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. 2013 Jan 1;4(1):48–53. doi: 10.4161/gmic.22328

Antimicrobials

Strategies for targeting obesity and metabolic health?

Eileen F Murphy 1, Siobhan F Clarke 2,3, Tatiana M Marques 2,4, Colin Hill 4,3, Catherine Stanton 2,4, R Paul Ross 2,4, Robert M O’Doherty 5, Fergus Shanahan 2,6,*, Paul D Cotter 2,4
PMCID: PMC3555886  PMID: 23018760

Abstract

Obesity is associated with a number of serious health consequences, including type 2 diabetes, cardiovascular disease and a variety of cancers among others and has been repeatedly shown to be associated with a higher risk of mortality. The relatively recent discovery that the composition and metabolic activity of the gut microbiota may affect the risk of developing obesity and related disorders has led to an explosion of interest in this distinct research field. A corollary of these findings would suggest that modulation of gut microbial populations can have beneficial effects with respect to controlling obesity. In this addendum, we summarize our recent data, showing that therapeutic manipulation of the microbiota using different antimicrobial strategies may be a useful approach for the management of obesity and metabolic conditions. In addition, we will explore some of the mechanisms that may contribute to microbiota-induced susceptibility to obesity and metabolic diseases.

Keywords: obesity, antimicrobials, gut microbiota, firmicutes, metabolic disease

Introduction

Obesity, the great pandemic of our time, is a major threat to public health and challenge to healthcare resources. This complex syndrome is influenced by host susceptibility and by environmental or lifestyle factors, such as diet and physical activity. Obesity is associated with a number of serious health consequences, including type 2 diabetes (T2DM), cardiovascular disease and a variety of cancers among others1 and has been repeatedly shown to be associated with a higher risk of mortality.2 The relatively recent discovery that the composition and metabolic activity of the gut microbiota may affect the risk of developing obesity and related disorders has led to an explosion of interest in this distinct research field (for review see refs.3 and 4). A corollary of these findings would suggest that modulation of gut microbial populations can have beneficial effects with respect to controlling obesity. A number of strategies including specific functional foods, probiotics, prebiotics and/or antimicrobials antibiotics, prebiotics and probiotics, have the potential to favorably influence host metabolism by targeting the gut microbiota. In this addendum, we summarize our recent data, showing that therapeutic manipulation of the microbiota using different antimicrobial strategies may be a useful approach for the management of obesity and metabolic conditions. In addition, we will explore some of the mechanisms that may contribute to microbiota-induced susceptibility to obesity and metabolic diseases.

Obesity and the Gut Microbiota

Both animal and human studies have shown that the composition of the gut microbiota is significantly altered in obesity and diabetes and characterized by reduced diversity.5-10 We and others have demonstrated the primacy of diet in influencing the microbiota in obesity.11,12 Further mouse studies have highlighted the role of the gut microbiota in the regulation of energy homeostasis,13,14 in the pathogenesis of insulin resistance,15-19 in fatty liver,20 in lipid and amino acid metabolism21 and as a modulator of host fatty acid composition.22 These studies suggest that interventions which target the metabolic activity of the gut microbiota may have efficacy in obesity and associated disorders.

A number of mechanisms have been proposed to contribute to microbiota-induced susceptibility to obesity and metabolic diseases. Enhanced energy harvest from dietary intake, due to an alteration in microbial composition, has been highlighted as a potential contributor to the pathogenesis of obesity. Other work has suggested that the gut microbiota and its products affect host energy regulation acting through mechanisms involving fasting-adipose adipose factor (FIAF),23 adenosine monophoshate (AMP)-activated protein kinase (AMPK),14 and G-protein-coupled receptor (GPR)41.24,15 Reciprocal signaling between the immune system and the microbiota, partially via the interaction between LPS and CD14/Toll-receptor (TLR)4, appears to also play a pivotal role in linking alterations in gut microbiota and chronic low-grade inflammation with risk of metabolic disease in the host.16 Indeed, germ-free mice are protected from the development of diet-induced obesity.14 However, whether the gut microbiota represents a realistic target is unclear.

A Microbial Intervention

The gut microbiota contains a large, and relatively uncharted, repository of molecules and metabolites that can be deployed in a variety of settings. One common feature among gut microbes is the ability to produce bacteriocins. Bacteriocins are bacterially produced, ribosomally synthesized, small, heat-stable antimicrobial peptides that can have broad or narrow spectrum activity against other bacteria and to which the producer has a specific immunity mechanism.25 Although bacteriocin production by probiotics has been regarded as a beneficial trait for some time,26 the full extent of the benefits of bacteriocin production in the gut is only beginning to be appreciated. The ability of some bacteriocins to modulate specific undesirable components of the gut microbiota, without causing major collateral damage to the remainder of the population, is a very attractive trait.27,28 While the majority of studies to date have focused on the ability of bacteriocin-producing probiotics to target and control well established gut pathogens, it is to be expected that as high-throughput sequencing analyses of human microbial populations evolves, new targets will emerge. Indeed, distinct clusters or enterotypes in the human microbiome have been described29 and provide further support for the use of targeted strategies. With respect to obesity, specific populations that merit targeting have yet to be clearly defined. Although increases in the Firmicutes to Bacteroidetes ratio have been observed in the gut of obese animals,6,10 the subject remains controversial,3,4 and it is anticipated that other, more specific, targets will emerge.30

