Parasites of parasites

Bacteriophages, which were briefly utilized as clinical antimicrobials in the early 20th century, present an opportunity to selectively reduce populations of undesirable microorganisms.  specific populations can be altered in response to treatment, including increases in members of the butyrate-producing genera Eubacterium and a decreased proportion of taxa most closely related to Clostridium perfringens. A small but significant decrease in circulating interleukin-4 (Il-4) can be obtained. data demonstrate the potential of bacteriophages to selectively reduce target organisms without global disruption of the gut community. 

The safety of phage use in gastrointestinal disorders has been demonstrated in clinical studies. 

Although bacteriophages (phages) and eukaryotic viruses (collectively known as “the virome”) outnumber bacteria and fungi in the intestine, little is known about the intestinal virome in patients with liver disease.  Microbial communities are composed of bacteria, fungi, viruses, and archaea that together encode over a hundred-fold more genes than the human genome [

The human intestinal virome is made up of about 90% bacteriophages (phages or prokaryotic viruses) and 10% eukaryotic viruses. Eukaryotic DNA and RNA viruses include plant and mammalian viruses and can have intestinal cells as their host. Some eukaryotic viruses can affect human health by causing disease, like the well-known enteric pathogens Norovirus, Rotavirus, and Enterovirus, while others are not pathogenic. Plant viruses are likely derived from the diet. On the other hand, the phageome consists of approximately 10(>15) bacteriophages and is largely composed of the order Caudovirales (family Siphoviridae, Myoviridae, and Podoviridae) and family Microviridae. In healthy subjects, the intestinal viral microbiome exhibits a high level of interpersonal heterogeneity with relative intrapersonal stability. However, changes in the virome community can be seen with changes in lifestyle such as diet and with different disease states. Deep sequencing of the intestinal viral microbiome in healthy individuals suggests that there is a small core group of phages shared among a majority of people, with a wider range of more rare phages that are unique to individuals. Understanding how the composition of the intestinal viral microbiome differs amongst individuals with different disease states will help elucidate the mechanism by which the viral microbiome influences disease. Already, differences in the viral microbiome have been implicated in the pathogenesis of obesity, type 2 diabetes, colon cancer, inflammatory bowel disease, and more.

Existing strategies for reversing or preventing progression of liver disease are limited and often liver transplantation is the only therapy available to patients once they progress to end-stage liver disease. Improved understanding of how the intestinal microbiome contributes to liver disease and with that, there emerges a complementary strategy in targeting the intestinal microbiome to treat liver disease. Both eukaryotic viruses and bacteriophages have been implicated in liver disease pathogenesis. Among the eukaryotic viruses are the known pathogenic and hepatotropic viruses, hepatitis A (Picornaviridae family) and E (Hepeviridae family) viruses, which can be transmitted by the oral-fecal route and detected in stool. Both HAV and HEV exist in two forms, a non-enveloped form comprised of a capsid surrounding the RNA genome and a quasi-enveloped form that is masquerading in a layer of host cell membrane. The non-enveloped form, which is found in the stool and saliva of infected individuals, can survive harsh conditions such as transit through the gastrointestinal tract and cross the intestinal barrier into the blood via mechanisms not yet well understood. 

There is evidence that once in the blood, HAV harnesses endosomal gangliosides to infect hepatocytes and Kupffer cells, where it replicates and exits back into the bloodstream in its quasi-enveloped form, which camouflages its antigenic proteins from neutralizing antibodies. Other known eukaryotic viruses that can be found in the intestinal virome and cause liver injury include Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Mammalian gut microbiomes and viromes can profoundly influence host fitness. Commensal gut bacteria and viruses beneficially interact with the host immune system and produce a wide range of secondary metabolites that can be beneficial for host physiology. In return, these self-invited guests depend on their host to maintain a stable ecosystem and access to nutrients.

Recent studies suggest that mammals and their individual gut symbionts can have parallel evolutionary histories, as represented by their congruent phylogenies.These so called 'co-phylogenetic' patterns can be seen as signatures of ancient co-speciation events. These patterns illustrate the possible cohesiveness of the mammalian host-gut microbiome/virome entity over evolutionary times. Current theory predicts that co-speciation between mammals and their gut symbionts could result from their  co-evolution. There is, however, only very limited evidence of such a co-evolution. Models can be developped that explain cophylogenetic patterns without relying on co-evolution. Individual gut bacteria and viruses are likely to diverge in patterns recapitulating host phylogeny when hosts undergo allopatric speciation, limiting inter-host bacterial/viral dispersal and genomic recombination.

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Steering Gut Symbiont-systems

Mammals have evolved complex mechanisms to control the composition and density of the gut microbiome/virome. The possible disruption of these mechanisms, in disease, strongly impacts gut inflammation, epithelium integrity, and overall homeostasis.

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Co-evolution as system model is likely too weak 

Although host fitness strongly depends on a wide variety of functions performed by its gut microbiome/virome (synthesis of certain vitamins, digestion of certain complex glycans, degradation of certain xenobiotics, certain coherence of the immune system and a competitive exlusion of possible pathogens) the contribution of individual baceria/viruses to the host fitness is predicted to be weak for two reasons.

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Host biogeography as a possible driver for co-phylogenic systems 

Supposed prerequisites

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