Inulin fiber supplement raises gut permeability marker in people with well-controlled HIV

A daily dose of the soluble fiber inulin, widely promoted as a gut-friendly prebiotic, produced an unexpected result in people living with well-controlled HIV and multiple metabolic disorders: every single participant in a small pilot study saw their zonulin levels rise sharply over just six weeks. Zonulin is an indirect biomarker of gut permeability, meaning the protein’s presence in serum is associated with increased intestinal leakiness. The finding, published in Frontiers in Molecular Medicine, runs counter to what researchers expected based on earlier fiber supplementation trials in other populations, and it raises questions about whether standard dietary advice around fiber applies uniformly across different patient groups.

The study enrolled ten participants from the Center for AIDS Research and Treatment at North Shore University Hospital, part of the Northwell Health system in the New York City metropolitan area. All had HIV viral loads below 100 copies per milliliter for at least six months, meeting the study’s definition of well-controlled infection, and all carried at least three acquired metabolic disorders. Every subject had type 2 diabetes mellitus. Nine had elevated body mass index, with seven in the obese range above 30 kilograms per square meter. Hyperlipidemia was present in seven participants and hypertension in six. Three had established cardiovascular disease, including one who had undergone coronary artery bypass grafting and another who had received a cardiac transplant for ischemic cardiomyopathy. The median age was 60.5 years, with an interquartile range of 55 to 66, and eight of the ten were male.

Each participant received organic inulin powder and was instructed to take 12 grams once daily during a one-week lead-in period, then increase to 24 grams daily, split into two doses, for the remaining 42 days of the intervention. This dosing scheme mirrored that of a previous randomized, double-blind, placebo-controlled, cross-over trial by Chambers and colleagues, which tested inulin and an inulin-propionate ester in adults with elevated body mass index ranging from 25 to 40 kilograms per square meter. In that earlier work, both inulin formulations significantly improved insulin resistance compared with a low-fermentable cellulose control, reduced interleukin-8 levels, and shifted gut bacterial composition, increasing Actinobacteria while decreasing Clostridia classes and specific Firmicutes species. The Northwell team wanted to know whether the same supplement would produce comparable metabolic benefits in a very different patient population.

The primary endpoint was the change in serum zonulin between baseline and six weeks. Zonulin is a protein expressed by gut epithelial cells that disassembles the tight junctions between them, increasing intestinal permeability. Identified as pre-haptoglobin-2, it acts as a regulator of the intestinal barrier, and elevated serum levels occur in states of increased permeability. Because it is measured in blood rather than through direct permeability testing, researchers describe it as an indirect biomarker. Elevated zonulin has been linked to a wide range of conditions, including type 1 diabetes, inflammatory bowel disease, multiple sclerosis, obesity, polycystic ovary syndrome, asthma, coronary artery disease, and HIV itself. Prior work has shown that treatment-naive people with HIV and those with CD4 counts below 350 cells per microliter carry higher zonulin levels than treated individuals with counts above that threshold, while uninfected controls show the lowest levels.

After 42 days of supplementation, the median zonulin level rose from 177.9 micrograms per milliliter at baseline, with an interquartile range of 97.8 to 268.6, to 532.4 micrograms per milliliter, with an interquartile range of 289.7 to 1532.7. The Wilcoxon signed-rank test returned a p value of 0.002, and the median difference between paired measurements was 339.2 micrograms per milliliter. Notably, every one of the ten subjects showed an increase, a level of consistency that is unusual in a clinically heterogeneous group. The researchers visualized individual trajectories using spaghetti plots, which confirmed the uniform upward direction across all participants.

Metabolic parameters told a different story. There were no significant differences between baseline and post-intervention values for body mass index, hemoglobin A1c, fructosamine, triglycerides, total cholesterol, HDL cholesterol, or LDL cholesterol. Median BMI moved from 31.45 to 31.25 kilograms per square meter. Median hemoglobin A1c shifted from 7.5 percent to 7.35 percent. Fructosamine declined from 299.5 to 282.5 micromoles per liter. None of these changes reached statistical significance, with p values ranging from 0.09 to 0.88. The authors caution that the study was not powered to detect small or moderate effects in these outcomes, so the absence of significant change does not definitively rule out a metabolic benefit.

