Background
The genetic FUT2 non-secretor status is phenotypically characterized by low levels of the glycan α1,2 fucose. Fucose in the intestines plays a crucial role in maintaining homeostasis between the gut and its microbiota, and loss of fucose can impair intestinal function and promote inflammation. While intestinal dysfunction and inflammation are well-documented in people with HIV (PWH), the potential link between the non-secretor genotype or phenotype and these pathological features remains unclear.
Methods
Ileum and colon biopsies, along with fecal samples, were collected from 25 PWH on antiretroviral therapy and 23 matched controls without HIV. Secretor genotype (based on rs516246 SNP) and FUT2 expression were determined by qPCR. Fucose levels in the ileum and colon were measured using a lectin array. Intestinal permeability was assessed by evaluating tight junction protein (ZO-1 and Occludin) expression through immunohistochemistry. Plasma markers of microbial translocation and inflammation were measured using multiplex arrays. Biological aging in the ileum, colon, and blood was assessed via epigenetic aging clocks. Fecal microbiota composition was analyzed using 16S rRNA sequencing.
Results
There was no difference in the frequency of the non-secretor genetic status between PWH and controls (p=0.3) or in FUT2 expression in the ileum or colon (p>0.5). However, phenotypically, α1,2 fucose levels were significantly reduced in the ileum (p<0.001; Fig. A) and colon (p=0.002) of PWH than controls. Lower fucose correlated (p<0.05) with increased intestinal permeability, elevated markers of microbial translocation (including Zonulin, LBP, sCD14), higher inflammatory markers (including CXCL9), and accelerated biological aging, as measured by the DunedinPACE and Horvath epigenetic clocks (Fig. B). Finally, lower fucose levels were linked to a dysbiotic microbiota, characterized by increased pro-inflammatory bacteria and reduced beneficial short-chain fatty acid producing bacteria (p<0.05).
Conclusions
Despite being genetically classified as secretors, PWH exhibit a non-secretor phenotype in their intestines, characterized by reduced levels of the anti-inflammatory fucose. This phenotype is associated with disrupted microbiota, compromised intestinal integrity, heightened inflammation, and accelerated biological aging. Understanding the mechanisms underlying this phenotype and its consequences may pave the way for developing novel strategies to prevent inflammation-associated comorbidities in PWH.