Abstract
This study aimed to determine the association between non-high-fat diet-induced obesity- (non-DIO-) associated gut microbiome dysbiosis with gut abnormalities like cellular turnover of intestinal cells, tight junctions, and mucin formation that can impact gut permeability. We used leptin-deficient (Lepob/ob) mice in comparison to C57BL/6J control mice, which are fed on identical diets, and performed comparative and correlative analyses of gut microbiome composition, gut permeability, intestinal structural changes, tight junction-mucin formation, cellular turnover, and stemness genes. We found that obesity impacted cellular turnover of the intestine with increased cell death and cell survival/proliferation gene expression with enhanced stemness, which are associated with increased intestinal permeability, changes in villi/crypt length, and decreased expression of tight junctions and mucus synthesis genes along with dysbiotic gut microbiome signature. Obesity-induced gut microbiome dysbiosis is also associated with abnormal intestinal organoid formation characterized with decreased budding and higher stemness. Results suggest that non-DIO-associated gut microbiome dysbiosis is associated with changes in the intestinal cell death versus cell proliferation homeostasis and functions to control tight junctions and mucous synthesis-regulating gut permeability.
Highlights
Increased prevalence of obesity and its associated comorbidities around the world became epidemic, with constant rising rates indicating no successful prevention and therapeutic strategies available
The expression of tight junction proteins like occludin, zonulin-1 (Zo1), and junctional adhesion molecule (Jam), as well as mucin synthesis gene mRNAs (Muc2 and Muc6), was significantly decreased in Lepob/ob mice (Figures 1(b)–1(d)), suggesting that obesity resulting from leptin deficiency decreased expression of tight junction and mucin synthesis genes, which might result to leaky gut with increased permeability
Akkermansia abundance influenced significantly in Metformin- treated patients as well as being known to be reduced in HFDinduced obesity [18, 19], our studies show that abundance of this group of bacteria is increased in Lepob/ob mice, suggesting that depletion of Akkermansia in obese humans might be associated with high fat diet intake
Summary
Increased prevalence of obesity and its associated comorbidities around the world became epidemic, with constant rising rates indicating no successful prevention and therapeutic strategies available This is because of complex pathophysiology of obesity that involves multifaceted interactions of genetics, diet, lifestyle, and environmental factors [1]. It is evident that gut microbiome dysbiosis becomes apparent earlier than measurable host metabolic dysfunctions, suggesting that gut microbiome dysbiosis might be the primary factor involved in the progression of obesity and type 2 diabetes during high fat/calorie diets; contribution of non-high-fat diet-induced obesity (nonDIO) in intestinal dysfunctions and gut microbiome dysbiosis link is not well known. The aim of present study was to define the association among non-DIO- (in Lepob/ob mice) linked gut microbiome dysbiosis with (a) cellular turnover homeostasis and structural maintenance of the intestine and (b) expression of tight junctions and mucus synthesis genes that regulates gut permeability
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