The supplement was well tolerated overall. Five subjects reported flatulence and three reported abdominal bloating, but no other adverse effects emerged, and there was no evidence of clinical harm. No participants dropped out, and none reported missing doses, though adherence was assessed only through weekly telephone queries rather than objective verification. CD4 lymphocyte counts remained stable, averaging 946 cells per microliter at baseline and 963 after the intervention period. One subject had a baseline virologic blip of 93 copies per milliliter that fell below 30 by the end of the study.

Why would inulin, which has shown metabolic promise in overweight and obese adults without HIV, produce the opposite pattern here? The authors speculate that pre-existing gut dysbiosis in people with well-controlled HIV and metabolic disorders may have altered the response. HIV infection causes severe damage to the gut-associated lymphoid tissue, the body’s most concentrated reservoir of CD4 cells, leading to enhanced intestinal permeability and systemic inflammation. Dysbiosis, meaning adverse shifts in gut microbial composition, is well documented in both HIV and metabolic disorders. A 2024 systematic review summarized multiple studies finding reduced microbial diversity, species differences, and increased microbial translocation in people with HIV, along with depletion of short-chain fatty acid-producing bacteria that normally exert anti-inflammatory effects. Altered gut microbiomes in this population have been associated with cardiovascular disease, metabolic disorders, psychiatric and neurologic conditions, frailty, liver disease, and cancer risk.

The authors also point to a separate trial from Stanford University in which healthy participants with normal median body mass index followed either a high-fiber or a fermented-food diet over ten weeks. The fiber arm failed to increase microbial diversity and did not raise short-chain fatty acid levels, and some subjects in that arm showed increases in immune activation. The fermented-food arm, by contrast, enhanced diversity and reduced numerous inflammatory markers. That result, combined with the current pilot, suggests that the biological response to fermentable fiber depends heavily on the starting state of the gut ecosystem rather than on the fiber itself.

Several limitations constrain how far these findings can be generalized. The sample was small, there was no control group, subjects were clinically heterogeneous, the intervention lasted only 42 days, and the study omitted gut microbiome assessment and direct measurements of intestinal permeability. Zonulin itself carries methodologic limitations as a surrogate marker, and other translocation markers such as intestinal fatty acid-binding protein, plasma flagellin, sCD14, and lipopolysaccharide-binding protein were not measured. Waist-to-hip ratios were not recorded, and dietary fiber intake outside the supplement was not analyzed. The authors recommend that future work include larger cohorts, serial microbiome sampling, metabolomics, direct permeability testing, and probiotic strategies such as fermented foods. For now, the message for clinicians is that short-term increases in fiber intake may not deliver short-term metabolic improvements in this population, and that routine supplementation should not be assumed beneficial without further evidence.

Subject of Research: A pilot study of inulin fiber supplementation in people with well-controlled HIV and metabolic disorders, measuring its effects on zonulin levels and metabolic parameters.

Article Title: Inulin supplementation in well-controlled HIV patients with acquired metabolic disorders is associated with increased zonulin levels- an indirect biomarker of gut permeability

Article References: Vikraman, P. K., Ahmed, S., Sohail, R., Akerman, M., Sison, C., Mani, V., & Hirsch, B. E. (2026). Inulin supplementation in well-controlled HIV patients with acquired metabolic disorders is associated with increased zonulin levels- an indirect biomarker of gut permeability. Frontiers in Molecular Medicine, 6, Article 1877763. https://doi.org/10.3389/fmmed.2026.1877763

Image Credits: AI Generated

DOI: 10.3389/fmmed.2026.1877763

Keywords: inulin, zonulin, gut permeability, HIV, metabolic disorders, prebiotic fiber, gut microbiome, dysbiosis, type 2 diabetes, pilot study, soluble fiber, systemic inflammation