Thursday, June 4, 2015

A Proposed Research Project on the Role the Gut Microbiota Plays in Carbohydrate Metabolism in Cats By Marion (Meg)Smart DVM, PhD


This is a draft of a proposed research project that examines the role of the gut micro biota and diet in the pathophysiology of obesity and diabetes in cats. I am retired June 30th, 2014; so am sharing my thoughts with my readers, as I think it is a proposal worth considering.


Hypothesis:
 In the cat the gut microbiota plays a significant role in the metabolism of exogenous polysaccharides. Dietary carbohydrates (fermentable fiber, polysaccharides and simple sugars) in the diet of the cat alter the gut microbiota such that the carbohydrates are metabolized to short chained fatty acids and sugars. The cat, as an obligate carnivore, typically derives glucose from gluconeogenesis of amino acids. The sugars and some of the short chained fatty acids derived from the gut fermentation impacts negatively on the cat’s energy metabolism this resulting in obesity, and insulin resistance.

Literature Review

The gut is densely populated with commensal and symbiotic microorganisms (the gut microbiota). Diet appears to play a predominant role in shaping the microbial population and thus promoting under certain circumstances dysbiosis that can lead to obesity and insulin resistance in humans. The genetic richness of the gut microbiota allows it to perform diverse and active metabolic activities (that are not associated with the human genome) such as processing dietary polysaccharides. The gut microbiota exchange metabolites with the host and interacts with host signalling pathways to modulate host bile acid, lipid and amino acid metabolism as well as the host gene expression. This is a very intimate relationship, one which we are now beginning to understand.

Sequencing-based approaches indicate that the human gut microbiota is comprised of more than 1000 phylotypes these can be classified into six bacterial divisions:  Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Fusobacteria and Verrucomicrobia.  At the genus level major constituents are obligate anaerobes from genera Bacteroides, Eubacterium, Clostridium, Ruminococcus, Peptococcus, Peptostreptococcus,, Bifidocacterium, and Fusobacterium.  Less common are facilitative anaerobes.

The differences present in the gut micro biota may reflect differences in long-term diet pattern which have been associated with human enterotypes. Bacteroides are associated with higher dietary consumption of protein and saturated fats, Prevotella enterotypes are associated with a high ingestion of carbohydrates and simple sugars and low protein and fat.

Studies in mice and humans found that the presence, composition and metabolic actions of the gut microbiota had an impact on energy metabolism. In the human study a 20% increase in gut Firmicutes and a 20% decrease in Bacteroides were associated with a 150 kcal increase in energy harvest by the host.

Microbial fermentation generates monosaccharaides and short chain fatty acids which can be absorbed and utilized as energy by the host. Microbiota generated short chain fatty acids (acetate, butyrate and propionic acid) which are readily absorbed by the enterocytes in the colon. Acetate enters the systemic circulation and reaches peripheral tissues; butyrate and propionate are utilized by the colonic epithelium and liver respectively. Methanogens in the gut are found to increase the efficiency of bacterial fermentation and short chained fatty acid production thus increasing fat pad mass in germ-free mice.

Short chain fatty acids (SCFA) also function as regulators of energy intake and energy metabolism. Non-digestible fermentable polysaccharides enhance gut microbiota production of short chain fatty acids, this enhanced production is associated with host satiety and reduce food intake. The reduced food intake is in part associated with the gut peptide hormones glucagon like peptide GLP-1 and peptide(P)YY and decreased secretion of the gut peptide ghrelin which increases food intake; through effects on the hypothermic, brainstem and reward-related circuits. SCFA reduce appetite and /or alter energy metabolism to produce healthy weight. 

The metabolic effects of the gut micro biota on obesity and insulin resistance is reviewed in detail by Shen, Obin  and Zhao 2013.  They conclude modern science has allowed us to investigate the intricate role that the gut micro biota plays in regulating or deregulating energy intake and metabolism, obesity associated inflammation and glucose insulin homeostasis. Many questions remain unanswered:


  •  What are the core features of a healthy and stable micro biota?
  • What features of the host/ microbiota cross talk are important in maintaining a stable microbiota and gut homeostasis?
  • How can this be manipulated to restore equilibrium in conditions of dysbiosis?
  • What compositional and functional changes occur in the gut microbiota associated  with obesity and its  complications?
The authors conclude that an integrative collaborative approach is required involving microbiologists, endocrinologist, nutritionist, and cell, molecular, computational and systems biologists

The cat as an Animal Model
Much of the research in this area has been done with genetically altered germ free mice, but the cat is a potential animal model for the study of the role that the  gut micro biota and dysbiosis plays in obesity, insulin resistance and type 2 diabetes.

The cat is a true carnivore and does not have a requirement for carbohydrates. Most cat diets  especially dry kibble have at least 30% grain based carbohydrates. The cat derives its glucose requirements from gluconeogenic amino acids and is in a constant state of gluconeogenesis.  Theoretically the cat cannot metabolize carbohydrates yet industry research indicates that dietary carbohydrate are tolerated and utilized by the cat. The carbohydrates, although suspected, have not been shown conclusively to be associated with the increased incidence of obesity and type 2 diabetes in the cat. Although investigated in mice and humans the role of the gut microbiota in the cat’s energy metabolism has not been studied.

Research:

Phase 1.

Part A: A survey comparing the diet, complete blood count, chemistry panel, and gut microflora of newly diagnosed diabetic cats, obese cats and normal age matched controls. This will require a detailed history, which in some cases may be difficult

Part B: Follow the changes in the gut flora CBC, and chemistry panel in the diabetic cats and the obese cats as they undergo treatment and weight loss.

Phase 2:

Phase 3:

References:
Shen J., Obin M.S., Zhao L. 2013 Review: The gut microbiota, obesity and insulin resistance. Molecular Aspects of Medicine 34:39-58.

Cani P.D.and Delzenne N.M. 2011 The gut microbiome as a therapeutic target. Pharmacology and Therapeutics 130:202-212

Greiner T, Backhed F. The effects of gut microbiota on obesity and glucose homeostasis. Trends in Endocrinology and Metaboism 22#4:117-123

Delzenne N.M., Cani P.D. 2010 Nutritional modulation of gut microbiota in the context of obesity and insulin resistance:Potential interest in prebiotics International Dairy Journal 20:277-280

O’Flaherty S., Klaenhammer T.R. 2010 The role and potential of probiotic bacteria in the gut, and the communication between gut microflora and gut/host International Dairy Journal 20:262-268

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