**5.1 Metabolic disorders**

Most genes and pathways that play crucial roles in metabolic diseases are conserved between flies and humans [268]. Diet-induced obesity in flies is associated with many of the pathophysiological consequences found in humans, including hyperglycemia, insulin resistance, cardiac arrhythmia and fibrosis, reduced longevity [269, 270] and nephrosis [271]. The gut is crucial for peripheral body fat storage and serves as a major site of dietary lipid absorption and absorbs other dietary macronutrients (sugars, proteins and fats). It also metabolizes both glucose and lipids into metabolic intermediates, which after loading into hemolymph get used in other tissues and organs. In flies, lipoprotein complexes containing apolipophorins carry sterols and diacylglycerols from the gut to other tissues [81]. Fly lipoproteins also contain Hh, a cholesterol-linked, gut-derived ligand that binds the transmembrane receptor Patched on fat body target cells to promote lipolysis during larval starvation [241, 272]. The human anti-obesity drug orlistat, a gastric lipase inhibitor, has been shown to reduce body fat accumulation in adult flies [56]. Supporting a crucial role for lipolysis, midgut lipid accumulation and global fat storage are reduced by the insulin signaling pathway inhibitor Foxo in enterocytes, via reducing the expression of *magro* as flies age [58]. Excessive lipid accumulation in the fly gut and fat body is also a feature of 'humanized' flies upon cross-species expression of the human peptide neurotensin in *Drosophila* midgut EE cells. Obesity in these flies is triggered by an evolutionarily conserved mechanism acting via the cellular energy sensor 5′ adenosine monophosphate (AMP)-activated protein kinase [229]. Additionally, the acidic pH of the gastric lumen may be important for fly obesity given that both global vacuolar-type H+ -adenosine triphosphatase (ATPase) mutants and flies treated with pharmacological inhibitors of alimentary acidity store extra fat [273]. This effect could be mediated via the gut microbiome, which both shapes and depends upon the acidity of the gut [88]. Collectively, these data emphasize the importance of gut physiology for fat homeostasis in *Drosophila* and highlight the intricate interaction between the gut epithelium and the gut microbiome.

The gut microbiota and its metabolism plays an important role in modulation of fat storage in the fly. As seen in humans, fly gut is enriched in *Lactobacillus* and *Acetobacter* species. Adult axenic flies overstore fats under various dietary conditions compared with natural gut microbiota flies [274]. *Lactobacillus* sp. abundance supports co-colonization by *Acetobacter* sp. in the adult gut, which in turn negatively correlates with the fat storage level of the fly [275]. The diet of a fly impacts the composition of the gut microbiota as a high-sugar diet shifts the gut microbiome to uracil-producing species, which promote fat storage and growth in *Drosophila* larvae [276]. The availability of dietary glucose to the adult fly depends on the microbiome because flies with commensal *Acetobacter tropicalis* eat more than axenic flies but store less TAG owing to the consumption of dietary sugar by the bacteria [277].

### **5.2 Neurodegenerative diseases**

**Alzheimer's disease (AD):** AD is a progressive neurodegenerative disease characterized by senile plaques consisting of misfolded β-amyloid (Aβ) fibrils and oligomers [278]. Presence of hyper phosphorylated tau protein in the various regions of the brain including cerebral cortex, locus coeruleus, and hippocampus [279] has also been suggested. Microbial dysbiosis [280], dietary changes [281], probiotics [282], or a variety of other disease conditions [283, 284] results in involvement of the GBA in the pathophysiology of neurodegenerative diseases. Multiple studies have shown an association between gut microbiome dysbiosis and the aggregation of Aβ peptides in intestinal epithelial cells [285, 286] and the CNS [287, 288] after high-fat diet feeding. Many neurodegenerative diseases exhibit accumulation of fibrillary, misfolded proteins similar to the propagation of prionopathies in the CNS [289]. Prionopathy also involves the GBA and the local immune system, where prions accumulate in dendritic cells in the Peyer's patches and other lymphoid follicles once entering the intestinal epithelium layer [290]. Senescenceaccelerated mouse model studies have identified systemic senile amyloid proteins in Peyer's patches [291]. By interacting with dendritic cells, the misfolded protein may transport to the ENS, and ultimately spread to the CNS compartment [290]. Gut bacteria can affect peripheral nerve functions through the production of neuromodulatory metabolites such as short-chain fatty acid (SCFAs) [292]. It has been suggested that Lactobacillus probiotics, given orally through feeding, showed improvement in the rough-eye phenotype, famous of the AD flies [293] and reduces *Wolbachia's* presence in the gut, which is known to be associated to neurodegenerative disorders. These studies emphasize on the relation between gut microbiota, GBA and the disorder. Pharmaceutical companies are hence targeting these probiotics and prebiotics in order to treat the disorder.

**Parkinson's disease (PD):** PD is a progressive brain disorder like other neurodegenerative diseases affects thinking, mobility, walking, balance and coordination. Research on PD using *Drosophila* has revealed links between gut microbiota composition and PD to one of the major genes *parkin*, which in an autosomal recessive fashion causes this disease [294, 295]**.** Both *Parkin* and *PINK1* genes disturb mitochondrial function and integration in PD patients. *Parkin* mutants shows steep rise in gut microbiota in comparison to control flies. Also *PINK1* mutants did not show much of a difference suggesting that gut microbiome gets affected independently in both autosomal recessive genes [294]. It is also found that *parkin* gene in ECs is required to maintain the microbial load. It has been seen that the microbial composition in *parkin* mutants is drastically different from those of wild-type flies.

**Autism spectrum disorder (ASD):** ASD is a developmental brain disorder characterized by impaired social behavior and disrupted communication and language. Loss of function mutants of histone demethylase KDM5 in *Drosophila* show how change in the abundance and composition of gut microbiota leads to impairment of social behavior, characteristic of ASD. Decreased levels of KDM5 cause intestinal epithelium disruption. As opposed to the control flies, the presences of gases produced by the overgrowth of bacteria cause bubble formation in the midgut in mutants [296]. It is found that KDM5 mutant flies has different composition of gut flora than controls [296]. The administered of *Lactobacillus plantarum* to KDM5 mutant flies rescued social behavior and other intestinal defects. Flies supplemented with *L. plantarum* also shows 2.3 fold increase approximately in longevity [296]. *kdm5*JmjC\**,* another kind of KDM5 mutant displayed impaired gut permeability, intestinal epithelium and microbiota. In this case as well, administration of *L. plantarum* rescued gut permeability, the

### *Gut Feeding the Brain:* Drosophila *Gut an Animal Model for Medicine to Understand… DOI: http://dx.doi.org/10.5772/intechopen.96503*

defective social interaction and communication. These studies have helped establishing a link between gut microbiota and ASD. The probiotics that rescued ASD flies are good candidates for pharmaceutical companies to be sold as therapeutic. These results can be used for drug discovery and in treatment of these otherwise, untreatable disorders.