In our study published in Gut earlier this year31 we explored the concept of targeting the gut microbiota using antimicrobials to impact on metabolic abnormalities in murine diet-induced obesity (DIO). Two antimicrobial strategies were used a bacteriocin-producing probiotic Lactobacillus and oral vancomycin. Vancomycin is a well-known clinical antibiotic that demonstrates anti-Firmicutes activity and has limited systemic effects32-34 while Lactobacillus salivarius UCC118 is a genetically well characterized probiotic strain35 that produces a broad-spectrum class II two peptide bacteriocin, Abp118, which is active against Firmicutes.36 To differentiate between the influence of the bacteriocin and that of the probiotic per se on metabolic dysregulation, a bacteriocin-negative (Bac-) isogenic derivative of L. salivarius UCC118 was used.37 This approach was used previously to establish the critical importance of Abp118 production with respect to the ability of L. salivarius UCC118 to control Listeria monocytogenes infection in the murine gut.

The experimental design involved the feeding of a high fat (45%; HF) diet to 4 groups of mice over a 12 week period following by an 8-week intervention period where mice continued to receive a (1) HF diet, (2) HF diet in addition to oral vancomycin, (3) HF diet in addition to L. salivarius UCC118 and (4) HF diet with the Bac- strain, respectively. A fifth control group received a low fat (10%) diet throughout the 20 week study. A number of analyses took place during and/or at the end of the intervention period. A high throughput DNA sequencing based analyses of the gut microbiota of faecal pellets collected at the end of the intervention period showed that both vancomycin and the bacteriocin-producing probiotic significantly altered the gut microbiota in diet-induced obese mice, but in distinct ways (Fig. 1). From a bacteriocin perspective, the latter observation is particularly notable as, to our knowledge, it is the first occasion upon which the full extent of the impact of a bacteriocin producing probiotic on the gut microbiota has been assessed in vivo. Bioinformatic analysis of sequence data showed that vancomycin dramatically impacted upon the overall composition of the gut microbiota whereas the bacteriocin had a more subtle impact. More specifically, at the family level, vancomycin brought about a significant decrease in the proportions of the Clostridiaceae, Bacteroidaceae and Porphyromonadaceae and a significant increase in the Enterobacteriaceae (from levels below the detection threshold to 28% of the population), Streptococcaceae, Desulfovibrionaceae and Alcaligenaceae relative to the HF only alone controls. Comparison of the L. salivarius UCC118 Bac+ with the non-bacteriocin-producing strain, L. salivarius UCC118Bac-, showed that the production of the antimicrobial resulted in an increase in Bacteroidaceae and a reduction in the proportions of Bifidobactereaceae in the gut microbiota of DIO mice.

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Figure 1. Schematic overview of the effect of bacteriocin-producing probiotic Lactobacillus salivarius UCC118 and oral vancomycin on the composition of the gut microbiota at family level in diet-induced obese mice.

Notably, some of the populations inhibited were not previously known to be targeted by the antimicrobials employed, highlighting the value of culture-independent analyses. It should also be noted that in arecent work involving mice and pigs fed a standard diet, high throughput sequencing again revealed that the production of Abp118 by UCC118 had a significant impact on the gut microbiota.38 Furthermore, traditionally vancomycin is directed against members of the Firmicutes and is reserved as a drug of “last resort” treatment of infections caused by Gram-positive bacteria. However, studies using high throughput sequencing have shown that vancomycin appears to reduce Bacteroidetes and other taxa in vivo.27,39 These obeservations highlight the advantages of using global profiling of the gut microbiota and emphasize the risks associated with relying solely on in vitro approaches to assess the impact of an antimicrobial (or other bioactive) on the gut microbiota.

In the obese mouse model both vancomycin and bacteriocin derived from L. salivarius UCC118 impacted on weight gain over the 8 week intervention period. However, a recovery in the rate of body weight gain for both strategies was observed, suggesting that compensatory microbial adjustments and/or host physiologic adaptations such as changes in energy expenditure, satiety and food intake11,40,41 (perhaps triggered by changes in the microbiota), may be at play. Of the interventions, only vancomycin treatment resulted in an improvement in the metabolic abnormalities. While these changes are desirable, the negative consequences of such a dramatic alteration of the gut microbiota, increasing Enterobacteriaceae populations and enhancing the risk of antibiotic resistance, ensure that a vancomycin-based weight management program will remain of theoretical interest and a proof of concept. It is noteworthy that the study shows the potential utility of bacteriocin-producing bacteria to favorably modify the gut microbiota but further work is required to identify bacteriocin-producing probiotics that can have a prolonged effect on energy, metabolism and weight control.

