Gut Microbiome, Intestinal Permeability, and Tissue Bacteria in Metabolic Disease: Perpetrators or Bystanders?

Abstract

The emerging evidence on the interconnectedness between the gut microbiome and host metabolism has led to a paradigm shift in the study of metabolic diseases such as obesity and type 2 diabetes with implications on both underlying pathophysiology and potential treatment. Mounting preclinical and clinical evidence of gut microbiota shifts, increased intestinal permeability in metabolic disease, and the critical positioning of the intestinal barrier at the interface between environment and internal milieu have led to the rekindling of the “leaky gut” concept. Although increased circulation of surrogate markers and directly measurable intestinal permeability have been linked to increased systemic inflammation in metabolic disease, mechanistic models behind this phenomenon are underdeveloped. Given repeated observations of microorganisms in several tissues with congruent phylogenetic findings, we review current evidence on these unanticipated niches, focusing specifically on the interaction between gut permeability and intestinal as well as extra-intestinal bacteria and their joint contributions to systemic inflammation and metabolism. We further address limitations of current studies and suggest strategies drawing on standard techniques for permeability measurement, recent advancements in microbial culture independent techniques and computational methodologies to robustly develop these concepts, which may be of considerable value for the development of prevention and treatment strategies.

Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice

“…Mounting preclinical and clinical evidence has highlighted the critical role of the intestinal barrier and gut microbiota in metabolic disease, which has led to the revival of the "leaky gut" concept. 33 Therefore, targeting and restoring intestinal barrier function is a tempting therapeutic approach, even though no clinical therapies currently exist. Recent advances have proposed restoring or regenerating barrier integrity by using intestinal stem cells as a therapy for repairing damaged intestinal mucosa.…”

NLRP3 inflammasome deficiency attenuates metabolic disturbances involving alterations in the gut microbial profile in mice exposed to high fat diet

“…The elevated levels of LPS, which were attenuated during NLRP3 deficiency, further support such a notion. Similarly, intestinal permeability and bacterial translocation are important contributors to chronic systemic inflammation and, might represent a continuous inflammatory stimulus capable of immune processes [60][61][62] . These findings could also be relevant for patients with CVD.…”

Immunologic Effects of Vitamin D on Human Health and Disease

“…Moreover, 1,25(OH) 2 D induces the production and secretion of antimicrobial peptides by the intestinal epithelial cells, Paneth cells, and intraepithelial lymphocytes [ 47 , 48 ]. These result in limitation of gut bacterial translocation into the interstitium and maintenance of intestinal homeostasis, which are believed to involve in the pathogenesis of multiple autoinflammatory and metabolic disorders [ 49 , 50 ].…”