Attenuated Mycobacterium tuberculosis-specific Th1 cytokine responses in household contacts with undernutrition and their partial reconstitution during six months of nutritional support.

Abstract

Undernutrition is the leading population-attributable risk factor for tuberculosis (TB), yet whether associated immune impairments are reversible with nutritional rehabilitation remains unclear. In TB LION (Puducherry, India), 105 QuantiFERON-positive household contacts were stratified by BMI (<18.5 vs ≥18.5 kg/m2). Participants with low BMI (n=53) received 6 months of food rations plus daily multiple micronutrient supplement (MMS) without iron. Fourteen cytokines were measured by Luminex in supernatants from the unstimulated (Nil) and M. tuberculosis (Mtb)-antigen-stimulated (TB2) IGRA assay at baseline and 6 months; 11 with acceptable detection rates constituted the primary analytic set. Linear regression tested associations of weight and hemoglobin change with composite immune pathway scores. At baseline, participants with low BMI had attenuated Mtb-specific Th1 cytokine responses (interaction GMR 0.70 for IFN-γ, 0.55 for IL-2; both p=0.005), despite comparable or elevated innate and regulatory cytokines. After 6 months, Th1 responses increased (IFN-γ change GMR 1.41, 95% CI 1.10-1.80, p=0.005, q=0.06; IL-2 1.63, 1.01-2.63, p=0.046, q=0.25, suggestive). This increase reflected falling unstimulated background, not higher stimulated output. Weight gain was unrelated to composite scores but associated with elevated concentrations of 7 of 14 cytokines (all p<0.05). Hemoglobin gain was inversely associated with Th17 and pro-inflammatory scores but not Th1. Six months of combined food rations and daily MMS was followed by improved antigen-specific Th1 cytokine responses, suggesting this impairment may be partially reversible on a clinically feasible timescale. As a single-arm study without a concurrent comparator with undernutrition measured at follow-up, observed changes cannot be causally attributed to the intervention. Trial registration: NCT03598842.