title: Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice.
abstract: A high-fat dietary intake induces obesity and subclinical inflammation, which play important roles in insulin resistance. Recent studies have suggested that increased concentrations of circulating lipopolysaccharide (LPS), promoted by changes in intestinal permeability, may have a pivotal role in insulin resistance. Thus, we investigated the effect of gut microbiota modulation on insulin resistance and macrophage infiltration.
  
  
  
  Swiss mice were submitted to a high-fat diet with antibiotics or pair-feeding for 8 weeks. Metagenome analyses were performed on DNA samples from mouse faeces. Blood was collected to determine levels of glucose, insulin, LPS, cytokines and acetate. Liver, muscle and adipose tissue proteins were analysed by western blotting. In addition, liver and adipose tissue were analysed, blinded, using histology and immunohistochemistry.
  
  
  
  Antibiotic treatment greatly modified the gut microbiota, reducing levels of Bacteroidetes and Firmicutes, overall bacterial count and circulating LPS levels. This modulation reduced levels of fasting glucose, insulin, TNF-α and IL-6; reduced activation of toll-like receptor 4 (TLR4), c-Jun N-terminal kinase (JNK), inhibitor of κ light polypeptide gene enhancer in B cells, kinase β (IKKβ) and phosphorylated IRS-1 Ser307; and consequently improved glucose tolerance and insulin tolerance and action in metabolically active tissues. In addition, there was an increase in portal levels of circulating acetate, which probably contributed to an increase in 5'-AMP-activated protein kinase (AMPK) phosphorylation in mice. We observed a striking reduction in crown-like structures (CLS) and F4/80(+) macrophage cells in the adipose tissue of antibiotic-treated mice.
  
  
  
  These results suggest that modulation of gut microbiota in obesity can improve insulin signalling and glucose tolerance by reducing circulating LPS levels and inflammatory signalling. Modulation also appears to increase levels of circulating acetate, which activates AMPK and finally leads to reduced macrophage infiltration.
authors: Internal Medicine Department-Faculty of Medical Sciences, State University of Campinas, Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, São Paulo, 13083-887, Brazil.
authors: B M
authors: BM
authors: Carvalho
authors: Internal Medicine Department-Faculty of Medical Sciences, State University of Campinas, Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, São Paulo, 13083-887, Brazil.
authors: D
authors: D
authors: Guadagnini
authors: Internal Medicine Department-Faculty of Medical Sciences, State University of Campinas, Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, São Paulo, 13083-887, Brazil.
authors: D M L
authors: DML
authors: Tsukumo
authors: Internal Medicine Department-Faculty of Medical Sciences, State University of Campinas, Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, São Paulo, 13083-887, Brazil.
authors: A A
authors: AA
authors: Schenka
authors: Internal Medicine Department-Faculty of Medical Sciences, State University of Campinas, Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, São Paulo, 13083-887, Brazil.
authors: P
authors: P
authors: Latuf-Filho
authors: Internal Medicine Department-Faculty of Medical Sciences, State University of Campinas, Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, São Paulo, 13083-887, Brazil.
authors: J
authors: J
authors: Vassallo
authors: Chemistry Institute, State University of Campinas, Campinas, São Paulo, Brazil.
authors: J C
authors: JC
authors: Dias
authors: Chemistry Institute, State University of Campinas, Campinas, São Paulo, Brazil.
authors: L T
authors: LT
authors: Kubota
authors: Internal Medicine Department-Faculty of Medical Sciences, State University of Campinas, Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, São Paulo, 13083-887, Brazil.
authors: J B C
authors: JBC
authors: Carvalheira
authors: Internal Medicine Department-Faculty of Medical Sciences, State University of Campinas, Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, São Paulo, 13083-887, Brazil. msaad@fcm.unicamp.br.
authors: M J A
authors: MJA
authors: Saad
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000085:Acetates / Q000097:blood; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001439:Bacteroides / Q000302:isolation & purification; D002465:Cell Movement / Q000502:physiology; D016207:Cytokines / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000382:microbiology* / Q000473:pathology; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology; D008070:Lipopolysaccharides / Q000097:blood; D008264:Macrophages / Q000473:pathology; D008297:Male; D054892:Metagenome / Q000187:drug effects*; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D011494:Protein Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000085:Acetates; D000900:Anti-Bacterial Agents; D016207:Cytokines; D007328:Insulin; D008070:Lipopolysaccharides; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases