Federica Spaggiari MicrobiotaMi

MicrobiotaMi Comment 18_21  by Federica Spaggiari

Related Journal Article:  Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma

This article was published in the: Nat Commun. 2021 Jan 8;12(1):187. doi: 10.1038/s41467-020-20422-7

Does the gut microbiota influence the peripheral immune response in NAFLD-related hepatocellular carcinoma?

Dysbiosis is widely known as one of the causes and drivers of the rise and development of several and diverse diseases. Moreover, microbiota is able to modulate the organism’s immune response, mainly through its metabolic activity. Thus, the patient’s outcome is closely dependent on the ability of the microbiota to suppress or boost the immune system’s activity. In their work, J. Behary et Al. analyzed these dynamics in patients with NAFLD related cirrhosis and tried to understand the role that specific members of the gut microbiota have in hepatocellular carcinoma emergence from NAFLD and in peripheral immune response modulation via gut-liver axis.

The cohort that the group considered was made up of three subgroups: NAFLD-HCC, NAFLD-cirrhosis and non-NAFLD control. Primary analysis had the goal to make confrontations between the aforementioned groups, showing the differences in the abundance of immune cells and microbes diverse populations. The count of immune cells in the peripheral blood highlighted that NAFLD-HCC patients had higher percentages of Treg and lower percentages of CD8+ T cells compared to the other groups. Shotgun metagenomic sequencing on DNA extracted from fecal samples corroborated dysbiosis in liver disease. Bacteroides xylanisolvens, Ruminococcus gnavus and Clostridium bolteae were abundant in both NAFLD-cirrhosis and NAFLD-HCC. In particular, Bacteroidetes caecimuris and Veilonella parvula were specifically enriched in NAFLD-HCC. Interestingly, enriched species in the latter condition produce SCFAs that have immunomodulatory capability.

As expected, SCFAs production related genes, such as pycA, pta, ptb were over expressed in NAFLD-HCC and higher quantities of SCFAs and their intermediates were detected in NAFLD-HCC patients fecal and serum samples. Eventually, acetate, butyrate, propionate and formate turned out to be specifically abundant in this condition.

Ex-vivo experiments showed that the bacterial extract from NAFLD-HCC subjects promotes the expansion of IL-10 producers Tregs and diminishes CD8+ and CD4+ T cells one. Moreover, it reduces the development of both monocytes and B cells. In general, BE from hepatocellular carcinoma patients is responsible for the suppression of a pro-inflammatory environment through an inhibition in IL-2 and IL-12 production.

As expected, a positive correlation, with few exceptions, was detected between NAFLD-HCC specific microbiota and Treg cells abundance. By contrast, CD8+ T cells showed to be inversely associated with the same bacterial populations. Not surprisingly, the exact same dynamics were described between Tregs and CD8+ T cells and butyrate quantities.

All in all, J. Behary et Al. study provides unprecedented insights of the hepatocellular carcinoma microbial signature, highlighting the role that Bacteroidetes and Ruminococcaceae, specifically enriched in this pathological condition, have in the progression and aggravation of patients’ condition. In particular, they promote immune tolerance and suppress cytotoxic activity acting on the peripheral immune system. Even though divergent opinions exist on the topic, the study supports the theory that abundant SCFAs, in particular butyrate, can create a tumor promoting environment.

The collected evidence could be helpful to design innovative and beneficial therapeutic strategies in order to avoid the establishment of an immune tolerance condition and the inhibition of the CD8+ T cell action. This can be achieved by operating at both microbiota composition or SCFAs production level. Targeting HCC enriched species or reducing the abundance of certain SCFAs, for example through the temporary modification of the diet, could be alternative approaches for more focused and tailored treatments.

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