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Review
. 2014 Aug;28(8):1221-38.
doi: 10.1210/me.2014-1108. Epub 2014 Jun 3.

Minireview: Gut microbiota: the neglected endocrine organ

Gerard Clarke  1 , Roman M Stilling, Paul J Kennedy, Catherine Stanton, John F Cryan, Timothy G Dinan
Affiliations
Review

Minireview: Gut microbiota: the neglected endocrine organ

Gerard Clarke et al. Mol Endocrinol. 2014 Aug.

Abstract

The concept that the gut microbiota serves as a virtual endocrine organ arises from a number of important observations. Evidence for a direct role arises from its metabolic capacity to produce and regulate multiple compounds that reach the circulation and act to influence the function of distal organs and systems. For example, metabolism of carbohydrates results in the production of short-chain fatty acids, such as butyrate and propionate, which provide an important source of nutrients as well as regulatory control of the host digestive system. This influence over host metabolism is also seen in the ability of the prebiotic inulin to influence production of relevant hormones such as glucagon-like peptide-1, peptide YY, ghrelin, and leptin. Moreover, the probiotic Lactobacillus rhamnosus PL60, which produces conjugated linoleic acid, has been shown to reduce body-weight gain and white adipose tissue without effects on food intake. Manipulating the microbial composition of the gastrointestinal tract modulates plasma concentrations of tryptophan, an essential amino acid and precursor to serotonin, a key neurotransmitter within both the enteric and central nervous systems. Indirectly and through as yet unknown mechanisms, the gut microbiota exerts control over the hypothalamic-pituitary-adrenal axis. This is clear from studies on animals raised in a germ-free environment, who show exaggerated responses to psychological stress, which normalizes after monocolonization by certain bacterial species including Bifidobacterium infantis. It is tempting to speculate that therapeutic targeting of the gut microbiota may be useful in treating stress-related disorders and metabolic diseases.

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Figures

Figure 1.
Figure 1.
Hormone-like metabolites produced or regulated by the gut microbiota. Microbial metabolites such as SCFAs with signaling functions are secreted into the gut lumen, transported across the epithelial barrier, and transported to the effector organs, including the brain, via the bloodstream. The gut microbiota is also capable of producing or releasing neurotransmitters such as serotonin or regulating the availability of precursors such as tryptophan. The microbiota also regulates the bioavailability of choline and its metabolites.
Figure 2.
Figure 2.
The gut microbiota as an endocrine organ. The endocrine system is primarily composed of glands that each produce a single or at most a small number of humoral agents. However, the microbiota produces numerous chemicals of a hormonal nature that are released into the bloodstream and act at distal sites. This biochemical capacity arises from the vast and diverse array of microbial cells that constitute the gut microbiota.
Figure 3.
Figure 3.
The gut microbiota and host metabolism. A, GF animals are protected from high-fat diet-induced obesity. A number of important studies have demonstrated that GF animals gain less weight than their conventionally colonized counterparts when fed a high-fat/high-sugar Western-style diet. GF animals also have less total body fat than mice raised conventionally, and when colonized with the microbiota of a conventional mouse, they show a robust increase in body fat. Moreover, obesity is associated with alterations in the composition of the microbiota. B, GF animals adopt the phenotype of the microbiota donor. Previously GF mice display an obese phenotype on receipt of a microbiota transplant from obese mice or when humanized with a microbiota from an obese individual. Similarly, GF animals lose weight upon receipt of a microbiota transfer from animals who have exhibited rapid weight loss after gastric bypass surgery.
Figure 4.
Figure 4.
Neuronal pathways of the gut-brain axis. In addition to hormonal cross-talk, the gut microbiota can influence brain and behavior by recruiting the neuronal pathways of the gut-brain axis. This term describes the bidirectional communication network between the gut and the brain. The CNS and ENS communicate along vagal and autonomic pathways to modulate many GI functions. Mood and various cognitive processes can mediate top-down/bottom-up signaling. Vagal afferent nerves transmit to central brain regions in response to numerous signaling molecules in the gut that can be regulated or secreted by the gut microbiota. This vagal innervation is essential for homeostasis and provides both motor and sensory innervation for several key functions including satiety, nausea, sensations of visceral pain, sphincter operation, and peristalsis. Spinal afferent nerves from the GI tract also project to the dorsal horn of the spinal cord. Not shown in this diagram are the HPA axis and the immune systems, which are also important components of the gut-brain axis.
Figure 5.
Figure 5.
Implications of endocrine output of the gut microbiota in health and disease. The hormonal output of the gut microbiota is vital for host health and well-being. In addition to the local impact in the GI tract and ENS, it is also critical for control of host metabolism and the normal development of the immune system. Through as yet unknown mechanisms, the gut microbiota also seems to be able to regulate glucocorticoid production in the HPA axis. Similarly, through controlling the availability of the serotonin precursor tryptophan, the gut microbiota can potentially influence brain and behavior. Metabolites produced by the gut microbiota from choline can also affect the cardiovascular system.
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Grants and funding

The Alimentary Pharmabiotic Centre is a research center funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan. The authors and their work were supported by SFI (Grants SFI/12/RC/2273, 02/CE/B124, and 07/CE/B1368) and by the Health Research Board (HRB) through Health Research Awards (Grant HRA_POR/2011/23 to T.G.D., J.F.C., and G.C.). The Centre has conducted studies in collaboration with several companies including GSK, Pfizer, Wyeth, and Mead Johnson. J.F.C. is also funded by the European Community's Seventh Framework Programme (Grant FP7/2007–2013, Grant Agreement 201 714). G.C. is supported by a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation (Grant 20771).