Investigating the association between diet-induced “leaky gut” and the development of prediabetes.
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Date
2023
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Abstract
Introduction
Type 2 diabetes (T2D) is the most common type of diabetes mellitus, which is reported to be associated
with life-threatening co-morbidities. This condition is characterized by hyperglycaemia due to a defect
of the insulin receptor, and its often preceded by prediabetes. Chronic consumption of a calorie diets is
the primary cause of T2D, and this diet has been associated with altered intestinal permeability in
diabetic patient. However, it remains unknown whether increased intestinal permeability complications
begin in the prediabetic state. Previous studies done in our laboratory developed a high-fat high
carbohydrate (HFHC) diet-induced prediabetic animal model, using male Sprague Dawley rats. This
model was found to mimic the human condition of prediabetes. In this model, the animals develop
prediabetes after 20 weeks of ingesting a HFHCdiet. Using this HFHC diet-induced animal model of
prediabetes, this study sought to investigate the changes on gut microbiota and the association between
prediabetes and markers associated with intestinal permeability. Furthermore, this study sought to
investigate changes in concentration level of markers associated with a leaky gut and glucose
homeostasis, following change to a low carbohydrate, high unsaturated fat (LCHUF) diet.
Method and Materials
12 male Sprague Dawley rats (3 weeks old) were randomly assigned into the non-prediabetic group and
diet-induced prediabetic group (n=6). Group A animals were exposed to a standard diet with normal
drinking water for 20 weeks, and group B animals were exposed to a HFHC diet supplemented with
15% fructose for a period of 20 weeks. After 20 weeks, the American Diabetes Association criteria for
diagnosis of prediabetes was used to diagnose prediabetes in all animals. The fecal samples were
analyzed to measure the gut microbiota composition of Firmicutes, Bacteroidetes, and Proteobacteria
in both animal groups. Furthermore, blood glucose, plasma insulin, serum zonulin, plasma
lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor-alpha (TNF-α), interleukin-6
(IL-6), C-reactive protein (CRP), and intestinal fatty-acid binding protein (IFABP) concentrations were
measured. The first manuscript measured all these parameters at 20 weeks.
In the second manuscript, 12 male Sprague Dawley rats were used and fed a HFHC diet for 20 weeks.
The prediabetic animals were subdivided into two groups. Group A animals remained on the HFHC
diet (the prediabetic control group), while the other 6 animals in group B were switched to a low
carbohydrate, high unsaturated fat (LCHUF) diet. Group B was then categorized as the prediabetic
group that had dietary intervention (PD+DI). All animals were then maintained on their respective
diets and monitored for further 12 weeks. The fecal samples were analyzed to measure the gut
microbiota composition of Firmicutes, Bacteroidetes, and Proteobacteria in both animal groups.
Furthermore, blood glucose, glycated haemoglobin (HbA1c), serum zonulin, plasma LPS, sCD14, TNFxvii
α, IL-6, CRP, and IFABP concentrations were measured. The second manuscript measured all these parameters at
32 weeks.
Results and Discussion
Prolonged consumption of a HFHC diet results in the development of prediabetes. This was evidenced
by a significant increase in fasting blood glucose and plasma insulin in the prediabetic animals
compared to the non-prediabetic animals. The HFHC diet also showed to dysregulate the gut microbiota
causing gut dysbiosis which enhances translocation of endotoxins from the gut lumen into the
bloodstream that elicits an inflammatory response. In the prediabetic group (PD), there was a reduction
in the Firmicutes levels and an increase in Bacteroidetes and Proteobacteria compared to the nonprediabetic
group (NPD). Serum zonulin, plasma sCD14, TNF-α, IL-6, CRP, and IFABP concentrations
in the PD group were increased compared to the NPD group, while plasma LPS concentrations were
similar. The low-grade inflammation that is observed in the prediabetic state is suggested to further
progresses onset of prediabetes. However, to reverse prediabetes and to combat a leaky gut problem,
the second manuscript illustrated that switching to a LCHUF diet can effectively improve glucose
homeostasis thus reverse prediabetes. This was evidenced by a significant decrease in fasting blood
glucose and HbA1c concentration. These results were accompanied by a decrease of Firmicutes and an
increase of Bacteroidetes and Proteobacteria suggesting that a LCHUF diet effectively improved gut
microbiome composition. This caused the release of serum zonulin and its effect on disassembling the
tight junctions to decrease. This was evidenced by a decrease in plasma LPS and sCD14 concentration.
In addition, we also observed a decrease in plasma TNF-α, IL-6, CRP, and IFABP indicating another
beneficial effect of this diet on reducing intestinal inflammation, and risks of insulin resistance.
Conclusion
Taken together, these results suggest that chronic consumption of the HFHC diet may be associated
with the dysregulation of gut microbiota, leading to increased intestinal permeability. This could be
associated with chronic subclinical inflammation that have been reported to result in the development
of insulin resistance in the pre-diabetic stage. In addition, a LCHSF diet markedly improved intestinal
permeability as well as the glucose regulation
Description
Masters Degree. University of KwaZulu-Natal, Durban.