The study shows the potential use of delayed-release nicotinic acid in improving the gut microbiota and insulin resistance, subsequently reducing the risk of prediabetes and diabetes. The modified niacin was able to reach the ileocolonic site intact and influencing microbiome by enhancing its α-diversity and abundance of Bacteroidetes. More research to come regarding gut flora–insulin resistance–diabetes axis.
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Diabetes Care
Cohort
March 2018
Objective
Gut microbiota represent a potential novel target for future prediabetes and type 2 diabetes therapies. In that respect, niacin has been shown to beneficially affect the host-microbiome interaction in rodent models.
Methods
We characterized more than 500 human subjects with different metabolic phenotypes regarding their niacin (nicotinic acid [NA] and nicotinamide [NAM]) status and their gut microbiome. In addition, NA and NAM delayed-release microcapsules were engineered and examined in vitro and in vivo in two human intervention studies (bioavailability study and proof-of-concept/safety study).
Results
We found a reduced α-diversity and Bacteroidetes abundance in the microbiome of obese human subjects associated with a low dietary niacin intake. We therefore developed delayed-release microcapsules targeting the ileo-colonic region to deliver increasing amounts of NA and NAM to the microbiome while preventing systemic resorption to avoid negative side effects (e.g., facial flushing). In vitro studies on these delayed-release microcapsules revealed stable conditions at pH 1.4, 4.5, and 6.8, followed by release of the compounds at pH 7.4, simulating the ileocolonic region.
In humans in vivo, gut-targeted delayed-release NA but not NAM produced a significant increase in the abundance of Bacteroidetes. In the absence of systemic side effects, these favorable microbiome changes induced by microencapsulated delayed-release NA were associated with an improvement of biomarkers for systemic insulin sensitivity and metabolic inflammation.
Conclusion
Targeted microbiome intervention by delayed-release NA might represent a future therapeutic option for prediabetes and type 2 diabetes.
More from the publication:
Rather than being viewed as simple commensals, the gut microbiome is now seen as playing an active role in the control of energy homeostasis and in the mediation of the adverse consequences of obesity. Several studies in the recent past in humans and rodents revealed that obesity is associated with a reduction in Bacteroidetes and with a lower diversity compared with healthy and lean subjects. Of physiological relevance, the composition of the gut microbiota can be altered by diet, because weight loss interventions have been reported to influence the abundance of Bacteroidetes and the overall microbial diversity.
Administration of niacin (nicotinic acid [NA] and nicotinamide [NAM]) has been shown to beneficially effect the host-microbiome interaction in a mouse model. Beneficial effects of niacin on both the gut microbiome and systemic glucose metabolism suggest this micronutrient is an interesting candidate for future targeted microbiome interventions (e.g., to prevent manifestation of type 2 diabetes from prediabetes). However, because the upper gastrointestinal tract efficiently resorbs soluble micronutrients, simply increasing the NA and/or NAM nutritional load would not be expected to deliver these molecules into the ileocolonic region, where most of the microbiome is located.
The aim of the current study was therefore
1) to examine NA and NAM in humans in relation to obesity and the gut phylogenome in a large human cohort of >500 well-characterized individuals and
2) to use a microencapsulation procedure to develop a novel delayed-release system to deliver significant amounts of NA and NAM into the human colon to beneficially affect the gut microbiome and systemic metabolism while preventing systemic side effects.
Several studies have reported the effect of the nutritional load and dietary patterns on the composition of the gut microbiome; however, to the best of our knowledge, our observation connecting niacin micronutrition and the human gut microbiome is novel. The positive correlations of niacin intake and niacin serum concentrations with α-diversity as well as the Bacteroidetes abundance suggest a favorable effect of niacin on the human gut microbial composition. We tested this hypothesis by developing delayed-release NA and NAM microcapsules to deliver increasing amounts of the micronutrients into the ileocolonic region.
As reviewed by Pišlar et al. in 2015, the median time of gastric emptying after ingestion of nondisintegrating tablets is ∼35 min, the small intestine transit time is 215 min (minimum–maximum 60–544), and the colon arrival time is 254 min or 4 hours (minimum–maximum 117–604). Thus our bioavailability curves with serum peak levels after 4−8 h indeed suggest a pH-dependent release of NA and NAM in the ileocolonic region. The dosage with our novel niacin formulations did not result in any severe safety signals according to laboratory parameters, and no flush phenomenon or clinical symptoms were observed.
In the current study, we found that the effect on the Bacteroidetes abundance and the systemic metabolism is specific to microencapsulated NA, whereas no effect was seen for any form of the NAM formulations. In this respect, it is important to mention that bacteria have been classified by virtue of their ability to synthesize NAD de novo from aspartic acid and/or the vitamin precursors NAM, NA, and NR. Therefore, the ability to use NAM was predicted on the basis of possession of homologs of nicotinamidase (PncA) and nicotinamide phosphoribosyltransferase (NadV).
Remarkably, Bacteroidetes were reported to be deficient in both genes, resulting in the inability to metabolize NAM. This finding explains the specificity of the increase in Bacteriodetes abundance to the delayed-release NA intervention found in our study.
Note that the proof-of-concept and safety study reported here represents the equivalent of a phase 1 clinical trial and was therefore performed in healthy human volunteers showing no major insulin resistance. The HOMA index was normal in those subjects at the beginning and did not significantly change within the normal range during the intervention. However, we point out that this finding does not argue against an effect of microencapsulated NA on systemic insulin sensitivity, because independent researchers have shown that even a metformin therapy over a period of 6 months does not further improve a normal HOMA in nonobese subjects. In addition, the HOMA index is not known to detect early stages of insulin resistance; therefore, the emphasis has recently shifted toward myokines and hepatokines as alternative clinical biomarkers for skeletal muscle and liver insulin resistance. Myostatin is expressed in skeletal muscle and is causally involved in muscle insulin resistance, because myostatin-null mice are protected from insulin resistance induced by diet-induced obesity. In humans, myostatin plasma levels have been shown to be strongly correlated to insulin resistance.
In summary, in the current study we present evidence
1) that the reduced α-diversity and Bacteroidetes abundance found in obese subjects is associated with a lower dietary niacin intake and
2) that a gut-targeted NA supplementation by delayed-release microcapsules is able to beneficially affect the microbiome and the systemic insulin sensitivity.