despite the nutrient restriction [86] . Using tissue-specific knockout mice, the impact of L. plantarum was determined to be mediated by NOD2 expression in intestinal epithelial cells (IEC), and IEC-specific MyD88 −/− mice still showed increased growth and weight gain in response to L. plantarum ruling out a role of TLR signaling [86] . Although the exact link between NOD2 signaling in IEC and weight gain are not fully elucidated, the study found an increase in type I interferon production and increased responsiveness of the liver to growth hormone leading to increased insulin-like growth factor 1 production [86] .…”

“…Using tissue-specific knockout mice, the impact of L. plantarum was determined to be mediated by NOD2 expression in intestinal epithelial cells (IEC), and IEC-specific MyD88 −/− mice still showed increased growth and weight gain in response to L. plantarum ruling out a role of TLR signaling [86] . Although the exact link between NOD2 signaling in IEC and weight gain are not fully elucidated, the study found an increase in type I interferon production and increased responsiveness of the liver to growth hormone leading to increased insulin-like growth factor 1 production [86] . Weight gain is not only impacted by NOD2 signaling in the intestine but studies looking at a lack of NOD2 expression in inhibitory γ-aminobutyric acid transporter-positive (GABAergic) neurons found increased weight gain and poor temperature regulation in older female mice [87] .…”

Non-invasive Analysis of Peptidoglycan from Living Animals

“…Recent evidence has revealed that bacterial cell walls are, in fact, biologically active agents to their host organisms ( Figure 1A ). 6-8…”

“…8,27 Critically the health effects were not limited to peptidoglycan fragments; the administration of purified bacterial sacculi from Lactobacillus plantarum ( L. plantarum ) led to significant growth improvement in undernourished mice. 6 Additionally, the impact of sacculi on host biology may not be confined to interactions in the GI tract. Radiolabeled sacculi that were orally administered to mice translocated to the circulatory system and led to subsequent systemic dissemination.…”