Growing up in a Bubble: Using Germ-Free Animals to Assess the Influence of the Gut Microbiota on Brain and Behavior

Abstract

There is a growing recognition of the importance of the commensal intestinal microbiota in the development and later function of the central nervous system. Research using germ-free mice (mice raised without any exposure to microorganisms) has provided some of the most persuasive evidence for a role of these bacteria in gut-brain signalling. Key findings show that the microbiota is necessary for normal stress responsivity, anxiety-like behaviors, sociability, and cognition. Furthermore, the microbiota maintains central nervous system homeostasis by regulating immune function and blood brain barrier integrity. Studies have also found that the gut microbiota influences neurotransmitter, synaptic, and neurotrophic signalling systems and neurogenesis. The principle advantage of the germ-free mouse model is in proof-of-principle studies and that a complete microbiota or defined consortiums of bacteria can be introduced at various developmental time points. However, a germ-free upbringing can induce permanent neurodevelopmental deficits that may deem the model unsuitable for specific scientific queries that do not involve early-life microbial deficiency. As such, alternatives and complementary strategies to the germ-free model are warranted and include antibiotic treatment to create microbiota-deficient animals at distinct time points across the lifespan. Increasing our understanding of the impact of the gut microbiota on brain and behavior has the potential to inform novel management strategies for stress-related gastrointestinal and neuropsychiatric disorders.

Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat

“…CNS transcriptional regulation has emerged as a prominent feature of the gut microbiota (Stilling et al 2014b;Luczynski et al 2016). GF studies have highlighted that expression of BDNF is highly dysregulated in these animals.…”

“…However, GF studies have several limitations Lundberg et al, 2016) and ultimately there is no translational equivalent, especially during critical neurodevelopmental windows. For example, GF animals are born under aseptic conditions where they are maintained in the absence of any colonizing bacteria throughout their lifetime (Williams, 2014;Luczynski et al, 2016). Therefore, there is a rapidly growing need for more informative and gut-specific approaches such a humanized microbiota-associated mice (Arrieta et al, 2016) to investigate microbiota-mediated signaling along the gut-brain axis.…”

The Microbiota, the Gut and the Brain in Eating and Alcohol Use Disorders: A ‘Ménage à Trois’?

“…Mice lacking microbes have marked changes in striatal (Diaz Heijtz et al, 2011), amygdala (Stilling et al, 2015), hippocampal (Neufeld et al, 2011;Clarke et al, 2013) and cortical (Hoban et al, 2016) gene expression, in addition to alterations at the morphological and spine density level (Luczynski et al, 2016b). Such findings are coupled with an exaggerated hypothalamic-pituitary-adrenal axis response and changes in anxiety, cognitive and social behaviors (Luczynski et al, 2016a). These brain (Becker et al, 1999;Lindvall Dahlgren and Wisting, 2016) Alcohol and substance use disorders ▪ Substance use disorders-cluster of cognitive, behavioral and physiological symptoms indicating that the individual continues using a substance despite significant substance-related problems (American Psychiatric Association, 2013) Alcohol and substance use disorders ▪ Underlying change in brain circuits that persist beyond detoxification; behavioral effects of these changes can be seen in relapse and craving (American Psychiatric Association, 2013) ▪ Symptoms include, but are not limited to craving, withdrawal, and tolerance ▪ Share similar neural correlates with Eating disorders with regard to altered reward signaling; involve issues with impulse control (Schulte et al, 2016) Substance use disorders ▪ 12-month prevalence and lifetime prevalence were 3.9% and 9.9%, respectively from 2012-2013 in the United States (Grant et al, 2016) ▪ Alcohol use disorders-medical diagnosis for severe problem drinking that consists of both physical and behavioral symptoms (American Psychiatric Association, 2013) Alcohol use disorders ▪ 12-month prevalence and lifetime prevalence were 13.9% and 29.1%, respectively (Grant et al, 2015) ▪ Harmful use of alcohol is leading cause of morbidity and mortality (Whiteford et al, 2013;Grant et al, 2015); accounts for approximately 2.5 million deaths per year worldwide (World Health Organization, 2011); fourth leading cause of disability worldwide (Whiteford et al, 2013) areas and behaviors are involved in ED and alcohol and substance use disorders pathology, thus it is plausible that the gut microbiota plays a role in such disorders.…”

Envolvimento Da Flora Intestinal Na Modulação De Doenças Psiquiátricas

“…As bactérias intestinais também são particularmente importantes para a síntese de triptofano, um aminoácido essencial para a síntese proteica e do 5-hidroxitriptano (serotonina), melatonina e metabólitos como o ácido quinurênico, ácido quinolínico e nicotinamida (36)(37)(38)(39)(40). Estudos que investigam o impacto de alterações da flora intestinal sobre o organismo -como através do uso de animais livres de germes (germ-free), tratados com antibióticos e probióticos, com infecção do trato GI ou através do transplante de fezes -sugerem que a comunicação encéfalo-intestinal é fortemente influenciada pela flora intestinal, modulando desde o funcionamento neuronal até o comportamento do indivíduo (1,(41)(42)(43). Os principais aspectos relacionados à comunicação existente entre o intestino e o encéfalo serão discutido a seguir.…”