New Evidence for a Thrifty Microbiome in Humans

When the gut microbiota has access to plentiful fermentable substrates from host diet, there is a variable fine-tuning of energy absorption (host metabolizable energy). We posit that this may be evidence of a "thrifty microbiome" that contributes to the propensity to gain or lose weight.
New Evidence for a Thrifty Microbiome in Humans

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Energy is the currency of life. From the first cell division and throughout life, the ability to produce, expend or metabolize energy substrates is key for survival. This bioenergetic demand is characterized as tug of war between various cells and organs to meet their energetic needs. The malfunction of these processes, whereby excess or insufficient energy is available to cells, is at the core of most metabolic diseases, including obesity and diabetes.

In 1962 James V. Neel proposed that some individuals possessed a biological propensity, driven by genetics, to develop obesity and type 2 diabetes.  He coined this physiological state a “thrifty genotype, … being exceptionally efficient in the intake and/or utilization of food.” [1]. 

His mechanistic focus was on evolution of genes in an environment with intermittent periods of famine stating, “Genes and combinations of genes which were at one time an asset may in the face of environmental change become a liability” during times of plentiful availability of food.

More recently, Fraser-Liggett and Shuldiner expanded this concept to the gut microbiome [2]. They posited that in addition to host genetics, the “constituents of the gut microbial community may introduce a survival advantage to its host in times of nutrient scarcity, promoting positive energy balance by increasing efficiency of nutrient absorption and improving metabolic efficiency and energy storage. However, in the presence of excess nutrients, fat accretion and obesity may result”. Their hypothesis is based on a body of evidence showing that nutrient absorption requires an active microbiome in the colon to ferment dietary components not digested in the small intestine. This fermentation then generates various energy sources (such as short-chain fatty acids) that can be absorbed by the host [3].

They aimed to test this intriguing concept using 16S rRNA gene sequencing to profile composition of the human gut microbiota in persons who were lean or had obesity but were unable to find evidence of a “thrifty microbiome” [4]. Their published experiment did not, however, directly measure the efficiency of nutrient absorption which is a key aspect of their thrifty microbiome concept.

In our recently published study, we used a paradigm of quantitative bioenergetics to directly measure the efficiency of nutrient absorption (also called metabolizable energy [5]) under tightly controlled dietary and environmental conditions (randomized crossover controlled feeding study).

The first key finding was that on a Western diet (Figure 1) consisting of highly processed foods that lacked dietary components that are accessible to the gut microbes for fermentation, the efficiency of nutrient absorption was uniformly high because calories are largely digested and absorbed in the small intestine.

Secondly, on a diet that consisted of whole foods designed to deliver energy substrates to the microbes in the colon (fiber, resistant starch, larger food particles; Microbiome Enhancer Diet) we found a large interindividual variation in the efficiency of nutrient absorption (Figure 1).  The efficiency of some research volunteers was almost as high as when consuming a Western diet. In other words, these participants may possess a “thrifty microbiome”. Others were less efficient at absorbing energy on a whole foods diet.  We found that multiple host and microbial factors contributed to the variability in metabolizable energy in response to dietary substrates.

Figure 1:

Variable Energy Absorption Efficiency (Host Metabolizable Energy) with a Diet High in Microbiota-Fermentable Substrates

Figure 1: Variable Energy Absorption Efficiency with a Diet High in Substrates Accessible to the Gut Microbiota for Fermentation
Source: Corbin et al., Nature Communications (2023)
WD = Western Diet; MBD = Microbiome Enhancer Diet

In our study, we were not able to fully parse out the exact proportion of the variation that was due to microbiome versus diet or host factors; however, it is clear from our data that the microbes play a key role in the efficiency of nutrient absorption.

Our work does not discount the role of thrifty genes, most of which affect energy intake [6]. Rather, this work opens a door to a better understanding of how energy balance varies between individuals and may predispose or protect some individuals from weight gain.  More detailed analyses of the microbial functions that differ between those with and without efficient nutrient absorption is needed and in progress.

In summary, within a paradigm where both host and microbes are deeply phenotyped, the precise quantification (quantitative bioenergetics) of the overall efficiency of nutrient absorption (metabolizable energy) is a key energy balance phenotype. This approach uncovered new evidence supporting the “thrifty microbiome” hypothesis, which we further define as a process driven by interactions between diet, host, and gut microbes to yield a coordinated energy balance phenotype.  


  1. Neel, J.V., Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am J Hum Genet, 1962. 14(4): p. 353-62.
  2. Fraser-Liggett, C. and A. Shuldiner, The Thrifty Microbiome: The Role of the Gut Microbiota in Obesity in the Amish. Nature Precedings, 2010.
  3. Krajmalnik-Brown, R., et al., Effects of gut microbes on nutrient absorption and energy regulation. Nutr Clin Pract, 2012. 27(2): p. 201-14.
  4. Zupancic, M.L., et al., Analysis of the Gut Microbiota in the Old Order Amish and Its Relation to the Metabolic Syndrome. PLOS ONE, 2012. 7(8): p. e43052.
  5. Elia, M. and J.H. Cummings, Physiological aspects of energy metabolism and gastrointestinal effects of carbohydrates. European Journal of Clinical Nutrition, 2007. 61(1): p. S40-S74.
  6. Turcot, V., et al., Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nature Genetics, 2018. 50(1): p. 26-41.

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Go to the profile of Sudarsan Mugunthan
8 months ago

 Very nice correlation drawn between gut microbiome health and nutrient utilisation. Great work. Thank you for sharing

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