Review
Biological effects of propionic acid in humans; metabolism, potential applications and underlying mechanisms

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Abstract

Undigested food is fermented in the colon by the microbiota and gives rise to various microbial metabolites. Short-chain fatty acids (SCFA), including acetic, propionic and butyric acid, are the principal metabolites produced. However, most of the literature focuses on butyrate and to a lesser extent on acetate; consequently, potential effects of propionic acid (PA) on physiology and pathology have long been underestimated. It has been demonstrated that PA lowers fatty acids content in liver and plasma, reduces food intake, exerts immunosuppressive actions and probably improves tissue insulin sensitivity. Thus increased production of PA by the microbiota might be considered beneficial in the context of prevention of obesity and diabetes type 2. The molecular mechanisms by which PA may exert this plethora of physiological effects are slowly being elucidated and include intestinal cyclooxygenase enzyme, the G-protein coupled receptors 41 and 43 and activation of the peroxisome proliferator-activated receptor γ, in turn inhibiting the sentinel transcription factor NF-κB and thus increasing the threshold for inflammatory responses in general. Taken together, PA emerges as a major mediator in the link between nutrition, gut microbiota and physiology.

Research Highlights

► Microbially produced PA regulates adipokine production in human adipose tissue► PA links microbial fermentation in the colon to obesity and/or diabetes type 2► PA effects are exerted through GPCR41 and 43, it activates PPARγ and inhibits NF-κB► PA emerges as a mediator in the link between nutrition, gut microbiota and physiology.

Introduction

The link between dietary intake and physiology is long-recognized as evident from the age-old adage “you are what you eat” and other colloquial –but not entirely unsupported– expressions like “Feed a cold, starve a fever” highlight the recognition within the general population of the connection between nutrition and pathology [1]. Indeed many investigators now assume that environmental factors, e.g. dietary patterns, are as important as the genetic makeup in the contribution for the phenotypes of individuals, especially the propensity for disease. Especially so-called prebiotic diets in general and long-chain O-linked oligofructoses (fructans) in particular [2], are associated with general better health, and indeed generation of genetically modified crops capable of producing large quantities of fructans has become an industry by itself [3]. Although many of the molecular and immunological aspects by which dietary components could influence physiology [4] or even pathology [5] have been uncovered it is fair to say that the exact mechanism by which nutritional modification of metabolism of the microbiota interacts with the host is still largely obscure at best [6]. Here we argue that propionic acid is an important link in the nutrition, microbiome and physiology triangle.

A large body of research indicates that dietary fiber has a profound effect on general health. These include the increase of post-meal satiety and the decrease of body weight, fat mass and the severity of diabetes [7], [8], [9], [10], [11], [12]. These effects may be contributed via the fermentation of dietary fiber by the colonic microbiota and in turn the production of various metabolites, such as SCFA, which are absorbed by the host and influence its energy homeostasis [8], [13]. The microbiota also influences the development of obesity and its associated diseases [14]. This influence depends on microbiota composition within an individual, which seems to be defined via a combination of environmental and genetic factors that could favor either obese or lean phenotype [15], [16].

Fermentation of dietary fiber by the colonic microbiota is the primary source for the production of SCFA, i.e. acetic, propionic and butyric acid (Fig. 1). SCFA have recently attracted considerable interest, because of their possible importance for host health. Most of the studies (and reviews) on the interaction of SCFA and mammalian physiology, however, concentrate either solely on the role of butyrate alone [17], or on the effects of complex SCFA mixtures, PA mainly being investigated in the context of ruminant physiology in general, and on its role in liver physiology and metabolism in particular. Although in ruminants PA and other SCFA are the major source of energy (PA is the primary precursor for glucose production in ruminants), whereas glucose is the major source for humans, there is good evidence, as we discuss below, that PA is an important factor in human physiology as well.

Section snippets

Propionic acid occurrence and production

PA occurs naturally in a few food products; for example PA is present in low quantities in milk and relatively higher levels in dairy products such as yogurt and cheese, obviously due to bacterial fermentation, mostly by propionibacteria [18], [19]. It is available also as a preservative (E280) in food products, since it has anti-fungal and anti-bacterial effects [20], [21]. These food-sources however, do not lead to significant amounts of PA in the human circulation as quantities involved pale

Inflammation

It is now well established that the gastrointestinal tract is permanently in a state of low-grade inflammation [51]. Dietary fiber intake, which is the primary substrate for PA production, has been associated with a reduction in low-grade inflammation [8] and in intestinal inflammatory pathogenesis [52], [53], [54]. PA, as we mentioned earlier, has anti-fungal and bacterial effects [55]. Moreover, PA has moderate inhibitory activity on cyclooxygenase [56], a major enzyme in the production of

Propionic acidemia

High quantity of PA could also have potential adverse effects. This has been described in the metabolic disorder propionic acidemia, which is caused by defects in propionyl-CoA carboxylase enzyme [98]. It is a biotin-dependent mitochondrial enzyme involved in the metabolism of odd-chain fatty acids and the amino acids methionine, threonine, isoleucine and valine by converting propionyl-CoA to methylmalonyl-CoA. This defect of the enzyme leads to increased amounts of PA and other acids and

Cyclooxygenase inhibition

As mentioned, PA has moderate inhibitory activity on cyclooxygenase [56], a major enzyme in the production of pro-inflammatory eicosanoids [57] and indeed several non-steroidal anti-inflammatory drugs (NSAIDs), such as fenoprofen, flurbiprofen, ibuprofen and naproxen, are PA analogues [116]. In view of the concentrations of PA in the colonic intestine, a direct anti-inflammatory effect of PA via cyclooxygenase is to be expected and this is a likely mechanism for the down-regulation of low-grade

Conclusions and perspectives

PA has long been underestimated in terms of its physiological impact, most studies addressing the effects of butyrate and to a lesser extent acetate. Although the latter two are probably of principal importance in intestinal physiology, systemically they are less likely to have significant effects. PA is mainly produced by the fermentation of indigested food by the microbiota in the colon, but can reach the blood compartment and the adipose tissue, where it reduces fatty acid levels in plasma

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