Microbial Modulation of Energy Availability in the Colon Regulates Intestinal Transit

Wichmann, Anita; Allahyar, Ava; Greiner, Thomas U.; Plovier, Hubert; Lundén, Gunnel Östergren; Larsson, Thomas; Drucker, Daniel J.; Delzenne, Nathalie M.; Cani, Patrice D.; Bäckhed, Fredrik

doi:10.1016/j.chom.2013.09.012

Cited by 314 publications

(269 citation statements)

References 38 publications

(44 reference statements)

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“…After treatment with L. reuteri, the mean increase of GLP-2 DAUC during OGTT was 43% compared with baseline and this was similar to the 76% increase seen for GLP-1 DAUC. An involvement of both peptides, the intestinotrophic GLP-2 and insulinotrophic GLP-1, in effects of a prebiotic treatment was found previously in animal models (8) and even in germ-free mice (39). Our study complemented these findings, showing that the probiotic strain L. reuteri increases the glucose-stimulated release of GLP-1 and GLP-2 in glucosetolerant human participants.…”

Section: Discussionsupporting

confidence: 79%

Intake of Lactobacillus reuteri Improves Incretin and Insulin Secretion in Glucose-Tolerant Humans: A Proof of Concept

et al. 2015

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OBJECTIVEIngestion of probiotics can modify gut microbiota and alter insulin resistance and diabetes development in rodents. We hypothesized that daily intake of Lactobacillus reuteri increases insulin sensitivity by changing cytokine release and insulin secretion via modulation of the release of glucagon-like peptides (GLP)-1 and -2. RESEARCH DESIGN AND METHODSA prospective, double-blind, randomized trial was performed in 21 glucose-tolerant humans (11 lean: age 49 6 7 years, BMI 23.6 6 1.7 kg/m 2 ; 10 obese: age 51 6 7 years, BMI 35.5 6 4.9 kg/m 2 ). Participants ingested 10 10 b.i.d. L. reuteri SD5865 or placebo over 4 weeks. Oral glucose tolerance and isoglycemic glucose infusion tests were used to assess incretin effect and GLP-1 and GLP-2 secretion, and euglycemichyperinsulinemic clamps with [6, H 2 ]glucose were used to measure peripheral insulin sensitivity and endogenous glucose production. Muscle and hepatic lipid contents were assessed by 1 H-magnetic resonance spectroscopy, and immune status, cytokines, and endotoxin were measured with specific assays. RESULTSIn glucose-tolerant volunteers, daily administration of L. reuteri SD5865 increased glucose-stimulated GLP-1 and GLP-2 release by 76% (P < 0.01) and 43% (P < 0.01), respectively, compared with placebo, along with 49% higher insulin (P < 0.05) and 55% higher C-peptide secretion (P < 0.05). However, the intervention did not alter peripheral and hepatic insulin sensitivity, body mass, ectopic fat content, or circulating cytokines. CONCLUSIONSEnrichment of gut microbiota with L. reuteri increases insulin secretion, possibly due to augmented incretin release, but does not directly affect insulin sensitivity or body fat distribution. This suggests that oral ingestion of one specific strain may serve as a novel therapeutic approach to improve glucose-dependent insulin release.Type 2 diabetes results from decreased insulin sensitivity and inadequate insulin secretion, which associate with diminished incretin response and subclinical chronic inflammation and subsequent impaired glucose tolerance (1-4). These pathogenic factors, frequently accompanied by hypercaloric high-fat low-fiber diets, may be associated with alterations in gut microbiota, which also occur in obesity (5) and type 2 diabetes (6).

