Intestinal Microbiome, Akkermansia muciniphila, and Medical Nutrition Therapy

Abstract

The gastrointestinal microbiome has become a topic of great interest in medicine in recent years. Genomic sequencing can now be done at a fraction of the cost of a few years ago, and this has allowed for the development and compilation of an extensive amount of data related to the species diversity of the human gastrointestinal microbiome.1 Studies have demonstrated that the intestinal microbiome is sensitive to the composition of the diet.2 It is also recognized that the composition of the microbiome can be altered rapidly in response to dietary changes, stress, chemical exposure, and exercise.3 Both the expanded understanding of the composition of the human microbiome and the ability to measure it through genomic analysis of the stool have resulted in clinicians frequently wanting to know what actionable conclusions can be taken away from an analysis of the gastrointestinal microbiome.

The gastrointestinal microbiome has become a topic of great interest in medicine in recent years. Genomic sequencing can now be done at a fraction of the cost of a few years ago, and this has allowed for the development and compilation of an extensive amount of data related to the species diversity of the human gastrointestinal microbiome.1 Studies have demonstrated that the intestinal microbiome is sensitive to the composition of the diet.2 It is also recognized that the composition of the microbiome can be altered rapidly in response to dietary changes, stress, chemical exposure, and exercise.3 Both the expanded understanding of the composition of the human microbiome and the ability to measure it through genomic analysis of the stool has resulted in clinicians frequently wanting to know what actionable conclusions can be taken away from an analysis of the gastrointestinal microbiome.

In 2002, I had the opportunity to meet Professor Marcel Roberfroid, phd, from the Department of Pharmaceutical Sciences at the Catholic University of Louvain in Belgium. Professor Roberfroid conducted research on the synergistic effects of nondigestive fiber (prebiotics) administered with probiotic organisms and he is credited with coining the term synbiotics.4 His work had demonstrated that supplementary doses of the prebiotic fiber inulin, derived from chicory, had a favorable influence on the composition gut microbiome.5 Controlled animal trials in his laboratory demonstrated that supplementation with inulin resulted in improved insulin sensitivity and increased serum glucagon-like peptide 1 (GLP-1).6 These favorable effects were associated with alteration in the gut microbiome, suggesting that gut bacteria may play an important role in the etiology of insulin resistance and type 2 diabetes and potentially obesity.

As Professor Roberfroid neared retirement, Nathalie Delzenne, phd, and Patrice Cani, phd, senior members of his research team, took over the management of his laboratory. In the past 10 years, their work on the role of the microbiome in health and disease has been remarkable in helping to better understand the potential actionable conclusions that can be derived from the analysis of a person’s microbiome.7,8 One key finding has been that the bacterial intestinal microorganism Akkermansia muciniphila plays a very important role in determining the influence of the gut microbiome on human health and also that this organism is sensitive to specific dietary factors.9,10

A muciniphila is an organism in the human microbiome that releases enzymes into the intestinal tract that help to regulate mucin, a major component of the mucous layer that resides on the surface on the gastrointestinal mucosa.11 The composition of this mucous layer and its associated microbiota (sometimes referred to as the biofilm) helps to protect the lining of the intestines—just a single cell in thickness—from injury.12 Damage to the integrity of the biofilm can result in alteration in intestinal permeability, a condition that is now widely described as leaky gut.13 Leaky gut refers to the breakdown of the intercellular junction between the intestinal mucosal cells, which then allows the diffusion of potentially immune-activating substances from the gut contents to have contact with the immune system of the intestinal tract that resides on the interior surface of the intestinal mucosa. The clinical result of this breakdown is activation of the gut-associated immune system into an inflammatory state, which can produce inflammatory disorders of the intestinal tract, as well as trigger systemic inflammation. This process has been termed endotoxicity because the toxic insult to the immune system comes from endogenous factors, including bacteria, endotoxins, and other products of digestion that make up the contents of the intestinal tract.14

In an April 2016 publication, researchers found that in an animal model, A muciniphila protects against endotoxemia-induced inflammation and atherosclerosis.15 The connection between the composition of the gut microbiome and atherosclerosis relates to the increase in systemic inflammation that results in activation of the cell-mediated immune system, which has been identified as one factor in the etiology of the disease.16 A muciniphila has been demonstrated to adhere to the enterocyte cells lining the intestinal tract and strengthen the integrity of this epithelial cell layer, resulting in resistance to leaky gut and activation of the intestinal immune system.17,18 Delzenne and Cani19 have shown that A muciniphila engages in “cross-talk” with the intestinal epithelium in such a way as to help resist obesity through an impact on metabolic regulation. In a human study, it was found that A muciniphila, given as a probiotic supplement, improved metabolic health in obese individuals who were placed on a calorie restricted diet for 6 weeks.20

The mechanism by which A muciniphila improves metabolism and helps to resist endotoxcity and leaky gut is related to its ability to regulate the mucin layer of the biofilm by increasing intestinal levels of endocannabinoids, which in turn regulate the secretion of GLP-1 by specific cells within the small intestine and colon.21 GLP-1 is an incretin hormone that increases insulin sensitivity, protects the insulin producing β-cells of the pancreas from injury, improves adipocyte metabolism, and serves as an anti-inflammatory mediator. The clinical effects of increased GLP-1 secretion include reduction in the risk to obesity, improvement in glucose tolerance, reduction in systemic inflammation, and improvement in lipid metabolism.

In February 2016, researchers from the Broad Institute, Harvard Medical School, the Busan Paik Hospital in South Korea, and other collaborators reported findings from a twin study that indicated that alteration in the gut microbiome and more specifically a decrease in the presence of A muciniphila, was a subclinical biomarker in humans for increased risk of obesity and type 2 diabetes.22

Medical Nutrition Therapy to Improve Microbiome A muciniphila

In 2005, Gibson and Shepherd,23 from the Department of Gastroenterology at Monash University Medical School in Australia, proposed that a diet low in fermentable oligo-, di-, and monosaccharides and polyphenols (FODMAP diet) had the potential to both prevent and treat digestive diseases such as irritable bowel syndrome, inflammatory bowel disease, and Crohn’s disease. Since then, numerous studies involving the FODMAP diet have demonstrated marked effects on the composition of the gut microbiome.24 In 2016, Gibson and Shepherd25 reported that the FODMAP diet resulted in a consistent prebiotic influence on gut microbiota in a randomized, controlled cross-over design trial. In this study, one of the most significant improvements found in the gut microbiomes of people consuming the FODMAP diet was an increase in A muciniphila.

Diets high in prebiotic nondigestible fiber improve the levels of A muciniphila in the microbiome.26 It has also been demonstrated in mice that specific phytochemicals in the diet, such as curcumin and epigallocatechin gallate (EGCG), improve the abundance of A muciniphila in the gut microbiome.27 A recent review of the role of A muciniphila in obesity-linked metabolic diseases from the Quebec Institute of Nutrition and Functional Foods described the importance of phytochemical-rich diets and phytochemical concentrates in increasing A muciniphila and reducing dysbiosis.28

Last, there has been considerable research evaluating the effect of specific probiotic supplements on the abundance of A muciniphila in the microbiome. Recent studies indicate that supplementation with specific multistrain mixtures of probiotic organisms can be helpful.29 This is a very active area of research that is opening a new level of understanding as to how diet, phytochemicals, prebiotics, and probiotics can be employed in medical nutrition therapy to increase the abundance of A muciniphila as part of an effort to prevent and manage metabolic disease.30