Mechanisms Contributing to Microbiota-Induced Susceptibility to Obesity and Metabolic Diseases

The gut microbiota has the potential to influence weight gain and fat deposition through a variety of mechanisms. Changes in gut microbiota composition have been shown to influence energy expenditure, satiety and food intake.11,40,41 There is increasing evidence that the gut microbiota and their metabolic products can influence gut hormones, inflammation, and gut motility.42-44 Another factor is the ability of the gut microbiota to extract energy by fermenting otherwise indigestible components of the diet (“energy harvest”). We have performed additional unpublished work to examine the effect of manipulating the gut microbiota using vancomycin and the bacteriocin-producing probiotic, L. salivarius UCC118, on the efficiency of energy harvest, using the levels of short chain fatty acids (SCFA), the major fermentation end products, and on the energy content of the feces. No difference was found in acetate and propionate production between lean and DIO mice over the 8 week feeding period. Only vancomycin treatment resulted in a decrease in faecal acetate (Fig. 2), while neither antimicrobial strategy altered fecal propionate levels or energy content. Although precise energy balance studies were not performed, when combined with our previous work where the energy content of the diet, food intake and faecal output were measured, these data further support our observations that changes in the microbiota are dissociated from markers of energy harvest.11 Indeed, our work suggested that the improvement in metabolic abnormalities observed with vancomycin treatment of DIO mice may be due to alterations in the inflammatory tone. Of note, a recent study by Cho et al.45 showed that subtherapeutic antibiotic therapy increased adiposity, altered bone development and increased hormone levels related to metabolism in young mice suggesting that exposure of the infant gut microbiota to antibiotics may have long-term metabolic consequences. This study highlights that age and lifestage are important factors to consider in the complex relationship between the gut microbiota and obesity.

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Figure 2. Acetate and propionate production (µmol/g) over the 8 week intervention period in (1) lean, DIO and vancomycin-treated DIO mice and (2) DIO mice treated with the bacteriocin-producing probiotic strain L. salivarius UCC118 Bac+ (1 × 109 cfu/day) compared with DIO mice treated with a non-bacteriocin-producing derivative L. salivarius UCC118Bac- (1 × 109 cfu/day). Data represented as mean ± SEM, n = 9–10. *p < 0.05

A recent study in TLR5-deficient mice suggests that malfunction of the innate immune system may promote the development of metabolic syndrome through a mechanism involving the gut microbiota.46 Our work showed that vancomycin treatment of DIO mice resulted in an improvement in the inflammatory and metabolic health of the host. In particular, plasma TNF-α levels were reduced in vancomycin-treated DIO mice compared with DIO controls and this corresponded with a trend toward a reduction in the gene expression of TNF-α levels in the liver and visceral adipose tissues. The fact that vancomycin treatment was associated with a decrease in inflammatory tone in DIO mice, despite an increase in the relative levels of Enterobactericeae, again highlights the complexities of the host/microbiota relationship. Furthemore, studies by others have suggested that the gut microbiota may contribute to the onset of insulin resistance and the low-grade inflammatory tone characterizing obesity through a mechanism involved in high-fat induced metabolic endotoxemia and toll-like receptors but the specific components of the gut microbiota responsible for the interaction remain to be identified.6,16,47 Interestingly, Serino et al.48recently identified a gut microbial profile specific to the diabetes-sensitive and diabetes-resistant metabolic phenotypes and found an increased Bacteroidetes to Firmicutes ratio and a reduction in Lachnospiraceae family and Oscillibacter genus associated with the diabetic phenotype.

In addition to SCFA production and energy extraction from the diet, a possible link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses seems likely. The G protein-coupled receptors, GPR43 and GPR41 have been identified as endogenous receptors for SCFAs. Maslowski et al.49 showed that stimulation of GPR43 by SCFAs was necessary for the resolution of inflammatory responses, in models of colitis, arthritis and asthma through a mechanism involving GPR43. In addition, new research has highlighted SCFAs and their receptors as potential targets for the treatment of obesity and diabetes. A recent study showed that chronic treatment of butyrate and propionate to DIO mice suppressed food intake, protected against high-fat diet-induced weight gain and glucose intolerance, and stimulated gut hormone secretion.43 Indeed, it has been suggested that the amount of SCFA produced by the gut microbes, more than the composition of the microbiota could impact on the host’s weight balance.50 However, deciphering the role of SCFA in obesity, diabetes and inflammatory conditions will depend on identifying the components of the obese gut microbiota actively involved in the production of SCFAs and interactions among them, in addition to, an improved understanding of how diet and age relate to SCFA levels.

Conclusion

There is increasing evidence to suggest that gut microbiota and their metabolic products can influence obesity and metabolic health. Harnessing the bacteriocin-producing capacity of the gut and identifying selective pharmabiotics which can alter the development of obesity and associated conditions as a consequence of changing the gut microbiota represents a realistic therapeutic strategy for future development.

Murphy EF, Cotter PD, Hogan A, O'Sullivan O, Joyce A, Fouhy F, Clarke SF, Marques TM, O'Toole PW, Stanton C, Quigley EM, Daly C, Ross PR, O'Doherty RM, Shanahan F. Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut. 2013;62:220–6. doi: 10.1136/gutjnl-2011-300705.

Footnotes

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