Gut microbiota, probiotics and diabetes

Abstract (provisional)

Diabetes is a condition of multifactorial origin, involving several molecular mechanisms related to the intestinal microbiota for its development. In type 2 diabetes, receptor activation and recognition by microorganisms from the intestinal lumen may trigger inflammatory responses, inducing the phosphorylation of serine residues in insulin receptor substrate-1, reducing insulin sensitivity. In type 1 diabetes, the lowered expression of adhesion proteins within the intestinal epithelium favours a greater immune response that may result in destruction of pancreatic beta cells by CD8+ T-lymphocytes, and increased expression of interleukin-17, related to autoimmunity. Research in animal models and humans has hypothesized whether the administration of probiotics may improve the prognosis of diabetes through modulation of gut microbiota. We have shown in this review that a large body of evidence suggests probiotics reduce the inflammatory response and oxidative stress, as well as increase the expression of adhesion proteins within the intestinal epithelium, reducing intestinal permeability. Such effects increase insulin sensitivity and reduce autoimmune response. However, further investigations are required to clarify whether the administration of probiotics can be efficiently used for the prevention and management of diabetes.

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Alex’s Notes: Hippocrates once stated, “All diseases begin in the gut.” Given that the human gut is home to ten times more bacteria than there are cells in our bodies, with over 400 known species, I don’t believe that statement is hyperbole. We know the gut microbiome has an intimate connection with our health and wellbeing, and that many dietary, lifestyle, and environmental factors influence its composition. As we continue to learn more and more about this mysterious world, we try to take advantage of it. Probiotic supplementation, for instance, has shown to benefit the insulin sensitivity of type-2 diabetics (T2D). Yet, this is just one more form of supplementation to offset things that can ultimately be prevented by proper diet and lifestyle choices. Still though, it makes you wonder just how effective probiotic therapy is in helping people, and this review aims to do just that on diabetics.

The guts of diabetics are different then the guts of healthy people, notably in the ratio of various bacterial species. Specifically, diabetics have lower counts of bacteria associated with anti-inflammatory properties (Bifidobacterium & Faecalibacterium). This shouldn’t be surprising, as numerous studies have demonstrated the link between the development of metabolic diseases such as obesity and the gut microbiome. Despite these associations, however, it has yet to be found whether these changes are a result of diabetes or whether they precede it.

One of the common features of all metabolic diseases is a chronic low-grade inflammatory state. Toll-like receptors (TLRs) play an important role in detecting the presence and nature of pathogens to provide a first line of defense against them. They also prompt an inflammatory response. TLR4 is one such receptor that binds to LPS (a compound found in most pathogenic bacteria) to prepare the body for the incoming pathogen. Interestingly, one study showed that injecting healthy adults with LPS induced acute inflammation that resulted in metabolic endotoxemia and systemic insulin resistance. Similarly, clinical trials have shown a relationship between T2D and LPS. One possible explanation is that activation of inflammatory pathways via LPS stimulated TLR4 ultimately leads to hepatic, muscle, and adipose tissue insulin resistance. This brings us full-circle, as diabetics have increased levels of LPS-containing bacteria escape their weakened gut barrier into the blood and continuously stimulate TLR4 to produce a chronic low-grade inflammatory state.

The above suggests that microbial dysfunction of the gut precedes diabetes, but it is actually more of a circular relationship. The diet and lifestyle factors that lead to T2D likely also lead to the changes in the gut that worsen and progress the condition, which in turn leads to a more out-of-balance microbiota that repeats the cycle. In this light, it is interesting to look at type-1 diabetes (T1D) because it is mainly a genetic condition caused by autoimmunity, not diet or lifestyle. Indeed, the influence of intestinal bacteria in the pathogenesis of T1D has been demonstrated. T1D individuals have a weakened intestinal barrier that allows pathogenic compounds such as LPS to enter the blood stream and trigger the same inflammatory responses mentioned in the previous paragraph. The changes in microbiota composition towards the pathogenic bacteria are already noticeable in childhood. Thus, it appears that the chronic inflammation and possibly also the hyperglycemic episodes common in diabetes lead to changes in the gut microbiota that then compound the metabolic disorder in a viscous cycle.

Fortunately, probiotics may hold some promise through mechanisms both related and unrelated to inflammation. One study, for example, found that T2D individuals consuming yogurt with L. acidophilus and B. lactis for six weeks had reduced fasting glucose and HbA1c levels, and increased antioxidant activity than the control groups. But given the benefits of dairy, it could have easily been the yogurt. Of course there is always the study mentioned in the first paragraph. Regardless, these effects may be specific to the strains of bacteria used and likely cannot be extrapolated to other strains or species.

All in all, there is a link between metabolic diseases in general and the gut. And just as I asked at the end of a previous article on the link between the microbiota and cardiometabolic outcomes, why not just stimulate the growth of the good guys from the beginning? Eat smart, train hard. Live longer, live stronger.

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