Low diversity gut microbiota dysbiosis: drivers, functional implications and recovery

Abstract

Dysbiosis, an imbalance in microbial communities, is linked with disease when this imbalance disturbs microbiota functions essential for maintaining health or introduces processes that promote disease. Dysbiosis in disease is predicted when microbiota differ compositionally from a healthy control population, but only truly defined when these differences are mechanistically related to adverse phenotypes. For the human gut microbiota, dysbiosis varies across diseases. One common manifestation is replacement of the complex community of anaerobes typical of the healthy adult gut microbiome with a community of lower overall microbial diversity and increased facultative anaerobes. Here we review diseases in which low-diversity dysbiosis has been observed and mechanistically linked with disease, with a particular focus on liver disease, inflammatory bowel disease, and Clostridium difficile infection.

Figure 1.. Recovery from disturbance through secondary succession:

An insult (e.g. antibiotics) raises intraluminal oxygen concentrations leading to a bloom of facultative anaerobes. One factor in recovery may be oxygen-tolerant anaerobes that are able to colonize and reestablish butyrate production. Colonocyte metabolism of butyrate depletes luminal oxygen allowing for further colonization by anaerobes. Interdependent metabolic networks of the anaerobes are restarted and the mature, complex climax community of the healthy adult gut is reached.

Figure 2.. Gut-liver axis.

Low-diversity dysbiosis is a significant contributor to the development and progression of chronic liver disease. Drivers of low-diversity dysbiosis include both environmental (diet, alcohol, antibiotics) and genetic determinants. Low-diversity dysbiosis is characterized by relative increases in facultative anaerobes, possibly due to loss of intraluminal hypoxia leading to changes not only in microbiota composition but also function. Carnitine is metabolized by facultative anaerobic bacteria and as this population expands, production of hepatotoxic trimethylamine (TMA) increases. Ethanol, both as a fermentation product of cellulosic substrates and as a fermentation substrate leading to acetaldehyde, disrupts intestinal tight junctions and is a mediator of both mucosal and hepatic inflammation. Reciprocal loss of butyrate-producing bacteria leads to reduction in butyrate formation, further compromising colonocytes and promoting bacterial translocation. Collectively, these functional changes lead to increases in bacterial load in the portal vein and delivery of inflammatory mediators (TMA, LPS, ethanol) to the liver with reduction in anti-inflammatory metabolites (SCFA). Within the liver, this leads to increased oxidative stress, marked inflammation, and fibrogenesis. As liver disease progresses, there is impaired hepatic synthesis of both primary and secondary bile acids, further driving low-diversity dysbiosis. Therapeutic interventions aimed to facilitate microbiome recovery include probiotics and FMT. Liver transplantation also leads to microbiome recovery and is a novel clinical model to assess the kinetics of recovery of low-diversity dysbiosis and its functional consequences. (TMA = trimethylamine; LPS = lipopolysaccharide; FMT = fecal microbial transplant)