{'fraction_non_alphanumeric': 0.025608465608465608, 'fraction_numerical': 0.011428571428571429, 'mean_word_length': 5.646976090014065, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Determinants of the severity of fatty liver diseases: Need all the pieces to solve the puzzle

Fatty liver disease (FLD) severity is determined by the interaction of many conditions, among them host genetics, nutrition, hormones, and the gut microbiome. Natural history studies of FLD clearly demonstrate the prognostic significance of liver fibrosis (LF) and show that increased allcause, and liverrelated, mortality mainly occur in persons who develop advanced fibrosis (AF). However, the factors that determine fibrosis progression are poorly understood. Most studies that aimed to identify the determinants of fibrosis in FLD were large crosssectional studies focusing on one, or at most a few, of the putative pathogenic conditions because data sets with concurrent information about LF severity, host genetics, diet/alcohol consumption, and gut microbiome are rare. In this issue of Hepatology, Kwan et al. report on an elegant study of an adult cohort with a spectrum of risk for FLD. Their findings link differences in LF severity, host genetics, and alcohol consumption with differences in gut microbial taxonomy and metagenomics. Briefly, the researchers analyzed comprehensive data from 217 Hispanic subjects who tested negative for viral hepatitis in the Cameron County Hispanic Cohort (CCHC) from South Texas.[1] Subjects in the cohort varied with regard to risk factors for FLD (~55% obese, 35% diabetic), presence of hepatic steatosis (67%), and LF severity (14% fibrosis overall; 6.5% advanced F3F4 fibrosis). The population was segregated into four groups based on gut microbiome taxonomy; the group that was most enriched with Prevotelloceae also included the most alcohol drinkers and had both the highest mean level of fibrosis and the greatest number of persons with AF. Further analysis demonstrated a significant correlation between Prevotella and fibrosis severity. Importantly, Prevotella abundance also correlated with alcohol consumption, even when heavy drinkers were excluded, suggesting that alcohol consumption per se reconfigured microbial taxonomy in the gut. To determine whether host genetics might also have influenced Prevotella abundance, the cohort was divided into groups with high versus low Prevotella abundance and screened for genetic differences using a combination of genomewide association studies and targeted PCR for selected singlenucleotide polymorphisms (SNPs). Prevotella abundance was found to strongly correlate with two SNPs (rs3769502 and rs7573751) in the NCK adaptor protein 2 (NCK2) gene (which encodes a factor that regulates Tcell receptor signaling). Interestingly, one of these SNPs was significantly more common in the South Texas Hispanic cohort than in a European cohort, suggesting that this host genetic factor might contribute ethnic differences in fibrosis severity through its effects on gut microbiome composition. Finally, the investigators performed metagenomics analysis to determine whether differences in bacterial metabolic activities would be mapped to differences in LF. Advanced LF was associated with decreased bacterial biosynthesis of fucose, lipoic acid, and certain B and K vitamins, as well as impaired urea cycle activity and enhanced ammoniagenesis, together providing a metagenomic “signature” that predicted LF with a receiver operator curve (ROC) of 0.87. The researchers reason that the signature has plausible pathobiological relevance for LF given that fucose depletion is predicted to disrupt hostmicrobial symbiosis and ammonia accumulation/ lipoic acid– B vitamin deficiency has been linked to oxidative stress. Although these findings are important and provocative, some study limitations merit mentioning. First, the study population included Hispanic subjects from one region of the USA. Therefore, the results obtained must be interpreted in that particular context without further generalization. Second, steatosis and LF diagnoses relied on noninvasive measurements generated by transient elastography. Liver stiffness and controlled attenuation parameter measurements provide good area under the ROC for the diagnosis of LF and steatosis, but at the thresholds used (respectively 7.1 kPa and 268 dB/m), false positives are frequent in settings where the prevalence of fibrosis is low, as observed in the CCHC cohort.[2,3] Finally, the researchers performed successive correlation analyses, each one considering only two conditions: gut microbiome and fibrosis; fibrosisassociated bacterial taxa and diet; Prevotella abundance and host genetics; and LF and gut metagenomics. Moreover, some of these analyses were performed in different subsets of the study cohort. Received: 12 December 2021 | Accepted: 12 December 2021