In contrast to Andean natives, high-altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e., no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa, and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also was elevated in Sherpa compared with lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and in Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and toward a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude.

Gastrointestinal (GI) ischemia during exercise is associated with luminal permeability and increased systemic lipopolysaccharides (LPS). This study aimed to assess the impact of a multistrain pro/prebiotic/antioxidant intervention on endotoxin unit levels and GI permeability in recreational athletes. Thirty healthy participants (25 males, 5 females) were randomly assigned either a multistrain pro/prebiotic/antioxidant (LAB⁴_ANTI; 30 billion CFU·day⁻¹ containing 10 billion CFU·day⁻¹ Lactobacillus acidophilus CUL-60 (NCIMB 30157), 10 billion CFU·day⁻¹ Lactobacillus acidophillus CUL-21 (NCIMB 30156), 9.5 billion CFU·day⁻¹ Bifidobacterium bifidum CUL-20 (NCIMB 30172) and 0.5 billion CFU·day⁻¹ Bifidobacterium animalis subspecies lactis CUL-34 (NCIMB 30153)/55.8 mg·day⁻¹ fructooligosaccharides/ 400 mg·day⁻¹ α-lipoic acid, 600 mg·day⁻¹ N-acetyl-carnitine); matched pro/prebiotic (LAB⁴) or placebo (PL) for 12 weeks preceding a long-distance triathlon. Plasma endotoxin units (via Limulus amebocyte lysate chromogenic quantification) and GI permeability (via 5 h urinary lactulose (L): mannitol (M) recovery) were assessed at baseline, pre-race and six days post-race. Endotoxin unit levels were not significantly different between groups at baseline (LAB⁴_ANTI: 8.20 ± 1.60 pg·mL⁻¹; LAB⁴: 8.92 ± 1.20 pg·mL⁻¹; PL: 9.72 ± 2.42 pg·mL⁻¹). The use of a 12-week LAB⁴_ANTI intervention significantly reduced endotoxin units both pre-race (4.37 ± 0.51 pg·mL⁻¹) and six days post-race (5.18 ± 0.57 pg·mL⁻¹; p = 0.03, ηp² = 0.35), but only six days post-race with LAB⁴ (5.01 ± 0.28 pg·mL⁻¹; p = 0.01, ηp² = 0.43). In contrast, endotoxin units remained unchanged with PL. L:M significantly increased from 0.01 ± 0.01 at baseline to 0.06 ± 0.01 with PL only (p = 0.004, ηp² = 0.51). Mean race times (h:min:s) were not statistically different between groups despite faster times with both pro/prebiotoic groups (LAB⁴_ANTI: 13:17:07 ± 0:34:48; LAB⁴: 12:47:13 ± 0:25:06; PL: 14:12:51 ± 0:29:54; p > 0.05). Combined multistrain pro/prebiotic use may reduce endotoxin unit levels, with LAB⁴_ANTI potentially conferring an additive effect via combined GI modulation and antioxidant protection.