Is It Time to Consider Gut Microbiome Readouts for Precision Diagnosis and Treatment of Alcoholic Liver Disease?

Potential conflict of interest: Nothing to report. See Article on Page 271 The mutualistic relationship that exists between gut microbes and the host aids in digestion and metabolism, defends against pathogens, and supports host immunity. Beneficial gut microbes and phages use various mechanisms to facilitate host defense, including competing for nutritional resources, producing antibiotics, providing metabolic inhibition, and spatial occlusion, as well as communicating with the host immune system. The human microbiome has the potential to be used as an early detection biomarker and tool to guide medical therapy, and the current research scenario focuses on envisaging its therapeutic role. Thus, this lends to the importance of the research presented by Smirnova et al., who investigated whether alcoholic hepatitis (AH) and its severity could be identified through readouts from the gut microbiome and metabolome.(1) Patients with AH are at high risk for mortality, and to complicate care for these patients, AH pathogenesis is not fully understood. Given that it is uncertain why only a subset of people chronically consuming high levels of alcohol develop AH, there are likely other personalized factors driving this disease, such as the gut microbiome. Most microbial ecology analyses aim to identify a specific microbiome arrangement associated with a stressor or disease. This may be accomplished by measuring microbial community properties, such as richness, evenness, and β‐diversity, using high‐throughput marker gene or shotgun metagenomics data. Smirnova et al. interrogated and characterized collected stool samples from patients with AH, mild and severe, to that of patients who are heavy drinkers without liver disease, as well as to healthy controls.(1) Samples from each subject group underwent analysis with 16S ribosomal RNA sequencing, inferred functional metagenomics, and stool metabolomics for short‐chain fatty acids (SCFAs) using a liquid chromatography/mass spectrometry platform. In the groups studied, the investigators were evaluating gut microbiomic and metabolomic changes induced by both a stressor (chronic high‐dose alcohol) and disease (alcoholic hepatitis). The investigators reported that compared to the healthy controls, Bacteroidetes abundance was depleted in heavy‐drinking controls, Firmicutes abundance declined in the alcohol groups, and Proteobacteria abundance was elevated most in patients with severe AH. Patients with AH had lower abundance of SCFA‐producing bacteria and SCFAs. And whereas there were microbiomic and metabolomic changes noted with both the stressor (alcohol) and disease (alcoholic hepatitis), no differences were found between the disease severity groups. Multiple confounding factors contribute to microbiota variation (Fig. 1). These factors include age, dietary habits, intestinal dysmotility, medications, and metabolic stress.(2) This may explain an important part of inter‐ and intraindividual variation in community composition and richness, regardless of host health. The alcohol‐consuming patients enrolled in the Smirnova et al.(1) study were of varying levels of disease severity and in different environments at time of stool collection. The majority of heavy alcohol control subjects had stool samples collected in an outpatient setting, whereas those with AH had sampling within 72 hours of hospital admission. Metabolic stress in itself is known to induce alterations in the gut microbiome compared to healthy controls,(3) and this has been reported to occur early following a metabolic insult and to be sustained throughout hospitalization.(3) Likewise, diet is a strong factor known to influence gut microbiome composition and function. Unfortunately, hospitalized patients are fed suboptimally, and if a meal is provided, it typically is lacking in the fermentable soluble fibers which serve as a food source for the gut microbiome, or the patient may not eat well for various reasons. A diet lacking in gut‐microbe–promoting nutrients could also lend to the variations found in the gut microbiome (e.g., SCFA‐producing bacteria) and inferred function metagenomics and SCFA levels. Most hospitalized patients receive antibiotics, and a large number of metabolically stressed patients receive acid‐suppressing medications (e.g., proton pump inhibitors [PPIs] or histamine 2‐antagonists). Both antibiotics and acid suppressants are known to alter the gut microbiota,(2,4) with PPIs being linked with small intestinal bacterial overgrowth, spontaneous bacterial peritonitis, and Clostridioides difficile infection.(2) The severe AH patients in this study were reported to have received more acid suppressants than the other patient groups, and although this was not realized with changes in fecal microbial composition, other metabolites or metabolic pathways not interrogated here consequentially may have been altered. Also, fecal samples are not necessarily reflective of the luminal microbiome, particularly the small intestine, where the incidence of small intestinal bacterial overgrowth is high among patients with chronic liver disease.(5) Stool microbiota composition and metabolism should be considered as if they represent snapshots of an ecosystem caught in a process of dynamic development. Gut microbial succession events seem to be influenced by a constant variation occurring over time and among individuals attributed to host physiology‐ and lifestyle‐selective pressure, rather than following deterministic patterns.(6) Therefore, whether these changes observed by Smirnova et al.(1) persist longitudinally would be of interest for future study.Fig. 1: Factors influencing the gut microbiome.A host stressor does not necessarily need to shift the gut microbiome to a specific dysbiotic arrangement in order to reduce host fitness, rather a stressor only needs to release normal regulation of microbiome membership. Therefore, despite the importance of microbial clustering, the full range of dynamics needed to understand the contribution of microbes to host health and disease may not be fully realized with these community patterns. Rather than having deterministic effects on microbial composition, certain stressors may have stochastic effects. To this concept, an Anna Karenina principle has been proposed by several fields of study, including microbiome investigators.(7‐9) This principle derives from the opening line of Tolstoy's Anna Karenina: "all happy families are all alike; each unhappy family is unhappy in its own way." The Anna Karenina principle states that a deficiency in any one number of factors dooms an endeavor to failure. Consequently, a successful endeavor (subject to this principle) is one where every possible deficiency has been avoided. This work by Smirnova et al.(1) corroborates that of several researchers in the field, which have also found that alcoholic liver disease (ALD) is associated with disruptions in the gut microbiome.(10) Laying the foundation, these studies support the need of a personalized approach which takes into consideration gut microbiomic and metabolomic influences when identifying and managing ALD. To accomplish this, future studies should aim for longitudinal methodological designs that account for confounders that may have, or currently are, impacting the gut microbiome and the extent of ALD.