Pathologic Inflammation in Malnutrition Is Driven by Proinflammatory Intestinal Microbiota, Large Intestine Barrier Dysfunction, and Translocation of Bacterial Lipopolysaccharide

Abstract

Acute malnutrition, or wasting, is implicated in over half of all deaths in children under five and increases risk of infectious disease. Studies in humans and preclinical models have demonstrated that malnutrition is linked to an immature intestinal microbiota characterized by increased prevalence of Enterobacteriaceae. Observational studies in children with moderate acute malnutrition (MAM) have also observed heightened systemic inflammation and increased circulating bacterial lipopolysaccharides (LPS; endotoxin). However, the mechanisms that underpin the systemic inflammatory state and endotoxemia, and their pathophysiological consequences, remain uncertain. Understanding these pathophysiological mechanisms is necessary to design targeted treatments that will improve the unacceptable rate of failure or relapse that plague current approaches. Here we use a mouse model of MAM to investigate the mechanisms that promote inflammation in the malnourished host. We found that mice with MAM exhibited increased systemic inflammation at baseline, increased translocation of bacteria and bacterial LPS, and an exaggerated response to inflammatory stimuli. An exaggerated response to bacterial LPS was associated with increased acute weight loss. Remarkably, intestinal inflammation and barrier dysfunction was found in the cecum and colon. The cecum showed a dysbiotic microbiota with expansion of Gammaproteobacteria and some Firmicutes, and contraction of Bacteroidetes. These changes were paralleled by an increase in fecal LPS bioactivity. The inflammatory phenotype and weight loss was modulated by oral administration of non-absorbable antibiotics that altered the proportion of cecal Gammaproteobacteria. We propose that the heightened inflammation of acute malnutrition is the result of changes in the intestinal microbiota, intestinal barrier dysfunction in the cecum and colon, and increased systemic exposure to LPS.

Inflammatory stimuli alter bone marrow composition and compromise bone health in the malnourished host

“…Recently, we demonstrated an increase in basal inflammatory cytokines, impaired intestinal barrier function, circulating endotoxin, and an exaggerated response to inflammatory stimuli in children with MAM ( 10 ). Similar features are reported in our studies in a mouse model that mimics the features of MAM ( 11 ). These features were associated with the development of a proinflammatory intestinal microbiota.…”

“…Therefore, we used an established mouse model of MAM ( 37 – 41 ) to investigate the impact of an acute infectious or inflammatory challenge on bone marrow and bone health. In this model, malnutrition led to systemic inflammation, impaired intestinal barrier function, circulating endotoxin, and an exaggerated response to inflammatory stimuli that promoted weight loss ( 11 ). Here we show that malnutrition also conditions the bone marrow for an altered response to 2 different inflammatory stimuli.…”

Malnutrition-related parasite dissemination from the skin in visceral leishmaniasis is driven by PGE2-mediated amplification of CCR7-related trafficking of infected inflammatory monocytes

“…However, there are likely other contributors to parasite dissemination in the malnourished mice since we observed that splenic infection was not completely abrogated when CCR7-deficient monocytes were transferred to the dermal site of infection. Collectively, these data indicate that parasite-induced production of PGE 2 , which is part of an exaggerated inflammatory response in the malnourished host [ 70 , 71 ], amplifies CCR7-dependent trafficking of parasite-bearing inflammatory monocytes to the visceral organs. In contrast, PGE 2 -mediated enhancement of the infection in neutrophils was localized and did not influence L .…”

Aging-Accelerated Mouse Prone 8 (SAMP8) Mice Experiment and Network Pharmacological Analysis of Aged Liupao Tea Aqueous Extract in Delaying the Decline Changes of the Body

“…The ratio of Firmicutes to Bacteroidota (F/B) is an important indicator to describe the structure of intestinal flora. The high-fat diet promotes the production of LPS and increases the F/B ratio [ 68 , 69 , 70 ]. Clinical studies have shown that the abundance of Bacteroidota in the intestinal bacteria of the elderly is reduced [ 71 , 72 ].…”