13Intestinal microbiota in liver disease
Introduction
The intestinal microbiota consist of the populations of bacteria, viruses, fungi and parasites that colonize the gastrointestinal tract from the mouth to the colon [1]. The vast majority of what is known about the microbiota comes from studies done on the 1014 mostly anaerobic bacteria which live in changing composition as we observe them from proximally to distally in the gut [2]. The composition of the microbiota varies with intestinal niche as well as host age, gender, ethnicity, diet and geographic location [1], [3]. The microbiota play varied roles in health and disease; from symbiotic partner to colonizer to pathogen.
The liver receives the majority of its blood supply via the portal vein and thus becomes the first filter of nutrients absorbed by the intestines. The intestinal microbiota break down non-digestible carbohydrates into short chain fatty acids that can serve as an energy source for intestinal epithelium. Additionally, the liver is the first filter of microbiota generated by-products such as endotoxin (lipopolysaccharide or LPS), bacterial metabolites (peptidoglycans) and bacterial DNA, collectively referred to as pathogen associated molecular patterns (PAMPs). Disruptions in gut wall integrity may qualitatively and quantitatively influence the PAMPs to which the liver is exposed and influence the progression of various liver diseases.
The intestinal microbiota may be altered, intentionally or unintentionally, through dietary changes, antibiotic use or probiotic supplementation. Currently, antibiotics are frequently employed to treat or prophylax against several of the manifestations of end stage liver disease [4], [5], [6]. There is emerging evidence of the microbiota's role in obesity, non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), alcohol induced liver disease and even hepatocellular carcinoma (HCC) and the potential for probiotics supplementation to mitigate these diseases' progression.
Section snippets
Energy homeostasis
The intestinal microbiota have developed a symbiotic relationship with its human host over the millennia and play a role in providing energy substrate for cells. Non digestible plant polysaccharides are fermented to short chain fatty acids (SCFA). SCFA serve as an energy source to host intestinal epithelium. Butyrate is the preferred energy substrate for colonocytes and its metabolism provides key substrates in cell metabolism [7]. SCFA also act as regulators of gut hormones like glucagon-like
The inflammatory cascade
The role of microbiota in liver disease largely derives from the inflammatory pathway that is triggered from the interaction between gut bacteria, the liver, and the immune system. At the heart of the process, is the interplay of the liver's macrophages, Kupffer cells, and PAMPs. One particular PAMP, endotoxin or lipopolysaccharide (LPS), is able to activate Kupffer cells at low levels by binding to Toll like receptors (specifically TLR 4), with the purpose of trying to clear pathogens from the
Antimicrobials
The role of altering microbiota for therapeutic potential is a burgeoning area for research in the field.
Neomycin has been a commonly used drug in mouse models examining the endotoxin phenomenon seen in liver disease. In a study by Broitman et al., the introduction of neomycin in rats fed a choline deficient diet had protective effects against fibrosis and cirrhosis. This was thought to be via reduction of endotoxin producing organisms [52]. Regarding its use in the treatment of hepatic
Conclusions
The intestinal microbiota have a wide ranging role in liver health and disease. As a symbiotic group of organisms, the microbiota and many of its products regulate energy metabolism, gut barrier integrity, immune activation and contribute to overall host homeostasis. When in dysbiosis, microbiota products can influence liver disease. The microbiota act in NALFD/NASH, via mediation of diabetes, obesity and PAMPs delivered to the liver, in alcohol induced liver disease via increased gut wall
Conflict of interests
The authors have no relevant conflicts.
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