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Section: Discussionsupporting

confidence: 79%

Intake of Lactobacillus reuteri Improves Incretin and Insulin Secretion in Glucose-Tolerant Humans: A Proof of Concept

et al. 2015

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“…The current findings demonstrate that loss of GLP-1R signaling also enhances the susceptibility to gut injury, albeit through different mechanisms, involving the IEL-GLP-1R signaling system. Germ-free mice exhibit increased levels of circulating GLP-1 and enhanced proglucagon expression in the murine brainstem (47) and distal gut (48), whereas microbial metabolites such as indole directly activate GLP-1 secretion from L cells (49). Collectively, these emerging findings link the gut microbiome and its metabolic byproducts with the control of central and peripheral GLP-1 production.…”

Section: Discussionmentioning

confidence: 91%

GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R

et al. 2015

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Obesity and diabetes are characterized by increased inflammation reflecting disordered control of innate immunity. We reveal a local intestinal intraepithelial lymphocyte (IEL)-GLP-1 receptor (GLP-1R) signaling network that controls mucosal immune responses. Glp1r expression was enriched in intestinal IEL preparations and copurified with markers of Tαβ and Tγδ IELs, the two main subsets of intestinal IELs. Exendin-4 increased cAMP accumulation in purified IELs and reduced the production of cytokines from activated IELs but not from splenocytes ex vivo. These actions were mimicked by forskolin, absent in IELs from Glp1r−/− mice, and attenuated by the GLP-1R agonist exendin (9-39) consistent with a GLP-1R–dependent mechanism of action. Furthermore, Glp1r−/− mice exhibited dysregulated intestinal gene expression, an abnormal representation of microbial species in feces, and enhanced sensitivity to intestinal injury following administration of dextran sodium sulfate. Bone marrow transplantation using wild-type C57BL/6 donors normalized expression of multiple genes regulating immune function and epithelial integrity in Glp1r−/− recipient mice, whereas acute exendin-4 administration robustly induced the expression of genes encoding cytokines and chemokines in normal and injured intestine. Taken together, these findings define a local enteroendocrine-IEL axis linking energy availability, host microbial responses, and mucosal integrity to the control of innate immunity.

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“…One such factor is likely to be the SCFAregulated excretion of incretin hormone glucagon-like peptide-1. Under conditions of low SCFA production in caecum, a low energy availability in colon stimulates the secretion of glucagon-like peptide-1, which slows the small intestinal transit and allows greater nutrient absorption, resulting a low faecal energy content (Wichmann et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Environmental spread of microbes impacts the development of metabolic phenotypes in mice transplanted with microbial communities from humans

et al. 2016

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Microbiota transplantation to germ-free animals is a powerful method to study involvement of gut microbes in the aetiology of metabolic syndrome. Owing to large interpersonal variability in gut microbiota, studies with broad coverage of donors are needed to elucidate the establishment of human-derived microbiotas in mice, factors affecting this process and resulting impact on metabolic health. We thus transplanted faecal microbiotas from humans (16 obese and 16 controls) separately into 64 germ-free Swiss Webster mice caged in pairs within four isolators, with two isolators assigned to each phenotype, thereby allowing us to explore the extent of microbial spread between cages in a well-controlled environment. Despite high group-wise similarity between obese and control human microbiotas, transplanted mice in the four isolators developed distinct gut bacterial composition and activity, body mass gain, and insulin resistance. Spread of microbes between cages within isolators interacted with establishment of the transplanted microbiotas in mice, and contributed to the transmission of metabolic phenotypes. Our findings highlight the impact of donor variability and reveal that inter-individual spread of microbes contributes to the development of metabolic traits. This is of major importance for design of animal studies, and indicates that environmental transfer of microbes between individuals may affect host metabolic traits.

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Microbial Modulation of Energy Availability in the Colon Regulates Intestinal Transit

Cited by 314 publications

References 38 publications

Intake of Lactobacillus reuteri Improves Incretin and Insulin Secretion in Glucose-Tolerant Humans: A Proof of Concept

Intake of Lactobacillus reuteri Improves Incretin and Insulin Secretion in Glucose-Tolerant Humans: A Proof of Concept

GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R

Environmental spread of microbes impacts the development of metabolic phenotypes in mice transplanted with microbial communities from humans

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