SV EN

GLP-1R signaling modulates colonic energy metabolism, goblet cell number and survival in the absence of gut microbiota

Online ahead of print, Molecular Metabolism, March 2024

In collaboration with Daniel J Drucker at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, we made the surprising observation more than 10 years ago that GLP-1R deficient mice dies. Further work led by our team member Thomas Greiner, with the support from the Mucin Biology Groups at the University of Gothenburg, revealed involvement of goblet cells.

The microbiota increases energy availability through fermentation of dietary fibers to short-chain fatty acids in conventionally raised mice. Energy deficiency in germ-free (GF) mice increases glucagon-like peptide-1 (GLP-1) levels, which slows intestinal transit. To further analyze the role of GLP-1-mediated signaling in this model of energy deficiency, we re-derived mice lacking GLP-1 receptor (GLP-1R KO) as GF. Our findings reveal a heretofore unrecognized role for GLP-1R signaling in the maintenance of colonic physiology and survival during energy deprivation.

To the article in Molecular Metabolism online

The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis

Open Access article, Nature Communications, 1 September, 2023

In this paper first author Marc Schöler aim to determine how dietary fatty acid composition affects the gut microbiota profile, microbiota-mediated metabolic regulation, and development of hepatic steatosis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and a leading cause of liver-related mortality. Hepatic steatosis, the first step in NAFLD development, is determined by several factors including uptake and disposal of fatty acids, de novo lipogenesis and fatty acid oxidation within the liver. The composition of dietary fatty acids can affect several of these processes.

To the article "The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis" in Nature Communications

Synergy and oxygen adaptation for development of next-generation probiotics

Open Access article, Nature, 3 August, 2023

In a study that our and Mattias Lorentzon's research groups published in Nature, we isolated Faecalibacterium prausnitzii, a butyrate-producing bacterium with anti-inflammatory properties, together with another bacterium, Desulfovibrio piger. The latter has beneficial effects on Faecalibacterium prausnitzii's growth and butyrate acid production. By then training the oxygen-sensitive Faecalibacterium prausnitzii in a favorable electrochemical environment, we were able to isolate more oxygen-resistant bacteria. We have now been able to show that the bacterial combination is safe for humans and we are now conducting studies to investigate if the addition of these bacteria has beneficial effects on blood sugar control in individuals with pre-diabetes.

To the article "Synergy and oxygen adaptation for development of next-generation probiotics" in Nature online.

Microbially produced imidazole propionate is associated with heart failure and mortality

Open access article, JACC Heart Failure, April, 2023

This article, by first author Antonio Molinaro, was recently published online in JACC Heart Failure and shows how the gut microbial metabolite ImP is increased in individuals with heart failure and is a predictor of overall survival.

Over the past years, it has become clear that the microbial ecosystem in the gut has a profound capacity to interact with the host through the production of a wide range of bioactive metabolites. The microbially produced metabolite imidazole propionate (ImP) is clinically and mechanistically linked with insulin resistance and type 2 diabetes, but it is unclear how ImP is associated with heart failure.

In this study, ImP serum was measurements in 2 large and independent clinical cohorts of patients (European [n = 1,985] and North American [n = 2,155]) with a range of severity of cardiovascular disease including heart failure. ImP is independently associated with reduced ejection fraction and heart failure in both cohorts, even after adjusting for traditional risk factors. This article shows that elevated ImP was a significant independent predictor of 5-year mortality.

To the article online

 

6α-hydroxylated bile acids mediate TGR5 signalling to improve glucose metabolism upon dietary fiber supplementation in mice

Article, Gut, February, 2023

In this article, Kassem Makki et al, show that modulation of the gut microbiota with oligofructose enriches bacteria involved in 6α-hydroxylated bile acid production and leads to TGR5-GLP1R axis activation to improve body weight and metabolism under western-style diet feeding in mice.

This article was first published online in June 2023 and was published in Gut, issue 72, February 2023.
To the article: Feb;72(2):314-324, 2023

The potential of tailoring the gut microbiome to prevent and treat cardiometabolic disease

Review article, Nat Rev Cardiol, 14 Oct, 2022

In this review, Rima Chakaroun, Lisa Olsson, Fredrik Bäckhed provide an overview of the current evidence on the interconnectedness of the gut microbiome and CVD against the noisy backdrop of highly prevalent confounders in advanced CVD, such as increased metabolic burden and polypharmacy. We further aim to conceptualize the molecular mechanisms at the center of these associations and identify actionable gut microbiome-based targets, while contextualizing the current knowledge within the clinical scenario and emphasizing the limitations of the field that need to be overcome.

 

To the full article in Nature Reviews Cardiology

Microbiome-derived ethanol in nonalcoholic fatty liver disease

Article, Nature Medicine, 10 Oct, 2022

Fredrik Bäckhed is one of the Co-authors of this article were it is concluded that the human gut microbiota produces large amounts of ethanol that might be clinically relevant for the pathogenesis of NAFLD. Ethanol production during an MMT should be considered as a noninvasive diagnostic approach for the detection of gut microbiota producing high levels of ethanol and NAFLD risk. In our prospective cohort, high postprandial plasma ethanol concentrations correlated particularly with high relative fecal abundance of lactic acid bacteria. Clinical trials targeting the gut microbiome have not yielded any meaningful outcome in NAFLD thus far. To what extent persistent endogenous ethanol production is causally involved in the highly complex pathogenesis of NAFLD, where a combination of environmental factors, genetic variants, obesity and disturbed lipid homeostasis interact, remains to be elucidated. Nevertheless, our findings suggest that further attention aiming to target the gut microbiota to reduce ethanol production and thereby lower additional risk for NAFLD is justified.


To the full article in Nature Medicine

 

Dynamics of the normal gut microbiota: A longitudinal one-year population study in Sweden

Article, Cell Host & Microbe, April 28, 2022

In this study, Lisa Olsson, Valentina Tremaroli and co-authors, investigated the temporal dynamics and the extent of intra- and inter-individual variation for the composition and functional potential of the normal gut microbiota. Our analyses showed that the intra-individual variation accounted for a large portion of the total variation in gut microbiota composition (23%) and that several functional pathways were highly dynamic (median ICC ≈ 0.5).

However, we observed that the extent of intra-individual compositional variation was individual specific and lower in communities with high relative abundance of F. prausnitzii, B. longum, and B. breve, as well as with low temporal variation of F. prausnitzii and low abundance of the ato terminal gene for butyrate synthesis. We noted that all communities, both stable and variable, displayed occasional blooming of species and potential functions belonging to Enterobacteriaceae and other facultative anaerobic or aerotolerant bacteria. Therefore, our results suggest that these fluctuations are part of normal gut microbiota dynamics and homeostatic interaction with the host.

To the article

 

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