Connecting gut microbiomes and short chain fatty acids with the serotonergic system and behavior in Gallus gallus and other avian species

Abstract

The chicken gastrointestinal tract has a diverse microbial community. There is increasing evidence for how this gut microbiome affects specific molecular pathways and the overall physiology, nervous system and behavior of the chicken host organism due to a growing number of studies investigating conditions such as host diet, antibiotics, probiotics, and germ-free and germ-reduced models. Systems-level investigations have revealed a network of microbiome-related interactions between the gut and state of health and behavior in chickens and other animals. While some microbial symbionts are crucial for maintaining stability and normal host physiology, there can also be dysbiosis, disruptions to nutrient flow, and other outcomes of dysregulation and disease. Likewise, alteration of the gut microbiome is found for chickens exhibiting differences in feather pecking (FP) behavior and this alteration is suspected to be responsible for behavioral change. In chickens and other organisms, serotonin is a chief neuromodulator that links gut microbes to the host brain as microbes modulate the serotonin secreted by the host's own intestinal enterochromaffin cells which can stimulate the central nervous system via the vagus nerve. A substantial part of the serotonergic network is conserved across birds and mammals. Broader investigations of multiple species and subsequent cross-comparisons may help to explore general functionality of this ancient system and its increasingly apparent central role in the gut-brain axis of vertebrates. Dysfunctional behavioral phenotypes from the serotonergic system moreover occur in both birds and mammals with, for example, FP in chickens and depression in humans. Recent studies of the intestine as a major site of serotonin synthesis have been identifying routes by which gut microbial metabolites regulate the chicken serotonergic system. This review in particular highlights the influence of gut microbial metabolite short chain fatty acids (SCFAs) on the serotonergic system. The role of SCFAs in physiological and brain disorders may be considerable because of their ability to cross intestinal as well as the blood-brain barriers, leading to influences on the serotonergic system via binding to receptors and epigenetic modulations. Examinations of these mechanisms may translate into a more general understanding of serotonergic system development within chickens and other avians.

Keywords: avians; behavior; chicken; gut microbiome; gut‐brain axis; serotonin; short chain fatty acids; translational science.

FIGURE 1

Microbial metabolite SCFAs transportation and role in gut serotonin production. Undissociated form of SCFAs in gut lumen diffuse through enterocytes while dissociated is transported through MCT1 into the circulation. Intestinal enterochromaffin cells synthesize serotonin from tryptophan using Tph1 enzyme. SCFAs in gut lumen stimulate Tph1 expression via zinc finger transcription factor. Secreted serotonin, before entering circulation, is either utilized in the liver or metabolized by enterocytes to 5-HIAA. Part of luminal SCFAs is utilized for energy production by enterocytes. Abbreviations: Enterochromaffin cells (ECC), serotonin (5-HT), zinc finger transcription factor (ZBP-89), tryptophan hydroxylase 1 (Tph1), 5-hydroxytryptophan (5-HTP), amino acid decarboxylase (AADC), monocarboxylated transporter 1 (MCT1), serotonin reuptake transporter (SERT), monoamine oxidase (MAO), hydroxyindoleacetic acid (5-HIAA), short Chain Fatty Acids (SCFAs) (Ritzhaupt et al., 1998; Bloemen et al., 2009; Essien et al., 2013; Reigstad et al., 2015). Figure created with BioRender.com.

FIGURE 2

Interaction of SCFAs and serotonergic system in the gut-brain axis. Part of the SCFAs produced in gut lumen interact with the central serotonergic system directly (crossing intestinal and blood-brain barrier) by epigenetic modulation and via activating extrinsic primary afferent vagus nerve (interaction of SCFAs through FFAR3). Serotonin is synthesized by both enterochromaffin cells of the gut epithelium and by gut microbiota. SCFAs also stimulate intestinal serotonin synthesis whereas extracellular serotonin binds to 5-HT3 receptors on afferent vagus nerve and communicates signals to the CNS. On the other hand, different external stressors affect gut microbial composition in birds through the HPA axis and influences production of microbial metabolites like SCFAs. The blue arrows indicate established connection in birds while the violet arrows indicate connections known to occur for some animals but not yet identified in birds (Liu et al., 2012; Sealy and Chalkley, 1978; Yamawaki et al., 2012; Huuskonen et al., 2004; Cook et al., 2021; Gill et al., 2013; Essien et al., 2013; Calefi et al., 2016; Noguera et al., 2018; Gershon and Tack, 2007; Meyer et al., 2012). Figure created with BioRender.com.