Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study

Abstract

Metabolic syndrome is characterized by a constellation of comorbidities that predispose individuals to an increased risk of developing cardiovascular pathologies as well as type 2 diabetes mellitus (T2DM)1. The gut microbiota is considered as a new key contributor involved in the onset of obesity-related disorders2. In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated T2DM, or hypertension3–8. As the administration of A.muciniphila has never been investigated in humans, we conducted a randomized double-blind placebo-controlled pilot study in overweight/obese insulin resistant volunteers, 40 were enroled and 32 completed the trial. The primary endpoints were on safety, tolerability and metabolic parameters (i.e., insulin resistance, circulating lipids, visceral adiposity, body mass). The secondary outcomes were the gut barrier function (i.e., plasma lipopolysacharrides (LPS) and gut microbiota composition. In this single-center study, we demonstrated that daily oral supplementation of 1010 bacteria either alive or pasteurized A.muciniphila for 3 months was safe and well tolerated. Compared to the Placebo, pasteurized A.muciniphila improved insulin sensitivity (+28.62±7.02%, P=0.002), reduced insulinemia (-34.08±7.12%, P=0.006) and plasma total cholesterol (-8.68±2.38%, P=0.02). Pasteurized A.muciniphila supplementation slightly decreased body weight (-2.27±0.92kg, P=0.091) as compared to the Placebo group, and fat mass (-1.37±0.82kg, P=0.092) and hip circumference (-2.63±1.14cm, P = 0.091) as compared to baseline. After 3 months of supplementation, A.muciniphila reduced the levels of relevant blood markers of liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study (NCT02637115) shows that the intervention was safe and well-tolerated and that the supplementation with A.muciniphila improves several metabolic paramaters.

Function of Akkermansia muciniphila in Obesity: Interactions With Lipid Metabolism, Immune Response and Gut Systems

“…A recent clinical trial (NCT02637115) indicated that 3-month oral administration of A. muciniphila in obese patients is safe and well-tolerated. Meanwhile, supplementation of A. muciniphila decreased the body weight and improved liver dysfunction as well as inflammation in patients, as shown in a double-blind, randomized human study (Depommier et al, 2019). It has been demonstrated that A. muciniphila could be isolated from purified hog gastric mucus (Van Der Ark et al, 2018) and cultured in vivo for medicinal application.…”

The interplay of type 2 immunity, helminth infection and the microbiota in regulating metabolism

“…Such work demonstrated a ‘causal’ contribution of the microbiota to metabolism and has since lead to the isolation of bacterial species able to improve the metabolic disease. One such species is Akkermansia muciniphila, which is currently being assessed as a treatment for obesity …”

“…One such species is Akkermansia muciniphila, which is currently being assessed as a treatment for obesity. 74 Of note, intestinal helminths, such as N. brasiliensis, H. polygyrus or Trichuris muris, are directly at the intersection of type 2 immunity, microbiota and metabolism. These parasites all reside within the intestine as adults, where they are in close proximity to, and have co-evolved with, the microbiota (Figure 2).…”

Potential correlation between carbohydrate‐active enzyme family 48 expressed by gut microbiota and the expression of intestinal epithelial AMP‐activated protein kinase β

“…Additionally, members of the Lachnospiraceae and Erysipelotrichaceae families have previously been suggested to be associated with microbe TMA generation and development of atherosclerosis (Qiu, Tao, Xiong, Yu, & Wei, 2018). These species have been suggested as playing a role in inhibiting obesity as well as improving intestinal barrier function, possibly through interaction with host intestinal epithelial cells via mucoprotein(Berry et al, 2012;Depommier et al, 2019;Lee et al, 2018).The differences in the gut microbial species from different experimental groups were further defined using LEfSe analysis (Figure 4). The composition of the gut microbiota at the phylum and genus levels induced by the experimental diets is shown in Figure 3.…”

“…without AMPK inhibition). These species have been suggested as playing a role in inhibiting obesity as well as improving intestinal barrier function, possibly through interaction with host intestinal epithelial cells via mucoprotein(Berry et al, 2012;Depommier et al, 2019;Lee et al, 2018).The differences in the gut microbial species from different experimental groups were further defined using LEfSe analysis (Figure 4). Species from Firmicutes phylum, Dubosiella, Chlamydia, Enterorhabdus, and Clostridium were identified to be significantly enriched in the mice fed with a red meat diet, potentially indicating a relatively unhealthy gut environment as these species have been associated with dysbiosis or pathogenicity (Kociolek & Gerding, 2016; Leclercq et al, 2017; Zhang et al, 2018).…”